HUT63848A - Process for producing pharmaceutical compositions comprising new 1-benzopyrqno/4,3-c/pyrazole derivatives and their active ingredients - Google Patents

Abstract

Compounds of formula (I), in which R1 represents hydrogen, cyano, C2-6 alkanoyl, C2-6 alkoxycarbonyl, CONH2, or R1 represents C1-6 alkyl or C2-6 alkenyl both of which may be substituted by cyano, halo, trifluoromethyl, hydroxy, benzoyl, C2-6 alkanoyloxy, C3-8 cycloalkoxycarbonyl, a 5-7 membered non-aromatic heterocyclic group containing 2 oxygen heteroatoms, CONR9R9', phenoxy or C1-6 alkoxy, in which C1-6 alkoxy may be further substituted by halo, hydroxy, C1-6 alkoxy or C2-6 alkanoyloxy; R2 represents hydrogen or chloro; R3 represents chloro or trifluoromethyl; or R2 and R3 are joined to form a fused benz ring; R4 represents hydrogen, C1-6 alkyl, C1-6 alkoxy or halo; R9 and R9', which may be the same or different represent hydrogen, C1-6 alkyl or benzyl, for use as immunomodulatory agents.

Description

The present invention relates to a novel [1] benzopyrano [4,3-c] pyrazole derivative of formula (I) wherein H is hydrogen, cyano, C2-C6 alkanoyl,

C2-C6 alkoxycarbonyl or carbamoyl; obsession

R | C 1-6 alkyl or C 2-6 alkenyl which is halogen, cyano, trifluoromethyl, hydroxy, benzoyl, C 2-6 alkanoyloxy or C 3-8 cycloalkoxycarbonyl; and a 5-7 membered non-aromatic heterocyclic group containing 2 oxygen atoms; a group of the formula R _g R _gt N-CO-, wherein R _g and R _g , which may be the same or different, are hydrogen, (C 1 -C 6) alkyl or benzyl; and phenoxy or (C 1 -C 6) alkoxy, where the alkoxy itself may be substituted with halo or (C 1 -C 6) alkoxy or (C 2 -C 6) alkanoyloxy, may be substituted;

R ₂ is hydrogen or chloro;

R ₃ is chlorine or trifluoromethyl; obsession

R ₂ and R 8 together represent a fused benzo ring; and

R ₄ is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl and C 1-6 alkoxy, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing these compounds as active ingredients.

• · · • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

It is necessary to clarify that when a group has a chain of at least three carbon atoms, it may be straight or branched, e.g., the hydrocarbon group having three carbon atoms includes both propyl and isopropyl groups, or the hydrocarbon group having four carbon atoms may be e.g. sec-butyl, isobutyl or tert-butyl. As used herein, the term halogen means fluorine, chlorine or bromine.

Preferably it is hydrogen, cyano, carbamoyl,

2- 4 alkanoyl, such as acetyl or C2-4 alkoxycarbonyl, e.g., methoxycarbonyl group, or a ^r ~ iq _CH2 group of the formula wherein _R10 is hydrogen, halogen, and cyano, trifluoro- methyl, hydroxy,

C 3-8 -cycloalkoxycarbonyl, especially cyclobutyloxycarbonyl, benzoyl, R 8 NH-CO- carbamoyl, e.g. Ν-methylcarbamoyl, N-ethylcarbamoyl or N-propylcarbamoyl; and a 5-, 6- or 7-membered non-aromatic heterocyclic group containing two oxygen atoms, such as 1,3-dioxolan-2-yl or 1,3-dioxan-2-yl; or R ₁₀ is optionally halogen, especially chlorine or bromine, hydroxy, cyano, trifluoromethyl, C 1-6 alkoxy, in particular methoxy or ethoxy, (C 1-6 alkoxy) - (1-6C) alkoxy; C 6 alkoxy), in particular 2-methoxyethoxy, (C 2 -C 6 alkanoyloxy) - (C 1 -C 6 alkoxy) -, preferably acetoxyethoxy, hydroxy (C 1 -C 6 alkoxy) -, preferably 2-hydroxyethoxy, C2-C6 alkanoyloxy, in particular acetoxy or propio.

nyl-o, -phenoxy or benzoyl; RgN-CO- such as carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl or N-propylcarbamoyl; and 5-, 6- or C 1-4 alkyl substituted with a 7-membered non-aromatic heterocyclic group containing two oxygen atoms, such as 1,3-dioxolan-2-yl or 1,3-dioxan-2-yl, such as methyl, ethyl, or propyl, but especially methyl or ethyl, or C 2 -C 4 alkenyl, such as vinyl.

Of particular interest are those compounds of formula I wherein R 1 is represented by the general formula wherein J is hydrogen, halogen, C 1-6 -alkoxy, cyano or carbamoyl, and p is Ο, 1. or 2; but in particular compounds of particular importance are hydrogen, methyl, cyanomethyl, carbamoylmethyl or (C1-C4) alkoxy-ethyl or 2-haloethyl.

As the substituent corresponding to the symbol R ₁ , we prefer the following groups in addition to hydrogen: methyl, ethyl, propyl, butyl, allyl, 2-methoxyethyl, 2-ethoxyethyl, 2-ethoxypropyl, , 2- (2-methoxyethoxy) ethyl, 2- (2-acetoxyethoxy) ethyl, 2- (2-hydroxyethoxy) ethyl, (cyclobutyloxycarbonyl) methyl- , carbamoyl, (N-methylcarbamoyl) methyl, 2-carbamoylethyl, 3-carbamoylpropyl, (N-ethylcarbamoyl) methyl, (N-propylcarbamoyl) methyl, , (N-isopropylcarbamoyl) methyl, (N-benzyl-N-methylcarbamoyl) methyl, carbamoylmethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-acetoxy- ethyl, cyano, cyanomethyl, 2-cyanoethyl, 2-phenoxyethyl, 2-chloroethyl, 2-bromoethyl, 2,2,2-trifluoroethyl,

2- (propionyloxy) ethyl, (1,3-dioxolan-2-yl) methyl, 2- (1,3-

-dioxan-2-yl) ethyl, 2- (1,3-dioxolan-2-yl) ethyl, acetyl, benzoylmethyl and ethoxycarbonyl; but it is particularly preferred to be methyl or 2-ethoxyethyl.

In the compounds of formula I of outstanding importance, R ₂ is hydrogen; R 4 is chloro or trifluoromethyl, with trifluoromethyl being more preferred; and R ₄ is hydrogen, fluoro, chloro or bromo, or C 1-4 alkyl or C 1-4 alkoxy, but especially hydrogen, and methyl, methoxy or ethoxy, and most preferred is hydrogen. and methoxy.

Preferably Rg is hydrogen or methyl, ethyl or benzyl, but especially hydrogen or methyl, while Rg is preferably hydrogen or benzyl.

The names of the major compounds of formula (I) are listed in the Examples in Table 4, and it should be noted that the names of the compounds also include their pharmaceutically acceptable salts.

Some of the compounds of formula I may contain one or more centers of asymmetry, so that these molecules are chiral and may exist in the form of various optically active isomers. If the molecule has a chiral center, such a compound of formula (I) may exist in two enantiomeric forms and it is understood that both pure enantiomers and mixtures thereof are encompassed within the scope of the present invention. Separation of enantiomers may be accomplished by methods known to those of ordinary skill in the art. Such processes include, for example, the formation of diastereomeric salt pairs or complexes which are easily separable, even by crystallization; furthermore, the formation of diastereomeric derivatives which can then be separated, for example, by crystallization, gas chromatography or liquid chromatography; selective diastereomeric derivative formation wherein one of the enantiomeric pairs reacts to form a derivative with a so-called enantiospecific reagent, such as, for example, enzymatic oxidation or reduction; and gas or liquid chromatography using chiral elements, wherein either the carrier is selected to be chiral, for example by attaching a chiral ligand to a silica gel, or by using a chiral solvent for chromatography.

Another possibility for the preparation of one of the enantiomers in the pure state is the asymmetric synthesis, which involves working with optically active reagents, substrates, catalysts or solvents or converting one enantiomer into another by so-called asymmetric transformation. A 2 * 4 • · * · »• ·« · ··

- (2-Ethoxypropyl) -4- [4- (chlorophenyl) [1] benzopyrano [4,3-c] pyrazol-3 (2H) -one, for example, both (R) - and ( It can be prepared in the S) -isomeric form.

When more than one asymmetric center is present in a molecule of a compound of formula (I), the compound may exist in the form of diastereomers, and it is again understood that the process of the invention involves the preparation of both individual diastereomers and mixtures of diastereomers. Methods of separating the diastereomers are generally known to those skilled in the art, including, for example, crystallization or liquid chromatography.

In addition, the compounds of the formula I may exist in the form of various tautomers or geometric isomers.

Certain compounds of formula (I) may exist in more than one crystalline form and all crystalline forms as well as mixtures thereof are encompassed by the present invention.

In addition, certain compounds of formula (I) may exist in solvated forms, for example as hydrates, and all solvated forms, including mixtures thereof, may be included in the invention.

The invention further relates to a process for the preparation of a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) as an active ingredient in a pharmaceutically acceptable carrier, diluent or

or other excipients. As used herein, the term "active ingredient" as used herein refers to any of the [1] benzopyrano [4,3-c] pyrazole of formula (I).

The active compounds may be administered orally, i.e., orally, rectally, i.e., rectally, parenterally, i.e. bypassing the digestive tract, and topically, with oral and topical administration being preferred. Accordingly, the pharmaceutical composition of the present invention may be any known oral, rectal, parenteral or topical dosage form. Pharmaceutically acceptable carriers, diluents and other excipients suitable for the preparation of such dosage forms are extensively addressed in the pharmaceutical literature. The pharmaceutical compositions of the present invention may have a different active ingredient content, generally ranging from 0.1 to 90% by weight. Generally, the compositions of the invention will be formulated in a unit dosage form. Substances used in the preparation of pharmaceutical compositions are all known, pharmaceutically-proven ingredients of the compositions described in the literature.

Formulations for oral administration which are considered to be the most suitable for the administration of the active compounds of the present invention may include those which are commonly used in medicine for this purpose, such as tablets, capsules, syrups, and aqueous or oily suspensions.

The tablet may be formulated by admixing the active ingredient with an inert diluent such as lactose or calcium phosphate, a disintegrating agent such as corn starch, and a lubricant such as magnesium stearate, and mixing it according to standard known methods. As is well known to those skilled in the art, tablets may be formulated so as to release the active ingredient of the present invention over a prolonged period of time to provide a sustained release and, if desired, enteric-coated, e.g. acetate phthalate for this purpose.

Likewise, the preparation of the capsule may be accomplished by the preparation of soft or hard gelatine capsules containing the active ingredient of the present invention, with or without various additives, and by coating the capsule with a conventional enteric coating. There is no difficulty in preparing a tablet or capsule containing the active ingredient in an amount of 0.1 to 500 mg. Other formulations for oral use include aqueous suspensions containing the active ingredient in an aqueous medium, and the ingredients include, in particular, a non-toxic suspending agent such as the sodium salt of carboxymethylcellulose, and the like. an oily suspension in which the active ingredient of the invention is suspended in a vegetable oil such as peanut oil.

Pharmaceutical formulations for topical administration according to the invention are also included in the dosage forms suitable for the preferred uses. These formulations contain the active ingredient in finely divided form and the carrier may be a pharmaceutically acceptable cream, ointment or gel. For example, a pharmaceutical cream can be prepared by incorporating the active ingredient into a cream base consisting of petroleum jelly and / or paraffin oil dispersed in an aqueous medium with a surfactant. The ointment may be prepared in a similar manner, but in this case the carrier will comprise, for example, a mineral oil, a petroleum jelly and / or a waxy substance such as paraffin or beeswax, and the active ingredient will be blended in this mass. In the preparation of the gel, the aqueous medium in which the active ingredient is distributed contains a gelling agent such as alkalinized Carbomer BP.

In addition, topical pharmaceutical compositions may contain the active compounds of the invention dispersed in an encapsulating material which can be transdermally delivered to the body by transdermal delivery. Such transdermal formulations are prepared by incorporating the active ingredient in a carrier suitable for topical application, such as those discussed above, but also admixing a transdermal absorption agent such as dimethylsulfoxide or propylene glycol.

Pharmaceutical forms for rectal administration are also well known in the pharmaceutical art, such as the suppository, which contains the active ingredient in a semi-synthetic glyceride or polyethylene glycol based mass.

Finally, the active compounds of the present invention may be employed in the form of parenteral formulations, for example, as a sterile, oily or aqueous suspension or in a sterile solution in a suitable solvent, all of which are known in the art.

In many cases, the compounds of the present invention may be used as active ingredients in pharmaceutical compositions in very small particle size form, in which case the so-called micronization can be carried out in a fluidization mill.

According to the invention, the pharmaceutical compositions may, if desired, also contain other biologically active ingredients compatible with the active ingredient.

The compounds of formula (I) have been shown to be immunomodulatory in their activity and generally act as immunosuppressants, but some active substances may also exhibit immunostimulatory activity in certain diseases or at certain stages of the disease. The compounds of the present invention are useful in the treatment of diseases that result from an abnormal immune response. Pharmaceutical compositions containing a therapeutically effective amount of a compound of Formula I are thus immune-related disorders such as tissue rejection reactions such as renal rejection; autoimmune diseases, such as rheumatoid arthritis or systemic lupus erythematosus, which is a collagen disease of the various organs that frequently involves skin manifestations, various skin conditions such as contact allergy, eczema or psoriasis; and in the treatment of neoplasia such as melanoma. For this purpose, one of the active compounds of the formula (I) should be administered to the patient in an amount sufficient to produce a suitable therapeutic effect, and may generally be in the range of from 1 to 2000 g per day, preferably from 1 to 500 mg.

Accordingly, an important aspect of the present invention is a method of treating immune-related disorders, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I).

The therapeutic effect of the compounds of formula (I) was demonstrated in laboratory animals cultivated for this purpose in accordance with standard procedures. In one such study, the drugs were administered orally and parenterally to BALB / c mice.

From the foregoing, it is apparent that the compounds of formula I are valuable immunomodulatory agents. The dosage of these active ingredients, i.e. the amount of active ingredient to be treated, depends on many factors, such as the age, severity and medical history of the patient, and it is always the careful judgment of the treating physician to determine it can be said that in mammalian species, including man, the appropriate oral dose is generally in the range of 0.01 to 40 mg / kg body weight per day, or even more likely in the range of 0.2 to 25 mg, even in a single in doses, even divided into several portions, the patient receives the active ingredient. For parenteral administration, the appropriate dosage will usually be in the range of 0.001 to 4.0 mg or, more often, 0.005 to 1 mg / kg body weight, in which case the patient may receive the active ingredient in single or divided doses, or continuously. infusion. Formulations for topical administration will generally contain from 0.01% to 20% by weight, more preferably from 0.05% to 5% by weight. Once again, the oral route is strongly preferred.

As discussed above, the present invention relates to a process for the preparation of compounds of formula (I). According to the invention, the compounds of formula I can be prepared by the following processes:

a) A compound of Formula II, including any tautomeric structures thereof, with a compound of Formula III: wherein R ₁₄ is (Q-O-) ₂ or (Q-S) ₂ , and Q-Ο- , Represents one of the groups represented by the formulas QS or Q ' ₂ N, wherein Q and Q' represent a C 1 -C 4 alkyl group or a benzyl group; or R ₄ = NH, R ₁₅ have the meanings qO- or groups of the formula Q-Sáltalános one; or R _{14 is} oxygen and R _{15 is} hydrogen, halogen or 1-imidazolyl.

b) A compound of formula (IV) wherein H is hydrogen, including the possible tautomeric structures, or R 4 is a group represented by the general formula R 8 - C - wherein R ₁₈ is hydrogen, C 1-4 alkyl, benzyl or a group corresponding to the symbol R (IIIa) and _R17 is R-CO- group, in a suitable solvent such as ethanol, with a base such as piperidine is reacted.

In one embodiment of the process, the compound of formula (I) can also be prepared by reacting a compound (IV) wherein and R g represents a, can be represented by the formula RLG-CO-, and _R17 is hydrogen, with a carboxylic acid chloride such as substituted benzoyl chloride in the presence of a base such as triethylamine and heating the resultant product in the presence of a base such as piperidine.

Compounds of formula (I) wherein alkyl or alkenyl is substituted as described above may be prepared by reacting the corresponding compound of formula (I) which is a compound of formula (I): · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · alkylated in the presence of hydride.

Compounds of formula I wherein R 1 is C 2 -C 6 alkanoyl may be prepared by acylation of the corresponding compound of formula I wherein R 4 is hydrogen, for example with an acyl halide.

Compounds of formula I wherein R 1 is a cyano group, it can be prepared by incorporating the cyano group into the molecule, for example, by reacting the corresponding compound of formula (I) wherein R _{x is} hydrogen in the presence of a base, such as sodium hydride, with cyanogen bromide. .

Compounds of formula (I) wherein R 1 is C 2 -C 6 alkoxycarbonyl may be prepared by substitution reaction wherein the corresponding compound of formula (I) wherein R _{1 is} hydrogen is substituted with 2-6 carbon atoms. alkoxy-CO-A-, wherein A is a leaving group such as cyano or halogen.

Compounds of formula (I) wherein R 1 represents a carbamoylalkyl, such as carbamoylmethyl, may be prepared from the corresponding formula (I).

by hydrolysis of a compound of the formula wherein R 1 is cyanoalkyl such as cyanomethyl.

Compounds of formula (I) in which R denotes a can be represented by the formula R ^ QNH-CO- wherein and wherein R _3Q equivalent of a readily hydrolyzable group such as chlorosulfonyl group, can be prepared by that (I) a compound of formula wherein R is halogen, is reacted with an R _3Q N = C = O with an isocyanate of formula. Subsequent hydrolysis, such as acid hydrolysis, of a compound of formula (I), wherein R 1 is a group of formula R 4 q NH-CO-, provides a compound of formula (I) wherein the carbamoyl group is meaning that these compounds can be prepared anyway.

Compounds of formula (I) wherein RgRg, N-CO-, which is essentially an acid amide, can be prepared by reacting a corresponding compound of formula (I) wherein A is a leaving group such as hydroxy, C 1-6 alkoxy, aryl-χΐχΐ, arylmethoxy or C 1-6 acyloxy. or a halogen atom, for example at a temperature of 0 to 250 ° C, optionally in an organic reaction medium, preferably in a solvent which dissolves the reaction. · 9 «« · ···

Reactants, and optionally in the presence of a catalyst, with a C 1 -C 6 alcohol or an amine of formula R 1 -R 8 .NH.

Compounds of formula (I) wherein R1 is a hydroxy-substituted group may be prepared by reacting a corresponding compound of formula (I) wherein a C2-C6 alkanoyloxy group, such as acetoxy, is present at the site. located, hydrolyzed; however, compounds of formula (I) wherein the moiety corresponding to the symbol is substituted by C 2-6 alkanoyloxy may be prepared by acylation of the corresponding hydroxy compound of formula (I).

Compounds of formula (II) may be prepared by reacting a compound of formula (V) with a hydrazine of formula R ₁ NH-NH ₂ .

Compounds of formula (III) wherein ^r 14 is ^a group represented by the formula (Q- ^O- ) 2 and R ₁₅ is a group represented by the formula Q-0- can be prepared in two ways. Alternatively, R ₅ a ~ ₃ CX compound of formula wherein X is halogen, Na-QO a sodium alcoholate of the formula: - wherein Q is C1-4 alkyl or benzyl - are reacted; and monitored by a procedure according to which an R ₅ ~ CN compound in an anhydrous acid such as hydrogen chloride in a reaction with an alcohol of formula Q-OH, by first preparing the corresponding R-C (= NH) -0-Q of formula or an acid addition salt thereof such as a hydrochloride, followed by reaction with an alcohol of the formula Q-OH.

Compounds of formula IV wherein ^R 16 ^R 18 is ^-CO- , wherein

R _g represents a group of formula -CO-, can be prepared from (IV) compound of the formula wherein R _{g to} R a -CO- radical, and R ₇ represents hydrogen, is acylated. The acylation may be carried out with an acid anhydride of the formula (R _g -CO) ₂₀ , in the presence of a salt such as a sodium salt of the corresponding acid, or with an acid halide such as an acid chloride of the formula R _g

Compounds of formula (IV), which is an R _Ig -CO- radical, and R _{7 is} hydrogen _to R wherein, also be prepared by acylation, however, in this case, a compound (II) to react with a (R _Ig -CO) ₂ O in the presence of a salt, such as a sodium salt, of the corresponding acid.

Compounds of formula (IV) wherein R ₁₇ is a group of formula R g-CO- and R is hydrogen, including tautomeric forms of the compounds, can be prepared by reacting a compound of formula (IV) R _LG wherein R a -CO- _fins at talános • · · ·, R ₁₇ stands for an R-CO- radical, a base such as piperidine in a suitable solvent such as ethanol.

Finally, compounds of formula (IV) wherein R ₁₆ and R _{16 are} a group represented by the formula R ₁₈ -CO-, wherein R 14 is as defined above and R ₁₇ is hydrogen, and reacting a compound of formula II wherein R 1 is hydrogen with an acid anhydride of formula R 4 -CO 2 O in the presence of a salt, such as a sodium salt, of the corresponding acid.

Compounds of formula V may be prepared by reacting a compound of formula VI wherein R _{23 is} hydrogen and malonic acid in the presence of an acid chloride such as phosphorus trichloride and a Lewis acid such as zinc chloride.

Compounds of formula V may also be prepared by reacting a compound of formula VI wherein R _{23 is} acetyl with a base such as sodium hydride and a dialkyl carbonate of formula (QO) ₂ CO Q is a C 1 -C 4 alkyl group or a benzyl group such as dimethyl carbonate.

Compounds of formula (V) wherein R ₄ is C 1-6 alkoxy may be prepared by reacting a compound of formula (VI) wherein R 4 is a halogen atom such as fluorine.

And R ₂ is an acetyl group, with a base such as sodium hydride and a dialkyl carbonate of formula (Q-O) wherein Q is C 1-4 alkyl or benzyl such as dimethyl carbonate.

Certain compounds of formulas II, III, IV, V and VI are known to be novel compounds not yet described. As these novel compounds are important elements of the practice of the invention, all new compounds should be considered within the scope of the invention.

The invention is illustrated in the following section, but these examples are not intended to be limiting in any way. In the experimental descriptions, the proportions and percentages are always given in parts by weight or in percent by weight, but the data on the composition of the solvent mixtures expresses the volume ratio. The products were characterized by elemental analysis and one or more spectroscopic material analysis methods, such as NMR spectra, infrared spectra or mass spectra.

Example 1

In 400 ml of toluene, 17.1 g of 60% sodium hydride dispersed in mineral oil is suspended, and the suspension is refluxed under a nitrogen atmosphere for 30 minutes, dropwise. · Ti · »· *

21 g of 2'-fluoro-6'-hydroxyacetophenone are added. After refluxing for a further 20 minutes, while continuing heating, diethyl carbonate (50.8 g) was added dropwise over 10 minutes, then refluxed with stirring for 20 hours. After cooling to room temperature, 150 ml of water were added dropwise, the two phases were separated, and the aqueous phase was washed with diethyl ether and then acidified with concentrated hydrochloric acid. The precipitate was filtered off, washed with water, dried and recrystallized from ethyl acetate. The resulting 5-ethoxy-4-hydroxycoumarin had a melting point of 110-111 ° C.

Example 2

A mixture of 10.0 g of 4-hydroxycoumarin, 14.25 g of ethylhydrazinium oxalate, 24.0 ml of triethylamine and 50 ml of anhydrous toluene was heated at reflux for 3 hours while the water formed during the reaction was charged will be removed from the system. The solid is then filtered off and partitioned between water and dichloromethane. The organic phase is dried and evaporated, and the resulting crude solid is recrystallized from butanol to give the desired 1-ethyl-3- (2-hydroxyphenyl) -2-pyrazoline. M.p. 147-150 ° C.

• · • «• 4 4 * * ·« «· 4 · · · · · · 4 · · · · · ·

Example 3

To a solution of 4-hydroxycoumarin (50.0 g) in anhydrous ethanol (1.2 L) was added 32.3 g of hydrazine dropwise with stirring over a period of 0.25 hours, and the reaction mixture was refluxed for 20 hours. The solution was cooled, acidified with 154 mL of concentrated anhydrous acetic acid and the ethanol evaporated in vacuo. The residual oil was poured into water (1.5 L), the precipitate was filtered off, washed with water and dried, and then recrystallized from isopropyl alcohol. That's how it got

3- (2-hydroxyphenyl) -2-pyrazolin-5-one m.p. 205-207 ° C.

4-6 Examples

In the same manner as in Example 3, the compounds of the formula II listed in Table 1, a compound of the formula V and a hydrazine of the formula R 1 -NH-NH _{2 were} prepared - R 1 and R 1 are represented in Table 1 by their reaction.

• · «« · 9 * • · · <♦ • «·· · · · · · · · · + J Φ N l> tn Φ td

H H ci o

rh r-1 tendon t-1 ι-1 ro CN 1 tn 1 σ> N 00 XD SHE t-1 e CN

Table <o Ό • rí Ό Ή

O X rd

Φ rd

Cl Ό

LD

O r- σι

CN

Ο σι σι

Ο> ιη vo

CO SHE * » · » r-1 CN CN <N

She CN *. CO stone LA K K CN co CN

m m m K K K out)> 1 m

M m

U K

K O U ro Ό ι — I XD

CU <

ro g xd

N tn • 3 * in vo

N Ή > tn 4J O XD ι-1 g 0 0 0 44 r-1 44 0 ro 4-> cl 44 + » X Φ Φ 44 N XD y ro cl td Φ -P • m tn ro ci g Φ > 1g 0 X) . • rn td X ι-1 ro xD xD ci XI ro 44 ro g ro • rn 44 N 4-> X tn M Φ tn tn • H 0 1-1 > > 1 ro ι-1 xD cl 44 tn 0 44 • r4 0 cl 0 • m 44 cl rh 0 0 1-1 f-1 cl »0 44 xD X! CU XD > -l Φ > 1 »0 X cn Λ Φ > 1 tn 1-1 tn XD Φ Φ ι — 1 44 '3 Φ > 1 • rn C tn X xD Φ Ή cl N cl ro • H xD > N t-1 tn • t ro 1-1 4-> 44 G φ 0 xD 44 tn X XD tn Φ g 0 XI cl g 0 Φ ι-1 + J 1 ------ 1 44 Φ • H < N 0

tn 1 44 • H 44 r ^- 1 ro 44 Φ cl Φ cl 44 44 cl X XD Φ Φ g Cl 44 XD N Φ 1 ro 44 tn 1-1 • H xD ci 44 • m Φ Φ ro > n H g G td Ό «0 44 td tn 0 ro xD m cl tendon ι-1 ro Ή xD g > n XI ro G ro N G M tn Φ 44 X tn • H g Φ > > 1 tn r-H ro Td • ro G td 44 td • H 0 • m cl • m ro 0 ι – 1 ι-1 0 g 44 cl • H xD 44 td CU 0 1 Φ • rn G XD XI Td | —1 r — 1 • H 44 tn xd 0 G Φ 44 ro g 0 • m X rH t-L 44 0 * 0 M XI X) cl 0 xD 44 tn N r-1 Φ ι — 1 tn ro 1 Φ 44 1-1 • r4 tn 0 CU Φ tn 0 N tn cl • H She CU > g you ro r | Φ • rl 44 N »0 φ N lm 44 Ή XD XD y > tn • r4 cl 44 > 1 Φ SHE G 44 g 0 G Φ 44 g

dilute the solution, then filter. The filtrate was evaporated in vacuo to give gum · ··· · · 9

24 3) The starting material is a mixture of 4-hydroxy-5-methyl coumarin and 4-hydroxy-7-methyl coumarin. The product was extracted from the aqueous mixture with dichloromethane and the extract was filtered to remove insoluble material. The combined organic solvent extracts were then washed with water, dried and concentrated to a small volume. Upon cooling, a solid precipitates from the solution, which is isolated by filtration.

The compounds of formula (II) prepared as described herein are:

Example 4: 3- (2-Hydroxy-phenyl) -1-methyl-2-pyrazolin-5-one;

Example 5: 3- (2-Hydroxy-6-methoxyphenyl) -1-methyl-2-pyrazoline

-5-one; and

Example 6: 3- (2-Hydroxy-6-methyl-phenyl) -1-methyl-2-pyrazoline

-5-one.

Example 7 A solution of 4-trifluoromethylbenzonitrile (g) in anhydrous diethyl ether (120 ml) and anhydrous methanol (6 ml) was cooled to 0-5 ° C and saturated with hydrochloric acid gas at this temperature. The reaction mixture was allowed to stand in a melting ice bath overnight, and the next day, the precipitated imidate salt was filtered off, washed with diethyl ether and dried in a desiccator. This dried solid is added to 78.3 ml of analytical reagent grade methanol for 5 days at room temperature. Ke4 ··································• · ♦ ··· '·

Stir the mixture, then filter and concentrate the filtrate in vacuo. The oil thus obtained is trimethyl ortho (4-trifluoromethyl) benzoate, which is used without further purification in the next step.

Example 8

a) A mixture of 4.0 g of 4-hydroxy-5-methoxy-coumarin, 3.0 ml of hydrazine hydrate and 84 ml of industrial methanol-denatured ethanol is refluxed for 4.75 hours. After cooling, 13.3 ml of anhydrous concentrated acetic acid were added to the reaction mixture, the alcohol was evaporated in vacuo and the residue was poured into water. Adding a small amount of dichloromethane to the gum precipitated from the mixture gives a crystalline product which is filtered. 3- (2-Hydroxy-6-methoxyphenyl) -2-pyrazolin-5-one, m.p. 208-210 ° C.

b) 2.06 g of 3- (2-hydroxy-6-methoxyphenyl) -2-pyrazolin-5-one, 5.04 g of 1- [4- (trifluoromethyl) benzoyl] imidazole and ml. anhydrous xylene was refluxed under nitrogen for 0.5 hour and then cooled to room temperature. The precipitated solid was collected on a filter and dissolved in a 1: 2 mixture of industrial methanol denatured with methanol and dichloromethane under reflux. A portion of the dichloromethane is then evaporated until a solid begins to precipitate out of the solution.

The mixture was cooled to room temperature and filtered. The crystalline product thus obtained is 9-methoxy-4- (4- (trifluoromethyl) phenyl) -1- (1-benzopyrano) -4,3-cis-pyrazol-3 (2H) -one which is above 280 ° C. melts during decomposition.

c) 9-methoxy-4- / 4- (trifluoromethyl) 0.94g -fenil_7 ^- / _ J ~ 1 -benzo-pyrano / 4,3-c_ _ / pyrazol-3 (2H) -one in 55 ml of anhydrous To a suspension of N, N-dimethylformamide was added 0.114 g of 60% sodium hydride dispersed in mineral oil.

After stirring for 10 minutes at room temperature, 90% (2-bromoethyl) ethyl ether (0.36 mL) was added dropwise and stirring was continued at room temperature for 16 hours. The mixture was then shaken with a little petroleum ether boiling at 62-68 ° C, acidified with 2M hydrochloric acid and filtered. The resulting 2- (2-ethoxyethyl) -9-methoxy-4- [4- (trifluoromethyl) phenyl] -1-benzopyrano [4,3-c] pyrazole-3 (2H) - m.p. 164-168 ° C.

Example 9

a) 5.0 g, prepared as described in Example 1

A mixture of 5-ethoxy-4-hydroxycoumarin, 2.2 g of methylhydrazine and 60 ml of industrial methanol-denatured ethanol is refluxed for 20 hours. After cooling, the solvent was evaporated in vacuo and the crude product (27) was treated with methanol (50 mL) and concentrated hydrochloric acid (20 mL). The mixture was refluxed for 2 hours, concentrated in vacuo and the residue was triturated with water. The resulting solid was filtered and dried to give the expected 3- (2-hydroxy-6-ethoxyphenyl) -1-methyl-2-pyrazolin-5-one.

b) 3.2 g of the solid obtained as described in a) above are heated together with 9.0 g of trimethyl ortho (4-chlorobenzoate) to 130-140 ° C and kept at this temperature for 45 minutes. The reaction mixture was cooled to room temperature, stirred with 50 ml of hexane, decanted and 80 ml of diethyl ether was added to the residual oil. The resulting solid precipitate was filtered off, washed with diethyl ether, dried and recrystallized from isopropyl alcohol. The resultant 9-ethoxy-4- (4-chlorophenyl) -2-methyl- (1-benzopyrano-4,3-cis-pyrazol-3 (2H) -one has a melting point of 197-199 ° C.

Example 10

(a) A solution of 3.6 g of 4-hydroxycoumarin, 5.0 g of a 70% aqueous solution of 2,2,2-trifluoroethylhydrazine and 27 ml of toluene is added and the mixture is refluxed for 4 hours. while removing water from the system. After cooling, the solid is collected on a filter, extracted with hot dichloromethane, the extract is filtered and the filtrate is evaporated. The solid product is recrystallized from toluene and dichloromethane to give 3- (2-hydroxyphenyl) -1- (2,2,2-trifluoroethyl) -2-pyrazolin-5-one, m.p. Mp: 163-165 ° C.

b) 1.2 g of the solid obtained above under a) are heated together with 3.0 g of trimethyl ortho (4-chlorobenzoate) to 125 ° C and maintained at this temperature for 10 minutes, then cooled and diethyl ether (10 mL) was added. The precipitated solid crude product was recrystallized from a mixture of Ν, il-dimethylformamide and methanol to give the desired 4- (4-chlorophenyl) -2- (2,2,2-trifluoroethyl) -1H-benzopyrano / 4 3-cis / pyrazol-3 (2H) -one, m.p. 214-215 ° C with decomposition.

Example 11

a) 3.8 g, prepared as described in Example 4

A mixture of 3- (2-hydroxyphenyl) -1-methyl-2-pyrazolin-5-one, 1.64 g of anhydrous sodium acetate and 30 ml of acetic anhydride was stirred at room temperature for 1.5 hours. The reaction mixture was poured into 10 volumes of water and extracted with ethyl acetate. The combined organic solvent extracts were washed with water, dried and evaporated, and the remaining semi-crystalline material was triturated with petroleum ether (b.p. 60-80 ° C), the crystals were filtered and dried. The product thus obtained is the expected [3- (2-hydroxyphenyl) -1-methylpyrazol-5-yl] acetate, m.p. 113-116 ° C.

b) Dissolve 4.5 g of [3- (2-hydroxyphenyl) -1-methylpyrazol-5-yl] acetate and 3 ml of triethylamine in 100 ml of tetrahydrofuran and then at 0-5 ° C under stirring, a solution of 4.4 g of 3,4-dichlorobenzoyl chloride in 80 ml of tetrahydrofuran was added over 10 minutes. After stirring at room temperature for 18 hours, a solution of 4.4 g of 3,4-dichlorobenzoyl chloride and 3 ml of triethylamine in 80 ml of tetrahydrofuran was added. Stirring was continued for a further 24 hours, then the reaction mixture was poured into 1 L of water and extracted with ethyl acetate. The combined organic solvent extracts were dried and evaporated to a concentration where a precipitate was observed. The 3,4-dichlorobenzoic acid is filtered off, the filtrate is concentrated in vacuo and the residue is recrystallized from ethyl acetate. The product thus obtained is the expected N-2- (5-acetoxy-1-methylpyrazol-3-yl) phenyl N - (3,4-dichlorobenzoate), m.p. 123 ° C.

c) Weight 1.0 g of 2- (5-acetoxy-1-methylpyrazol-3-yl) phenyl (3,4-dichlorobenzoate), 0.27 ml of piperidine and 10 ml of ethanol, then refluxed for 2 hours, then cooled to 0 ° C. The product is filtered off and recrystallized from ethanol. 4- (3,4-dichlorophenyl) -2-methyl-7'-benzopyrano-4,3-cis-pyrazol-3 (2H) -one, m.p. 193-194 ° C.

Example 12

To a solution of 2.32 g of [3- (2-hydroxyphenyl) -1-methylpyrazol-5-yl] -7-acetate obtained in Example 11 (a) in 50 ml of anhydrous tetrahydrofuran, A solution of trimethylamine (1.5 mL) and dry tetrahydrofuran (10 mL) was treated successively with 2.1 g of 2-naphthoyl chloride. After stirring for 20 hours, another 0.75 ml of triethylamine and 1.05 g of 2-naphthoyl chloride are added. Stirring was continued for a further 20 hours, finally poured into 10 volumes of water and extracted with ethyl acetate. The combined organic solvent extracts were washed first with saturated sodium carbonate solution, then with water, then dried and concentrated in vacuo. The residue was triturated with diethyl ether to give a solid which was filtered.

(b) To the crude product (2.43 g) obtained in (a) above is added 0.63 ml of piperidine and 19 ml of anhydrous ethanol, and the mixture is refluxed for 30 minutes. After cooling, the mixture was filtered to give [2- (4,5-dihydro-1-methyl-5-oxopyrazol-3-yl) phenyl] - (2-naphthoate), m.p. 210 ° C.

c) The filtrate was refluxed for an additional 1 hour, then concentrated and cooled. The resulting solid was filtered off to give the expected 2-methyl-4- (2-naphthyl) -1,7-benzopyrano [4,3-c] pyrazol-3 (2H) -one, m.p. 159-161 ° C.

Example 13

A mixture of 2.32 g of 3- (2-hydroxyphenyl) -2-pyrazolin-5-one and 10.2 g of triethyl ortho (4-chlorobenzoate) is heated to 130-135 ° C for 1 hour. kept at the temperature. After cooling, the mixture was diluted with diethyl ether, and the resulting precipitate was filtered, washed and dried, and then recrystallized from industrial methanol-denatured ethanol using charcoal clarification. 4- (4-chlorophenyl) -1H-benzopyran-4,3-cis-pyrazol-3 (2H) -one so obtained: m.p. 255-257 ° C.

14-18. examples

As described in Example 13, a compound of formula (II) is reacted with a compound of formula (III) to produce the compounds of formula (I) listed in Table 2. The symbols R 1 and Q in the formula R 1 and R 1 in formula (II) and the compound of formula (III) in the formula R 1 -C 10 CO 2) are given in Table 2 and R 2 is hydrogen. .

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Example 19

16 g of 3- (2-hydroxyphenyl) -2-pyrazolin-5-one are weighed.

1- (4-Chlorobenzoyl) imidazole (37.5 g) and xylene (200 ml). The mixture was refluxed for 3 hours with stirring, then allowed to cool to 70 ° C and filtered. The resulting 4- (4-chlorophenyl) -1-benzopyrano- [4,3-c] pyrazol-3 (2H) -one has a melting point of 255-257 ° C.

Example 20

A mixture of 5.5 g of trimethyl ortho (4- (trifluoromethyl) benzoate) prepared in Example 7 and 1.94 g of 3- (2-hydroxyphenyl) -2-pyrazolin-5-one is obtained. After reacting at -140 ° C for 4 hours, the reaction mixture was cooled to 0 ° C, and the resulting solid was filtered off and washed with diethyl ether. The filtered solid was then triturated with hot water and filtered again. The resulting 4- (4- (trifluoromethyl) phenyl) -N-1-benzopyrano-4,3-cis-pyrazol-3 (2H) -one has a melting point of 271-273 ° C.

Example 21

A mixture of 3- (2-hydroxyphenyl) -2-pyrazolin-5-one (30.2 g), 1- (4- (trifluoromethyl) benzoyl) imidazole (86.5 g) and xylene (800 ml) was stirred under nitrogen under reflux for 4 hours. The reaction mixture was allowed to cool to 40 ° C and filtered. That's how it got

4- [4- (trifluoromethyl) phenyl] -1H-benzopyran-4,3-cis / pyrazol-3 (2H) -one, m.p. 270-272 ° C.

Example 22

a) 3.52 g of 3- (2-hydroxyphenyl) -2-pyrazolin-5-one, 1.64 g of sodium acetate and 30 ml of acetic anhydride are added, the mixture is stirred for 3 hours at room temperature and then poured into water and 62 ml. Petroleum ether (10: 1), boiling at -68 ° C, and the solid is filtered off. The crude product thus obtained is 1-acetyl-3- (2-hydroxy-phenyl) -pyrazol-5-yl] -acetate, m.p. 62-64 ° C.

b) to a mixture of 1.53 g of the crude [1-acetyl-3- (2-hydroxyphenyl) -pyrazol-5-yl] -acetate above, 2.1 ml of triethylamine and 25 ml of anhydrous tetrahydrofuran under stirring, At 0-5 ° C, 3.21 g of 4- (trifluoromethyl) benzoyl chloride are added dropwise. After stirring at room temperature for 64 hours, the reaction mixture was poured into water and the product was extracted with ethyl acetate. The combined organic solvent extracts were washed with water, then with saturated sodium bicarbonate solution, and then again with water, dried and concentrated in vacuo. The residue was digested with hot isopropyl alcohol, filtered and the filtrate was evaporated. The oil thus obtained is crude 2- (1-acetyl-5-acetoxypyrazol-3-yl) phenyl (4- (trifluoromethyl) benzoate).

• · ·

c) To the oil of (b) above, 0.7 ml of piperidine and 22 ml of anhydrous ethanol are added and the mixture is refluxed for 1 hour, then cooled to 0-5 ° C and filtered. The crude product thus obtained was purified by preparative layer chromatography on silica gel using methylene chloride / methanol 9: 1 as mobile phase. The purified product is 4- (4- (trifluoromethyl) phenyl) -N-benzopyrano-4,3-cis-pyrazol-3 (2H) -one, m.p. 268-272 ° C. C.

Example 23

2.9 g of 3- (2-hydroxyphenyl) -2-pyrazolin-5-one, 3.2 g of potassium carbonate and 30 ml of anhydrous xylene are weighed. The mixture is heated under reflux with stirring, while 6.9 g of 4-trifluoromethylbenzoyl chloride are added dropwise over a period of 15 minutes. The reaction mixture was refluxed for a further 2 hours and then filtered hot. The filtered solid was washed with toluene, water, and finally diethyl ether. The resulting 4 - / ^ 4- (trifluoromethyl) phenyl _ / - / _ L_ / benzopyrano / ^- 4,3-c_ / pyrazol-3 (2H) -one mp: 259-263 ° C.

Example 24

3- (2-Hydroxy-phenyl) -1-methyl-2-pyrazolin-5-one (1.90 g) prepared in Example 4 is dissolved in 100 ml of warm toluene and cooled to room temperature. A solution of 1.4 g of 4-chlorobenzaldehyde, 1 ml of piperidine and 50 ml of a solution is added over a period of 5.25 hours. of anhydrous toluene, which is heated under reflux with stirring, continuously removing the water formed from the system. The reaction mixture was then concentrated in vacuo and the residue was triturated with diethyl ether and then recrystallized from isopropyl alcohol. The resulting 4- (4-chlorophenyl) -2-methyl-1H-benzopyrano / 4,3-cis / pyrazol-3 (2H) -one has a melting point of 204-205 ° C.

Example 25

A mixture of 16.7 g of [2- (2-chloroethoxy) ethyl] -acetate, 103 g of sodium bromide, 200 ml of Ν, Ν-dimethylformamide and 100 ml of methylene dibromide is stirred at 100 ° C. hours, then poured into a mixture of 300 ml of diethyl ether and 200 ml of water. The organic phase was separated, washed with water and evaporated to give an oil which was distilled under vacuum. N- (2- (2-Bromoethoxy) ethyl) N-acetate is a hot distillate at 100-103 ° C (9 mm Hg).

Example 26

3.70 g of 4- (4-chlorophenyl) -1H-benzopyrano [4,3-c] pyrazol-3 (2H) -one prepared in Example 13 in 145 ml of anhydrous Ν, Ν-dimethyl -formamide solution under nitrogen with stirring 0.60 g * · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Sodium hydride dispersed in mineral oil is added.

then 1.38 ml (2-bromoethyl) acetate was added dropwise and stirring was continued at room temperature for an additional 16 hours. The mixture was poured into a mixture of water and petroleum ether (boiling point 60-80 ° C, 10: 1), followed by hydro-4- (4-chlorophenyl) -3-oxo-1H-benzopyrano-4,3-c-7 m.p. 126-129 ° C, ~ pyrazol-2-yl-ethyl-1-acetate.

27-41. Examples are the compounds of formula I listed in Table 3. In each case, the starting compound was 4- (4-chlorophenyl) -1,6-benzopyrano / 4,3-cis / pyrazol-3 (2H) -one (A) obtained in Example 13, by one

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Notes to Table 3:

1) Water (2 L) was added to the reaction mixture, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The combined extracts were washed with water, dried and concentrated to a point where crystallization started. The product precipitated for cooling was filtered.

2) The resulting solid is dissolved in a mixture of dichloromethane and ethanol and concentrated until crystallization begins. The product was isolated by filtration.

3) The reaction mixture was extracted with ethyl acetate and the combined extracts were washed with water, dried and finally concentrated to give crystallization. The product was isolated by filtration.

4) Pour the reaction mixture into 10 volumes of water and acidify with 2M hydrochloric acid. The resulting precipitate was filtered off, dried and dissolved in a 1: 2 mixture of industrial methanol denatured with methanol and dichloromethane. The dichloromethane is evaporated and the remaining solution is placed in an ice bath and the precipitated solid is collected by filtration.

5) The reaction mixture was poured into 500 ml of water and extracted with ethyl acetate. The combined extracts were washed with water, dried and evaporated, and the solid residue was recrystallized from isopropyl alcohol.

· <· • · * «« «

6) The reaction mixture was poured into water, and the resulting precipitate was filtered off and dried, then triturated with acetone and filtered again. The residue was digested with hot methanol-denatured industrial ethanol, filtered again, and the residue was dissolved in dichloromethane. The solution was anhydrified, filtered and the filtrate was evaporated and the residue was triturated with gasoline and filtered again.

7) The reaction mixture was quenched by pouring into 300 ml of water containing 5 ml of 2M hydrochloric acid and extracted with dichloromethane. The combined extracts were dried, evaporated and the residue was dried between diethyl ether and water, evaporated and the residue was partitioned between diethyl ether and water. The two layers were separated, the aqueous portion was extracted with diethyl ether, and the combined ethereal extracts were concentrated to 10 mL. The resulting precipitate was collected on a filter, washed with petroleum ether boiling at 40-60 ° C and dried. The crude product thus obtained was recrystallized from ethanol and then purified by flash chromatography on silica gel eluting with dichloromethane / methanol (98: 2). The column was recrystallized from ethanol to give the desired product.

8) The reaction mixture was partitioned between 600 mL of 5 M hydrochloric acid and 300 mL of diethyl ether. The aqueous layer was separated and extracted once more with diethyl ether and the combined organic solvent extracts were washed well with water, dried and evaporated. The residue was purified by flash chromatography on silica gel with methylene chloride and methanol.

Eluting with a 97: 3 mixture. The solid dissolved in the column was recrystallized twice from diethyl ether / ethyl acetate twice to give the desired product.

10) The reaction mixture was poured into water and then acidified with 2M hydrochloric acid. The resulting precipitate was collected on a filter and recrystallized from N, N-dimethylformamide.

11) The reaction mixture was poured into water and the precipitate collected was collected on a filter and recrystallized from isopropyl alcohol.

12) 60% sodium hydride dispersed in mineral oil.

13) The reaction mixture was poured into 500 ml of water and extracted with diethyl ether. The combined ethereal extracts were washed with water, dried and evaporated, and the residue was recrystallized from ethanol.

14) The reaction mixture was poured into 2 L of water, acidified with 5 M hydrochloric acid and extracted with ethyl acetate. The combined extracts were washed with water, dried and evaporated, and the resulting oil was crystallized from diethyl ether.

Example 42

Similarly as in Example 26, 0.74 g of sodium hydride dispersed in mineral oil, 180 ml of anhydrous N, N-dimethylformamide, 5 g of 4- (4-chloro) prepared in Example 13 are weighed. phenyl) - (1) benzopyrano43 [4,3-c] pyrazol-3 (2Η) -one and 1.97 ml of 2- (bromomethyl) -1,3-dioxolane, and the mixture is stirred at room temperature for 16 hours. An additional 0.74 g of sodium hydride and 1.97 ml of 2- (bromomethyl) -1,3-dioxolane are added and the reaction mixture is stirred for another 24 hours at room temperature and then for 1 hour at 70-80 ° C. The mixture was cooled to room temperature, poured into water, the precipitate was collected by filtration, dried and recrystallized from ethanol / dichloromethane to give 2 - [(1,3-dioxolan-2-yl) methyl] - 4- (4-chlorophenyl) - [1-benzopyrano [4,3-c] pyrazol-3 (2H) -one, m.p. 230-231 ° C.

Example 43

Similarly to Example 26, 0.44 g of sodium hydride dispersed in mineral oil, 100 ml of anhydrous N, N-dimethylformamide, 3.0 g of 4- (4- chlorophenyl) - [l] benzopyrano [4,3-c] pyrazol-3 (2H) -one and 2.9 g of l-bromo-2-ethoxypropane, and the mixture was stirred at room temperature for 16 hours, After stirring for 5 hours at about 60 ° C, the mixture is cooled to room temperature, poured into water and extracted with diethyl ether. The combined ethereal extracts were dried and evaporated and the residue was purified by flash chromatography on silica gel eluting with 1: 3 ethyl acetate / petroleum ether (80-100 ° C). Chromatographic purification gave a red solid which was recrystallized from ethanol. 2- (2-Ethoxypropyl) -4- (4-chlorophenyl) - [1] benzopyrano [4,3-c] pyrazol-3 (2H) -one, m.p. 118-119 ° C. C.

Example 44

Similarly to Example 26, 1.82 g of sodium hydride dispersed in mineral oil, 450 ml of anhydrous N, N-dimethylformamide, 15.0 g of 4- [4- (4- (trifluoromethyl) phenyl] - [1] benzopyrano [4,3-c] pyrazol-3 (2H) -one and 7.62 g of (2-bromoethyl) acetate, followed by stirring at room temperature After 48 hours, the reaction mixture was poured into water. The precipitate formed is filtered off, dissolved in ethyl acetate and the solution is washed with water, the solvent is evaporated off under vacuum and the residue is recrystallized from isopropyl alcohol. There was thus obtained [2- (2,3-dihydro-3-oxo-4- [4- (trifluoromethyl) phenyl] - [1] benzopyrano [4,3-c] pyrazol-2-yl} m.p. 134-136 ° C.

45, Example

Similarly to Example 26, 0.74 g of sodium hydride dispersed in mineral oil, 150 ml of N, N-dimethylformamide, 5.0 g of 4- (4-chlorophenyl) - [l] benzo are weighed. Pyrano [4,3-c] pyrazol-3 (2H) -one and 2.52 ml of 2- (2-bromoethyl) -1,3-dioxane were added and the mixture was stirred at room temperature for 42 hours and then poured into water. . The product is extracted with diethyl ether, the extract is washed with water, then the diethyl ether is evaporated and the residue is recrystallized from ethanol. The resulting 2- [2- (1,3-dioxan-2-yl) ethyl] -4- (4-chlorophenyl) - [1] benzopyrano [4,3-c] pyrazole-3 ( 157-163 ° C.

Example 46

17.93 g of [2- {2,3-dihydro-3-oxo-4- [4- (trifluoromethyl) phenyl] - [1] benzopyrano [4.3] prepared as in Example 44. A mixture of -c] pyrazol-2-yl} ethyl] acetate, 22 ml of 2M hydrochloric acid and 750 ml of industrial methanol denatured ethanol is heated under reflux for 18 hours, then cooled to 0 ° C and collect the precipitate on a filter. 2- (2-Hydroxyethyl) -4- [4- (trifluoromethyl) phenyl] - [1] benzopyrano [4,3-c] pyrazol-3 (2H) -one so obtained: 199-201 ° C.

Example 47

1.53 g of {2- [2,3-dihydro-3-oxo-4- (4-chlorophenyl) - [1] benzopyrano [4,3-c] pyrazole, prepared as in Example 26. -2-yl] ethyl} acetate is suspended in 80 ml of industrial methanol denatured with ethanol and 2 ml of dilute hydrochloric acid are added. The reaction mixture is refluxed for 6.5 hours, then allowed to cool to room temperature and set aside for 16 hours. The resulting crystalline-

filter and wash with industrial methanol-denatured ethanol. The resulting 2- (2-hydroxyethyl) -4- (4-chlorophenyl) - [1] benzopyrano [4,3-c] pyrazol-3 (2H) -one has a melting point of 179-183 °. C.

Example 48

1.5 g of {3- [2,3-dihydro-4- (4-chlorophenyl) -3-oxo [1] benzopyrano [4,3-c] pyrazole, prepared as in Example 41. A mixture of -2-yl] -propyl} -acetate, 1.9 ml of 2M hydrochloric acid and 75 ml of industrial methanol-denatured ethanol is refluxed for 5 hours, cooled to room temperature and the precipitate is filtered off. The resulting 2- (3-hydroxypropyl) -4- (4-chlorophenyl) [1] benzopyrano [4,3-c] pyrazol-3 (2H) -one has a melting point of 166-168 '. C.

Example 49

11 g of [2- {2- [2,3-dihydro-4- (4-chlorophenyl) -3-oxo [1] benzopyrano [4,3-c] obtained in Example 39 are weighed out. ] pyrazol-2-yl] -ethoxy} -ethyl] -acetate, 100 ml of 5 M hydrochloric acid and 100 ml of water are added, and the mixture is refluxed for 24 hours, then concentrated and the solid residue is recrystallized from 100 ml of isopropyl alcohol. . The resulting 2- [2- (2-hydroxyethoxy) ethyl] -4- (4-chlorophenyl) - [1] benzopyrano [4,3-c] pyrazol-3 (2H) -one mp 110-112 ° C.

Example 50

0.68 g of 2,3-dihydro-4- (4-chlorophenyl) -3-oxo [1 H -benzopyrano [4,3-c] pyrazole-2-acetonitrile, prepared as in Example 28, is weighed and 6 ml of concentrated sulfuric acid. The mixture is heated to 120 [deg.] C., maintained at this temperature for 0.5 hour, then poured into ten volumes of water, the precipitate is filtered off, washed and dried. The resulting 2,3-dihydro-4- (4-chlorophenyl) -3-oxo [1] benzopyrano [4,3-c] pyrazole-2-acetamide has a melting point of 279-283 ° C.

Example 51

Similarly to Example 50, 1.0 g of 2,3-dihydro-4- (4-chlorophenyl) -3-oxo [1] benzopyrano [4,3- A mixture of c] pyrazole-2-propiononitrile and 10 ml of concentrated sulfuric acid was heated to 120-125 ° C for 15 minutes. The product thus obtained and recrystallized from industrial methanol denatured with ethanol

2,3-dihydro-4- (4-chlorophenyl) -3-oxo [1] benzopyrano [4,3-c] pyrazole-3-propionic acid, m.p. 264-266 ° C.

Example 52

a) 2.16 g, prepared as in Example 31

2,3-Dihydro-4- (4-chlorophenyl) -3-oxo [1] benzopyrano [4,3-c] pyrazole-2-acetic acid suspension in 50 ml methylene chloride 48 To a suspension of 0.24 ml of anhydrous N, N-dimethylformamide with stirring, then 1, Sulfinyl chloride (51 mL) was added. After stirring at room temperature for 16 hours, the reaction mixture was concentrated in vacuo, the residue was triturated with anhydrous diethyl ether and the solid filtered to give the expected [2,3-dihydro-4- (4-chlorophenyl) -3-oxo [1J-benzopyrano [4,3-c] pyrazol-2-yl] -acetyl chloride is obtained.

b) Dissolve 1.08 g of the above acid chloride in 100 ml of anhydrous tetrahydrofuran and add 0.43 ml of a 70% by weight aqueous solution of ethylamine. The reaction mixture was stirred at 0-5 ° C for 1.5 hours and then filtered. The filtrate was diluted with 100 ml of diethyl ether, cooled in an ice bath for 3 hours, and the precipitated solid was filtered off. Leaving the filtrate to stand for several days, additional solid precipitates from the solution, which is filtered to give a second generation product. The two materials were combined and washed with water and petroleum ether boiling at 60-80 ° C. N-ethyl-2,3-dihydro-4- (4-chlorophenyl) -3-oxo [1 H -benzopyrano [4,3-c] pyrazole-2-acetamide, m.p. 238-239 ° C. .

Example 53

1.87 g of 2,3-dihydro-4- (4-chlorophenyl) -3-oxo [1] benzopyrano [4,3-c] pyrazole-2-acetic acid are obtained as in Example 52 (a). According to the method described above, it is converted into the acid chloride having a weight of 1.89 g. The acid chloride is suspended at 0-5 'C in 172 ml of anhydrous tetrahydro49 furan and 0.69 ml of 25 g / 100 ml of an aqueous solution of methylamine is added dropwise. The reaction mixture was stirred in a melting ice bath for 2.5 hours, then the solid was filtered off and washed with water and diethyl ether. The resulting 2,3-dihydro-4- (4-chlorophenyl) -N-methyl-3-oxo-1-benzopyrano [4,3-c] pyrazole-2-acetamide has a melting point of 244-250 °. C.

Example 54

1.7 g of [2,3-dihydro-4- (4-chlorophenyl) -3-oxo [l] benzopyrano [4,3-c] obtained in Example 52 (a) are weighed. pyrazol-2-yl] -acetyl chloride and 95 ml of anhydrous tetrahydrofuran, the mixture is stirred at 0-5 ° C while 0.2 ml of a propylamine solution in 10 ml of anhydrous tetrahydrofuran are added dropwise. After stirring for 50 minutes at 0-5 ° C, another 0.1 ml of propylamine solution in 5 ml of anhydrous tetrahydrofuran was added and the mixture was stirred at 0-5 ° C for an additional 2-3 hours, followed by 95 ml of anhydrous diethyl ether. diluted with ether and stirred at the same temperature for another hour. The reaction mixture was filtered, the filtrate was washed with water, dried and concentrated in vacuo. The residue was chromatographed on p

The column was purified on Florisil adsorbent, eluting with dichloromethane followed by dichloromethane: methanol (95: 5). Trituration with diethyl ether afforded the expected solid by chromatography on the expected 2,3-di • 4 ·

50 hydro-4- (4-chlorophenyl) -3-oxo-N-propyl-1H-benzopyrano-4,3-cis-pyrazole-2-acetamide is obtained, m.p. 218-223. ° C.

Example 55

1.0 g of 4- (4-chlorophenyl) -1H-benzopyrano-4,3-cis-pyrazol-3 (2H) -one prepared in Example 13 and 20 ml of toluene are weighed, and 0.53 g of chlorosulfonyl isocyanate is added at room temperature with stirring. The reaction mixture was heated to 70 ° C and stirred at this temperature for 15 minutes, then cooled to 0 ° C and filtered. The filter residue was washed with diethyl ether and resuspended in a mixture of 6 mL of concentrated acetic acid and 3 mL of water. The mixture was heated to 60 ° C, held at this temperature for 15 minutes, filtered, dried, and recrystallized from methylene chloride / methanol (4: 1). The resulting 2,3-dihydro-4- (4-chlorophenyl) -3-oxo-1H-benzopyrano / 4,3-cis-pyrazole-2-carboxamide m.p. 215-216 ° C.

Example 56

3.0 g of 4- (4-chlorophenyl) -1,3-benzopyrano [4,3-c] pyrazol-3 (2H) -one, prepared as described in Example 13, are weighed, 2.79. Potassium carbonate (g) and acetone (20 ml) were added dropwise at room temperature under stirring, and acetyl chloride (0.86 ml) was added dropwise. The reaction mixture was stirred at room temperature for 42 hours.

After stirring, a further 6.98 g of potassium carbonate was dissolved in 15 ml of acetone, analytical reagent grade, 3.6 ml of acetyl chloride was added and stirring continued at room temperature for another 18 hours. An additional 2.79 g of potassium carbonate and 1.44 ml of acetyl chloride were added and the mixture was stirred at room temperature.

2.25 hours and then refluxed for 1 hour. After cooling to room temperature, water was added, the precipitate was collected by filtration, dried and recrystallized from acetonitrile. The thus obtained 2-acetyl-4- (4-chlorophenyl) -1H-benzopyrano [4,3-c] pyrazol-3 (2H) -one has a melting point of 224-226 ° C.

Example 57 g, prepared as in Example 13

A mixture of 4- (4-chlorophenyl) -1-benzopyrano-4,3-cis-pyrazol-3 (2H) -one and 200 ml of ethyl chloroformate is heated under reflux for 5 hours with stirring. An additional 50 ml of ethyl chloroformate was added and the mixture was cooled to room temperature after refluxing for 4 hours. The precipitated solid was collected by filtration, recrystallized from acetonitrile and purified by flash chromatography on silica gel eluting with dichloromethane / methanol (9: 1). The fractions taken from the column were evaporated to leave a solid which was recrystallized from ethyl acetate. The melting point of the ethyl 2,3-dihydro-4- (4-chlorophenyl) -3-oxo-1,1-benzopyrano-4,3-cis-pyrazole-2-carboxylate thus obtained: 187-188 ° C.

• ·

Example 58

5.0 g, prepared as in Example 13

A mixture of 4- (4-chlorophenyl) -1-benzopyrano-4,3-cis-pyrazol-3 (2H) -one and 50 ml of ethyl cyanoformate was heated to reflux with stirring, 3.5 After cooling to room temperature, dilute with petroleum ether (30 ml), filter, and dry the residue on the filter. The melting point of the ethyl 2,3-dihydro-4- (4-chlorophenyl) -3-oxo-1H-benzopyrano [4,3-c] pyrazole-2-carboxylate thus obtained was 187. -189 ° C.

Example 59

0.97 g of 2,3-dihydro-4- (4-chlorophenyl) -3-oxo- (1-7-benzopyrano) -4,3-cis-pyrazole prepared according to Example 52 (a). -2-yl N-acetyl chloride is suspended in 76 ml of anhydrous tetrahydrofuran and then dissolved in 10 ml of anhydrous tetrahydrofuran, 0.7 g of cyclobutanol and 0.35 g of triethylamine are added. The resulting reaction mixture was stirred at room temperature for 2.67 hours, then filtered, the filtrate diluted with diethyl ether, washed with water, dried and concentrated in vacuo. The residue was purified by preparative layer chromatography on silica gel using methylene chloride / methanol 9: 1 as mobile phase. The fast moving band was dissolved in ethyl acetate, evaporated in vacuo and the resulting gum was triturated with diethyl ether and petroleum ether (b.p. 62-68 ° C) and filtered. The resulting cyclobutyl / 2,3-dihydro-4- (4-chlorophenyl) -3-oxo-1-benzopyrano-4,3-cis-pyrazole-2-acetate / m.p. ° C.

Example 60

3.3 g, prepared as described in Example 20

A solution of 4- (4- (trifluoromethyl) phenyl) -1- (benzopyrano) -4,3-cis-pyrazol-3 (2H) -one in 60 ml of anhydrous N, N-dimethylformamide with stirring, 0.48 g of 60% sodium hydride dispersed in mineral oil are added under nitrogen. After stirring at room temperature for 0.5 hour, 1.46 g of bromoacetonitrile was added in one portion and, after stirring for an additional 18 hours at room temperature, was poured into ice water. The mixture was extracted with ethyl acetate, and the combined extracts were washed with water, dried and evaporated, and the resulting solid was recrystallized from propanol. That's how it got

2,3-dihydro-3-oxo-4- [4- (trifluoromethyl) phenyl] -1H-benzopyrano-4,3-cis-pyrazole-2-acetonitrile; C.

Example 61

As in Example 60, 1.35 g of 4- [4- (trifluoromethyl) phenyl] -1H-benzopyrano-4,3-cis-pyrazol-3 (2H) -one, 21 g of 60% sodium hydride dispersed in mineral oil, 0.77 g of (2-bromoethyl) ethyl ether and 50 ml of · ·

- anhydrous Ν, Ν-dimethylformamide, and the mixture was stirred at room temperature for 42 hours. The crude product was purified by flash chromatography on silica gel eluting with ethyl acetate and recrystallized from isopropyl alcohol. The resulting 2- (2-ethoxyethyl) -4- (4- (trifluoromethyl) phenyl) -1H-benzopyrano-4,3-cis-pyrazol-3 (2H) -one has a melting point. 126-128 ° C.

Example 62

Combine 8.22 g, prepared as described in Example 46 using 2- (2-hydroxyethyl) -4-4- (trifluoromethyl) -fenil_7- / f l_7benzo _J-pyrano / 4,3-c_ / pyrazole -3 (2H) -one and 500 ml of 48% aqueous hydrobromic acid. The reaction mixture was stirred at reflux for 28 hours, cooled to 0 ° C, the precipitate was collected by filtration, washed with water, dried and recrystallized from acetonitrile. The resulting 2- (2-bromoethyl) -4 / ^- 4- (trifluoromethyl) -fenil_ / ~ 7 _ / "benzo-pyrano / 4,3-c_ _ / pyrazol-3 (2H)! 145-147 ° C.

Example 63

a) similar to that described in Example 60, were added 5.0 g of 4- / ~ 4- (trifluoromethyl) -fenil_7- / ^- l_7benzo-pirano_ / 4,3-c_ / ~ pyrazol-3 (2H) -one, 0.7 g of 60% sodium hydride dispersed in mineral oil, 2.4 ml of ethyl 4-bromobutyrate and

230 ml of anhydrous Ν, Ν-dimethylformamide. After stirring at room temperature for 24 hours, the reaction mixture was poured into a mixture of water (2.3 L) and boiling point (60-80 ° C), acidified with 5 M hydrochloric acid, and the precipitated product filtered off and dried. The ethyl {2,3-dihydro-3-OXO-4- (4- (trifluoromethyl) phenyl) -1H-benzopyrano-4,3-cis-pyrazole-2-butyrate thus obtained had m.p. 112-115 ° C.

b) 3.0 g of ethyl (2,3-dihydro-3-oxo-4- [4- (trifluoromethyl) phenyl] -1H-benzopyrano [4,3-c] pyrazole-2- butyrate / ml 5M hydrochloric acid was stirred at 96-105 ° C for 5 hours.

The mixture was allowed to cool to room temperature and after 1 hour the precipitated solid was collected on a filter, washed with water, then with diethyl ether and dried.

Melting point of the thus obtained 2,3-dihydro-3-oxo-4- (4-trifluoromethyl) -phenyl-1H-benzopyrano [2,3-c] pyrazole-2-butyric acid: 197 -200 ° C, shrinks at 189 ° C.

c) 1.8 g of 2,3-dihydro-3-oxo-4- (4- (trifluoromethyl) phenyl) -1H-benzopyrano [4,3-c] pyrazol-2-butyric acid To a suspension of 1 ml of dichloromethane was added 0.2 ml of Ν, Ν-dimethylformamide, followed by 1.2 ml of sulfinyl chloride, with stirring. After stirring for 24 hours at room temperature, the reaction mixture was concentrated in vacuo to give the expected 4- (2,3-dihydro-3-oxo-4- (4-trifluoromethyl) phenyl) -1H-benzopyranone. 4,3-cis-pyrazol-2-yl} -butyryl chloride is obtained.

• · «•«

d) The acid chloride obtained in (c) is dissolved in 88 ml of anhydrous tetrahydrofuran and 0.6 ml of concentrated aqueous ammonium hydroxide is added with stirring at 0-5 ° C. The reaction mixture was stirred for 1 hour at 0-5 ° C, another 0.2 ml of concentrated ammonium hydroxide was added and stirring was continued at 0-5 ° C for a further 0.75 hours. The resulting precipitate was collected on a filter, washed with tetrahydrofuran, water, and dried. The resulting 2,3-dihydro-3-oxo-4- [4- (trifluoromethyl) phenyl] -1-benzopyrano [4,3-c] pyrazole-2-butanoic acid melting point: 221 ° C.

Example 64 g, prepared as in Example 47

A mixture of 2- (2-hydroxyethyl) -4- (4-chlorophenyl) -1H-benzopyrano [4,3-c] pyrazol-3 (2H) -one and 300 mL of sulfinyl chloride was stirred while refluxing for 3.5 hours. The excess sulfinyl chloride was evaporated in vacuo, the residue was stirred with acetonitrile and filtered, and then recrystallized from methylene chloride. 169-170: -one 4,3-c_ / pyrazol-3 (2H), melting point ^- to give 2- (2-chloroethyl) -4- (4-chlorophenyl) -Γ Tbenzo l-pyrano / received ° C.

Example 65

Capsules are prepared by grinding 10 parts by weight of active ingredient with 240 parts by weight of lactose.

57, and the mixture is filled into hard gelatine capsules.

Each capsule contains 10 mg of the active ingredient.

Example 66

In the preparation of the capsule, 50 parts by weight of the active ingredient and 300 parts by weight of lactose and 3 parts by weight of magnesium stearate are ground and mixed. The mixture is then filled into hard gelatin capsules so that each capsule contains 50 mg of the active ingredient.

Example 67

The tablet is made from the following ingredients:

agent 10 parts by weight Lactose 190 corn starch 22 Poly (vinylpyrrolidone) 10 Magnesium stearate 3

The active ingredient, lactose and a portion of the starch are ground and mixed and the mixture is granulated with a solution of polyvinylpyrrolidone in ethanol. The dried granulate is mixed with the magnesium stearate and the starch residue, and the resulting mixture is (a) 10 mg; b) 100 mg; c) Compressed into tablets containing 500 mg of active ingredient.

Example 68

The tablets were prepared as described in Example 67 and then coated in the usual manner. The coating is prepared using a solution of 20% cellulose acetate phthalate and 3% diethyl phthalate in a 1: 1 mixture of ethanol and dichloromethane.

Example 69

For suppositories, 100 parts by weight of active ingredient are prepared with 1300 parts by weight of semi-synthetic glyceride suppository base and the mixture is poured into molds. Each suppository contains 100 mg of active ingredient.

Example 70

In the preparation of an ointment, the active ingredient is mixed in the base material and homogenized until the active ingredient is distributed uniformly. The ointment is then filled into 10 g jars with a lined screw cap. Ointment composition:

agent

0.1 g

Fehérvazelin

10.0 g

As stated above, the compounds of the present invention are immunomodulatory agents, in particular immunosuppressants.

which may produce adequate therapeutic effects at doses of 200 mg / kg or less. The effect of the compounds of outstanding importance is already manifested at doses of 50 mg / kg or lower. The therapeutic efficacy of the compounds of outstanding interest was determined by the skin hypersensitivity reaction test, which was parenterally administered to BALB / c mice.

The test procedure is as follows:

Female mice weighing 16-24 g were divided into groups of eight. Each animal is shaved on its abdomen and the shaved area is treated with 20 ul of 4-ethoxymethylene-2-phenyl-2-ol, 1: 1 (v / v) acetone / ethanol (5 g / 100 ml) for sensitization. oxazolin-5-one solution (oxazolone). Immediately after sensitization, the animals are dosed intraperitoneally with the appropriate doses of the active compounds listed in Table 4 at doses of 50, 30, 10, 3, 1, 0.3, 0.1, 0.03 and 0.01 mg / kg. 100 µl, suspension in sterile water containing 1.5% by volume of sorbitan ester (tradename: Tween 80). Each animal receives the same 100 µl suspension every 24 hours for a further 7 days.

In each set of experiments, two groups of BALB / c mice, at least 8-8 animals, served as controls simultaneously. Individuals from the control group were treated exactly like other experimental animals, but the daily injections did not contain the active ingredient.

• · · · • Μ * * * • · · »··

99 9 '· • · ···· ··

A treatment of oxazolone in acetone / olive oil (3: 1 by volume) was used to treat one ear of both experimental and control animals. (In some cases, oxazolone was used in a more concentrated solution of 1.5 g / 100 ml, but also in a mixture of acetone and olive oil.) Twenty-four hours later, each animal was measured using a screw micrometer to measure the thickness of the treated and untreated ears. The difference in ear thickness is considered to be the extent of the oxazolone-induced response in each animal compared to the response in the treated and control animals to provide information on the efficacy of the agents tested as immunomodulators. Drugs are considered effective at a given dose if they result in a 20% or greater reduction in ear thickness in the drug-treated animals compared to the control group and this reduction is statistically significant (p <0.05). , i.e., at least two of three animals, or more than three of the experimental animals, can be detected in the majority of animals at the given dose level _ / see, e.g., Int. Arch. Allergy 38: 246-259 (1970)].

All of the compounds of Formula I listed in Table 4 were found to be effective in studies of 50 mg / kg in at least two of three animals, unless otherwise noted (see footnote to table). the dose for each compound is given in Table 4, where one or more numbers preceded by the name of the compound indicate the number of examples or examples for the preparation of the active ingredient.

Table 4

Example Example Number of compound name

Minimum effective dose (mg / kg)

8 / b 9-methoxy-4- / 4- (trifluoromethyl) - phenyl · - / - / _ 1_Zbenzo-pyrano / ^- 4,3-c / - pyrazol-3 (2H) -one <3 8 / c 2- (2-ethoxyethyl) -9-methoxy-4- / 4- - (trifluoromethyl) phenyl ~ benzopyran [4,3-c] pyrazol-3 (2H) -one 3 9 9-ethoxy-4- (4-chloro-phenyl) -2-methyl / 1_ / benzopyrano / ^- 4,3-c / pyrazol-3 (2H) -one 50 10 4- (4-chlorophenyl) -2- (2,2,2-trifluoro-ethyl) - £ 1_ / benzopyrano / ^- 4,3-c pyrazol-3 (2H) -one 50 11 4- (3,4-Dichlorophenyl) -2-methyl- (1-benzo) -pyrano [4,3-c] pyrazol-3 (2H) -one 50 12 2-methyl-4- (2-naphthyl) - / ^- 1 / benzo-pyrano / 4,3-C / pyrazol-3 (2H) -one 50 13 19 4- (4-Chloro-phenyl) - (1-benzo-pyran) / 4,3-C- / pyrazol-3 (2H) -one 3 14 24 4- (4-chlorophenyl) -2-methyl- rano / 4,3-C- / pyrazol-3 (2H) -one 10

• ·

example

name

effective dose (mg / kg)

2-ethyl-4- (4-chlorophenyl) -1,5-benzo-50

-pyrano [4,3-c] pyrazol-3 (2H) -one

4- (4-chlorophenyl) -2-methyl-9-methoxy

-N-benzo-pyran / 4,3-c / pyrazol-3 (2H) -one

4- (4-Chloro-phenyl) -2,9-dimethyl- [1-5] benzo-pyrano [4,3-c] pyrazol-3 (2H) -one 2-methyl-4- [4- (trifluoro) -methyl) -phenyl-3- (1H) -benzopyran [4,3-c] pyrazol-3 (2H) -one

4- [4- (Trifluoromethyl) phenyl] -1,3-benzopyran [4,3-c] pyrazol-3 (2H) -one

2- (2,3-Dihydro-4- (4-chlorophenyl) -3-oxo-50

- (benzo-pyran [4,3-c] pyrazol-2-yl) -ethyl} -acetate

4- (4-Chloro-phenyl) -2- (2-methoxy-ethyl) -1H-10-benzo-pyrano [4,3-c] pyrazol-3 (2H) -one

2,3-dihydro-4- (4-chlorophenyl) -3-oxo-50

N-benzopyran-4,3-cis-pyrazole-2-acetonitrile

2- (2-phenoxyethyl) -4- (4-chlorophenyl) -50

- [1-7-benzo-pyran / 4,3-c] pyrazol-3 (2H) -one

2-Allyl-4- (4-chlorophenyl) -1'-benzo-50

-pyrano [4,3-c] pyrazol-3 (2H) -one

Table 4 (continued)

The smallest

Example A Name of compound effective dose (mg / kg)

2.3-Dihydro-4- (4-chlorophenyl) -3-oxo [1] -50-benzopyrano [4,3-c] pyrazole-2-propionitrile

4- (4-Chloro-phenyl) -2-propyl- [1] benzopyrano-50 [4,3-c] pyrazol-3 (2H) -one

2.3-Dihydro-4- (4-chlorophenyl) -3-oxo [1] - <30 (a) benzopyrano [4,3-c] pyrazole-2-carbonitrile

2- (2-Ethoxyethyl) -4- (4-chlorophenyl) - [1] -1-benzopyrano [4,3-c] pyrazol-3 (2H) -one

2-Butyl-4- (4-chlorophenyl) - [1] benzopyrano-50 [4,3-c] pyrazol-3 (2H) -one

4- (4-chlorophenyl) -2- [2- (2-methoxyethoxy) ethyl] -50

- [1] Benzopyrano [4,3-c] pyrazol-3 (2H) -one {2,3-dihydro-4- (4-chlorophenyl) -3-oxo [1] -50 benzo Pyrano [4,3-c] pyrazol-2-yl} -acetophenone [2- {2- [2,3-dihydro-4- (4-chloro-phenyl) -3-oxo-50]

- [1] benzo-pyrano [4,3-c] pyrazol-2-yl] ethoxy} ethyl] acetate

2- [2- (1,3-dioxolan-2-yl) ethyl] -4- (4-chloro-50

phenyl) - [1] benzo-pyrano [4,3-c] pyrazol-3 (2H) -one

2 - [(1,3-dioxolan-2-yl) methyl] -4- (4-chloro-50

-phenyl) - [1] benzo-pyrano [4,3-c] pyrazol-3 (2H) -one • · • · · · · · · · · · · · · · · · · · · · · · · · · ·

- 64 - ...........

Table 4 (continued)

. example number The name of the compound The smallest effective dose (mg / kg) 43 2- (2-ethoxypropyl) -4- (4-chlorophenyl) - [1] - benzopyrano [4,3-c] pyrazol-3 (2H) -one 50 44 {2- [2,3-dihydro-3-oxo-4- [4- (trifluoro -methyl) -phenyl] - [1] benzopyrano [4,3-c] - pyrazol-2-yl} ethyl] acetate 50 45 2- (2- (1,3-dioxan-2-yl) ethyl] -4- (4-chloro- phenyl) - [1] benzo-pyrano [4,3-c] pyrazole 3 (2H) -one 50 46 2- (2-hydroxyethyl) -4- [4- (trifluoromethyl) - phenyl] - [1] benzo-pyrano [4,3-c] pyrazole 3 (2H) -one 50 47 2- (2-hydroxyethyl) -4- (4-chloro-phenyl) - [1] - benzopyrano [4,3-c] pyrazol-3 (2H) -one 50 48 2- (3-hydroxypropyl) -4- (4-chlorophenyl) [1] benzopyrano (4,3-c] pyrazol-3 (2H) -one 50 49 2- [2- (2-hydroxyethoxy) ethyl] -4- (4-chloro- phenyl) - [1] benzo-pyrano [4,3-c] pyrazole 3 (2H) -one 50 50 2,3-dihydro-4- (4-chlorophenyl) -3-oxo [1] - benzo-pyrano [4,3-c] pyrazole-2-acetamide 3 51 2,3-Dihydro-4- (4-chlorophenyl) -3-oxo [1] benzopyrano [4,3-c] pyrazole-2-propionic acid amide 50

- Table 65 4 (continued)

"Example number The name of the compound The smallest effective dose (mg / kg) 52 N-ethyl-2,3-dihydro-4- (4-chlorophenyl) -3- oxo [1] benzo-pyrano [4,3-c] pyrazol-2- acetamide 50 53 2,3-dihydro-4- (4-chlorophenyl) -N-methyl-3- oxo [1jbenzo-pyrano [4,3-c] pyrazole-2- acetamide 50 54 2,3-dihydro-4- (4-chloro-phenyl) -3-oxo-N- propyl- [1jbenzo-pyrano [4,3-c] pyrazole -2-acetamide 50 55 2,3-Dihydro-4- (4-chlorophenyl) -3-oxo [1] -benzopyrano [4,3-c] pyrazole-2-carboxamide <50 56 2-acetyl-4- (4-chloro-phenyl) - [1jbenzo- pyrano [4,3-pyrazol-3 (2H) -one 50 57, 58 Ethyl [2,3-dihydro-4- (4-chlorophenyl) -3-oxo- 50 - [1jbenzo-pyrano [4,3-pyrazol-2-carboxylate ] 59 cyclobutyl [2,3-dihydro-4- (4-chlorophenyl) -3- 50 oxo [1jbenzo-pyrano [4,3-c] pyrazole-2-acetate ] 60 2,3-dihydro-3-oxo-4- [4- (trifluoromethyl) - phenyl] - [1jbenzo-pyrano [4,3-c] pyrazole-2- acetonitrile <3 61 2- (2-ethoxy-ethyl) -4- [4- (trifluoromethyl) - phenyl] - [1] benzopyrano] 4,3-c] pyrazole 3 (2H) -one 3

···· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ···

Table 4 (continued)

The example number The name of the compound Minimum effective dose (mg / kg) 62 2- (2-bromoethyl) -4- [4- (trifluoromethyl) - phenyl] - [1] benzo-pyrano [4,3-c] pyrazole -3 (2H) -one 3 63 2,3-dihydro-3-oxo-4- [4- (trifluoromethyl) - phenyl] - [l] benzo pyrano [4,3-c] pyrazole-2- butanamide 50 64 2- (2-chloroethyl) -4- (4-chlorophenyl) [1] benzopyrano [4,3-c] pyrazol-3 (2H) -one 50

The following compounds were prepared in the same manner as in the Examples and were also effective in the above-described skin hypersensitivity test at 50 mg / kg:

{2- [2,3-Dihydro-4- (4-chlorophenyl) -3-oxo [1] benzopyrano [4,3-c] pyrazol-2-yl] ethyl} propionate having mp 112-114 ° C.

2,3-Dihydro-N-isopropyl-4- (4-chlorophenyl) -3-oxo [1] benzopyrano [4,3-c] pyrazole-2-acetamide, m.p. 238-241 'C, decay.

N-benzyl-2,3-dihydro-4- (4-chlorophenyl) -N-methyl-3-oxo [1] benzopyrano [4,3-c] pyrazole-2-acetamide, m.p. :

182-183 'C.

Note:

(a) In the study at the dose level of 30 mg / kg, performed in two animals, it was effective in both cases.

The compounds of the present invention have also been found to be effective in a number of other in vivo assays, suggesting that they are useful as immunomodulators, namely immunosuppressive agents. The compounds were administered orally or parenterally. For some compounds, the effect on humoral immunity also had to be demonstrated, for example, after the above-described assay based on oxazolone-induced hypersensitivity of the skin, serum levels and changes in antibodies raised against oxazolone, and the so-called graph-versus-host reaction. as described in the literature [S. R. Smith, C. Terminelli, C. T. Kipilman and Y. Smith, J. Immunopharmacology 3, 133-170 (1981).

Examples of compounds are 8./b, 8./c, 10-15, 18,

20, 26, 27, 30, 33, 35, 37, 38, 40, 42, 44-47,

49, 52 and 55-64. Examples 1 to 4 were found to be effective in the above-mentioned antibody-based test after parenteral administration of 50 mg / kg. In this series of tests, a compound is considered to be effective if the relapse caused by the 50 mg / kg dose

A decrease in serum anti-oxazolone antibody concentration, as determined by ELISA, results in a factor of 0.5 or greater, calculated as follows:

O.D. (Cp - O.D. {Tp

OD (Cp - OD (C ₂ ) where

O.D. (cp = a control serum optical density 1/128 dilution; O.D. ( ^C 2> = a control serum optical density 1/256 dilution; O.D. (τρ = a treated animal won serum optical density

Diluted 1/128.

Both the serum from the treated animal and the control serum were diluted with phosphate buffered saline, pH 7.3, containing 0.05% (v / v) Tween 20 surfactant.

Claims (12)

Claims CLAIMS 1. Compounds of formula (I) wherein they are hydrogen, cyano, C2-C6 alkanoyl, C2-C6 alkoxycarbonyl or carbamoyl; obsession R | C 1-6 alkyl or C 2-6 alkenyl which is halogen, cyano, trifluoromethyl, hydroxy, benzoyl, C 2-6 alkanoyloxy or C 3-8 cycloalkoxycarbonyl; and a 5-7 membered non-aromatic heterocyclic group containing 2 oxygen atoms; a group of the formula R _g R _g , N-CO- wherein R _g and R _g are, the same or different, hydrogen, (C 1 -C 6) -alkyl or benzyl; and phenoxy or (C 1 -C 6) alkoxy, where the alkoxy itself may be substituted with halo or (C 1 -C 6) alkoxy or (C 2 -C 6) alkanoyloxy, may be substituted; R ₂ is hydrogen or chloro; R 4 is chloro or trifluoromethyl; obsession R ₂ and R 4 together represent a fused benzo ring; and R ₄ is hydrogen, halogen, C 1-6 alkyl or C 1-6 alkoxy. Compounds according to claim 1, wherein ig is J- (CH ₂ ) p -, wherein J is hydrogen, halogen, C 1 -C 6 alkoxy, carbamoyl or cyano, and p is Ο, 1 or 2; R ₂ is hydrogen; R 4 is chloro or trifluoromethyl; and R ₄ is hydrogen or C 1-6 alkoxy. Compounds according to claim 2, wherein R 1 is hydrogen, methyl, cyanomethyl, carbamoylmethyl, 2-haloethyl or C 1-4 alkoxyethyl. Compounds according to claim 3, wherein R-1 is methyl or 2-ethoxyethyl. 5. By name, the following compounds: 2- (2-ethoxyethyl) -9-methoxy-4- [4- (trifluoromethyl) phenyl] - [1] benzopyrano [4,3-c] pyrazol-3 (2H) -one; 2 meti1-4- [4- (trifluoromethyl) phenyl] - [1] benzo-pyrano [4,3-c] pyrazol-3 (2H) -one; and 2- (2-ethoxy-ethyl) -4- [4- (trifluoromethyl) phenyl] - [1] benzo-pyrano [4,3-c] pyrazol-3 (2H) -one. 6. A pharmaceutical composition, characterized in that a 1-5. A compound of formula (I) according to any one of claims 1 to 6 in combination with a pharmaceutical carrier, diluent and / or other excipients. The pharmaceutical composition of claim 6 in unit dosage form. * ·· ♦ 4 4 ··· • 4 «94 · 4 4 · 4 4 9 ·· 4 4 · · · »4 4 4 · ··« 4 · 4444 · 8. A method of treating diseases associated with the function of the immune system, wherein a patient in need of such treatment has a method according to any one of claims 1-5. A therapeutically effective amount of a compound of formula I as claimed in any one of claims 1 to 6. 9. Use of a compound of formula (I) according to any one of claims 1 to 6 as an immunomodulator. 10. Compounds of formula (I) according to any one of claims 1 to 3, characterized in that they are useful as active ingredients in pharmaceutical compositions for the treatment of diseases related to the function of the immune system. 11. A process for the preparation of a compound of formula (I) according to claim 1, characterized in that a) a compound of Formula II, including any tautomeric structures thereof, with a compound of Formula III: wherein R ₁₄ is (Q-O-) or (Q-S) ₂ , and R 1c is a Q-Ο- 'means one of _two formula groups ^N_ be described, wherein Q and Q' is Q or QS 1-4 carbon atoms or benzyl; or R ₁₄ is NH, R is the _Ig is selected from the group of the formula Q-0- or QS; or R _{14 is} oxygen and R _{15 is} hydrogen, halogen or 1-imidazolyl; obsession b) reacting a compound of formula (IV) wherein R g is hydrogen, and when intended to include the possible tautomeric structures therefor or _to R a, can be represented by -CO- formula R _Ig group where present _to R 4 is hydrogen, (C 1 -C 4) -alkyl, benzyl or a group represented by the general formula (IIa) and R | R ₇ is _5-CO-, are reacted with a base. Compounds of formula (II) wherein R 1 and R ₄ are as defined in claim 1.