HRP930210A2 - Heterobicyclic compounds and pharmaceutical preparations containing them - Google Patents

Description

The invention relates to heterobicyclic compounds and pharmaceutical preparations containing them. Flavoxate, which is 8-(2-piperidino ethoxycarbonyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, and has the formula

[image]

it is used as a pharmaceutical agent for disorders of the urinary tract, because it has a relaxing effect on smooth muscles thanks to its antagonistic calcium effect. This activity is expressed in the smooth muscles of the bladder or may refer to the corresponding center in the central nervous system.

The compounds of this invention, described below, basically include a more complex amino moiety in place of the piperidino group.

Further changes include alternatives to the ethoxycarbonyl group that creates an intermediate space between the amino moiety and the benzopyran ring, an alternative to the 2-, 3-, 6-, and 7-substitution pattern of the benzopyran ring, replacement of the ring heteroatom with a sulfur atom or a sulfinyl, sulfonyl, or imino group, and/ or 2,3-dihydrogenation of the benzopyran ring. These structural variations give new compounds the ability to interact with different biological systems, which is confirmed by the affinity of these new compounds for α1-adrenergic and 5HT1A-serotoninergic receptors. Flavoxate is practically devoid of affinity for tin receptors.

Compounds of the Invention

The compounds of the invention have the general formula I

[image]

where

----- represents a single or double bond;

X represents an oxygen or sulfur atom or an imino, alkylimino, sulfinyl or sulfonyl group;

W represents a valence bond or a carbonyl, thiocarbonyl, methylene or hydroxymethylene group;

R 2 represents a hydrogen atom or an alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, substituted heterocyclyl or aryl group; substituents for the aforementioned groups are one or more halogen atoms and/or one or more alkyl, cyano, hydroxy, alkoxy, phenyl, phenoxy, trifluoromethyl, nitro, amino, alkylamino, dialkylamino, acylamino, alkylsulfonylamino or benzyl groups;

R 3 represents a hydrogen atom or an alkyl, hydroxyalkyl, alkoxyalkyl, aralkyl, phenyl, hydroxyalkyl or aralkyl group;

R6 represents a hydrogen or halogen atom or a nitro, amino, alkylamino, dialkylamino, acylamino, alkylsulfonylamino, cyano, hydroxy, alkoxy or alkyl group;

R7 represents a hydrogen atom or an alkoxy group;

Y represents one or more of the following groups, each of them is shown so that the left side is attached to the heterobicyclic ring, and the right side is attached to the Z group:

(Y1) -CO-,

(Y2) -COO-,

(Y3) -CONH-,

(Y4) -CON(CH3)-,

(Y5) -CON(OH)-,

(Y6) -CH(OH)-,

(Y7) -CH(OAlkyl)-,

(Y8) -CH=CH-,

(Y9) -CH=CH-COO-,

(Y10) -CH=CH-CONH-,

(Y11) -CH=NO-,

(Y12) -CH2-,

(Y13) -CH2COO-,

(Y14) -CH2CONH-,

(Y15) -CH2NH-,

(Y16) -CH2N(CH3)-,

(Y17) -CH2N(COCH3)-,

(Y18) -CH2N(CONH2)-,

(Y19) -CH2NHCO-;

(Y20) -CH2N(CH3)CO-,

(Y21) -CH2NH-CONH-,

(Y22) -CH2NHSO2-,

(Y23) -CH2O-,

(Y24) -CH2S-,

(Y25) -CH2SO-,

(Y26) -CH2SO2-,

(Y27) -CH2SO2NH-,

(Y28) -CH2SO2N(CH3)-,

(Y29) -NH-,

(Y30) -N(CH3)-,

(Y31) -N(COCH3)-,

(Y32) -N(CONH2)-,

(Y33) -NHCO-,

(Y34) -N(CH3)CO-,

(Y35) -NH-CONH-,

(Y36) -NHSO2-,

(Y37) -O-,

(Y38) -S-,

(Y39) -SO-,

(Y40) -SO2-

(Y41) -SO2NH-,

(Y42) -SO2N(CH3)-,

(Y43) -CONHO-,

(Y44) -CON(COCH3)-,

(Y45) -CSNH-,

(Y46) -CSN(CH3)-,

[image] (Y48) -NHCOO-, i

(Y49) -COS-;

Z represents a straight or branched chain alkylene group having 1 to 6 carbon atoms and optionally having one hydroxy substituent; and

B represents one of the following groups:

(B1)

[image]

where Q represents a methylene or ethylene group and A represents one of the following groups:

(A1) phenyl group substituted with one or more halogen atoms and/or one or more alkyl, alkoxy or hydroxy groups,

(A2) 2-pyrimidinyl group, i

(A3) group of the general formula

[image]

where ----- has already been previously defined and E represents an oxygen atom or a valence bond,

(B2)

[image]

where each of L1 and L2 independently represents a hydrogen atom, phenyl, 4-fluorobenzoyl or 2-oxo-1-benzimidazolinyl group, or a group of the general formula (CH2)n-O-A where n is 0, 1 or 2 and A is the same as previously defined , with the condition that L1 and L2 are not both hydrogen atoms,

(B3)

[image]

where each of R10 and R11 independently represents a hydrogen atom or an alkoxy or alkylthio group, R12 represents a hydrogen atom or an alkyl group, and n is 2 or 3,

(B4)

[image]

where R12 has already been previously defined and R13 represents a hydrogen atom or an alkoxy group, and

(B5)

[image]

where R12 is already previously defined.

When - - - represents a double bond, W represents a carbonyl group and X represents an imino group, the ring may undergo tautomerization to give the 4-hydroxy-quinoline structure; such tautomeric compounds are an integral part of the presented invention.

The invention also includes prodrugs, enantiomers, diastereoisomers, N-oxides and pharmaceutically acceptable salts of the compounds of general formula I.

The term "prodrugs" as used herein refers to derivatives of compounds of general formula I in which reactive groups such as amino, imino or hydroxy groups (especially as or within the W, R2, R3, R6, Z, B1 and B2 moieties) or acidic imino groups (eg those shown in Y3, Y10, Y19, Y27, Y36 and Y41) masked; derivatives release the compound as such within the living organism and thus have the same pharmacological effect on the organism as the compound itself. "

"Prodrugs" can be formulated to alter the pharmacokinetic properties of the compound, for example, a delayed or extended release form of the compound can be formulated, or otherwise the adsorption metabolism, distribution, or plasma half-life of the compound can be altered. Compounds Prepared in Examples 114 and 120 -122 below are examples of prodrugs.

Group

[image]

will be referred to as F1 in the following text. The preferred values of the substituents in group F1 are as follows:

---: double bond,

X: oxygen atom,

W: carbonyl group,

R2: phenyl group,

R3: methyl group,

R6: hydrogen atom, i

R7: hydrogen atom.

A group having all these preferred substituents is a 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-yl group.

Preferred groups that can represent Z are trimethylenes and tetramethylenes. It is preferred that Y represents one of the groups Y2, Y3, Y37, Y40, Y41 or Y42. It is preferred that B represents one of the groups B1 or B3, especially the 1-(2-methoxyphenyl)-piperazinyl group.

Other common abbreviations used in the text are Me for methyl, Et for ethyl, Ac for acetyl, Alk for alkyl THF for tetrahydrofuran, DMF for dimethylformamides and DMSO for dimethylsulfoxides.

The adrenergic antagonist activity of the compounds of this invention makes them useful as agents for acting on tissues rich in α1-adrenergic receptors (such as blood vessels, prostate

and urethra). Accordingly, the anti-adrenergic compounds found to be such by virtue of their receptor binding within the present invention may be useful as therapeutic agents in the treatment of, for example, hypertension and micturition problems associated with lower urinary tract obstructive diseases, including but not limited to benign prostatic hypertrophy.

The serotoninergic activity of the compounds of this invention makes them useful as tissue-acting agents, particularly in the central nervous system, where 5HT1A receptors are active. 5HT1A receptors are believed to regulate the action and release of serotonin, as well as the release of other neurotransmitters, and have been found both pre- and post-synaptically. The compounds of this invention have biological activity in blocking binding between these receptors and their various ligands (eg serotonin). Accordingly, compounds of the present invention that interact with 5HT1A-receptors (found to be such based on their receptor binding profile) may be useful therapeutic agents in the treatment of anxiety and depression.

Surprisingly, the compounds of the present invention (especially those showing affinity for both α1-adrenergic and 5HT1A-serotoninergic receptors) show high selectivity for the lower mammalian urinary tract, i.e. they are significantly more effective in antagonizing urethral contractions than in lowering blood pressure. In contrast, known α1-antagonists, such as prazosin, which is 1-(4-amino-6,7-dimethoxy-2-quinazonlinyl)-4-(2-furoyl)-piperazine (GB 1156973), do not show such selectivity (and in fact cause hypotension as a common side effect), while flavone derivatives, structurally similar to flavoxates, such as terflavoxate, which is 8-(1,1-dimethyl-2-piperidino-ethoxycarbonyl)-3-methyl-4- oxo-2-phenyl-4H-1-benzopyran hydrochloride (EP 00'72620), have no effect on urethral contractions. Of course, those compounds of this invention that are not selective to the lower urinary tract are preferred as antihypertensive agents, but even selective compounds can often be used as antihypertensives because of their low toxicity.

The compounds of the present invention also showed good antagonistic activity against potassium chloride-induced contractions of a portion of rat bladder. This effect can be attributed to calcium antagonist activity, and thus the new compounds are useful as spasmolytics of the lower urinary tract (ie, useful in the treatment of urinary incontinence, leakage syndrome and similar disorders).

Most of the compounds of this invention exhibit little toxicity. Thus, they can be used in high amounts, thus compensating for the relatively low level of activity shown by some of the compounds. Of course, compounds that show both high activity and low toxicity are preferred.

The invention further provides a pharmaceutical composition containing a compound according to the invention, or a prodrug, enantiomer, diastereoisomer, N-oxide or a pharmaceutically acceptable salt of such a compound, in a mixture with a pharmaceutically acceptable solvent or carrier.

Synthesis of the compounds of this invention

The compounds of this invention may generally be prepared (except when the groups R 6 and the substituents on R 2 are OH, NH 2 or aminoalkyl and Y = Y 15 or Y 29 ) as follows:

Procedure a:

By condensation of the compounds Fl-Y-Z-L, where L represents a halogen atom or a leaving group such as a tosyloxy group, with the compound H-B. The condensation is usually, but not necessarily, carried out at a temperature within the range of 20-140°C in a polar solvent such as dimethylformamide or methanol, usually in the presence of a base such as potassium carbonate. Such condensations are illustrated in Examples 1 to 3, '7 to 9, 11, 13 to 16, 21, 23 to 31, 38 to 42, 46 to 49, 54 to 59, 69, 73, 77, 78 and 84 below. to the text. See also Gibson's chapter in Patai, The Chemistry of the Amino Group, p. 45 et seq., Wiley Interscience, New York, 1968. An alternative procedure for the preparation of the compounds of this invention is condensation (under the same conditions as described above paragraph) of the compound Fl-Y-H with the compound L-Z-B where L is the same as previously defined. This condensation is shown in Examples 5, 6, 66, 79 and 81 below. Compounds having Y = Y15 or Y29 can also be prepared by this procedure (see Gibson's chapter in Patai, supra).

Compounds of formula (I) having an NH2 group in R6 or as a substituent in R2 can be prepared by reduction of the corresponding compounds (I) where R6 or the substituent in R2 is a NO2 group. Such a reduction can be carried out:

- with a Ni-Raney catalyst in a protic solvent chosen from methanol, ethanol, isopropanol, water and their mixture; or

- with SnCl2, H2O, optionally in the presence of hydrochloric acid, or in a protic solvent such as methanol, ethanol, isopropanol, water, acetic acid or their mixture, or in an aprotic solvent such as ethyl acetate; or

- with Fe and aqueous hydrochloric acid in a protic solvent such as methanol, ethanol, isopropanol, water or their mixture.

The temperatures of the above reactions will be chosen in the range between 20°C and 100°C. (J. March, Advanced Organic Chemistry, III Ed., page 1103, Wiley Interscience, 1985). Examples of these reductions are shown in Examples 94 and 124.

Compounds of formula (I) having an NHAlk group as R6 substituent can be prepared by monoalkylation, starting from the corresponding compounds (I) where R6 = NH2. For example, this can be carried out first by reacting the amino compound (I) with an excess of trifluoroacetic anhydride and then by reacting the thus obtained trifluoroacetyl derivative with an alkyl-L reagent and finally by deprotection of the thus obtained trifluoroacetyl-alkylated derivative by treating it with potassium carbonate in methanol or with sodium borohydride in methanol or dimethylsulfoxide. These reactions are described in Examples 32 and 33, where they were carried out on Y groups.

Alternatively, compounds of formula (I) having NHAlk or N(Alk)2 groups as R6 substituent or as a substituent on the phenyl group in R2 can be obtained by alkylating the corresponding compounds (I) where R6 = NH2 with appropriate alkanals in the presence of reducing agents such as which is sodium cyanoborohydride. Descriptions of these reactions are shown in Examples 96 and 97 below. Compounds which have an OH group as R6 or as a substituent in R2 can be prepared starting from the corresponding compounds (I) alkoxy substituted in said positions. This can be done by treating the starting compounds with, for example, BBr 3 in dichloromethane at 0-40°C (T.W. Greene, Protective Groups in Organic Synthesis, page 87', Wiley Interscience, 1981) or by the procedures described in the notes themselves.

Compounds of the general formula I in which ---- is a single bond can be obtained either by selective hydrogenation of the corresponding compounds in which ---- represents a double bond or by conversion of the corresponding starting materials in which the bond 2,3 is already saturated, such starting materials are available according to reaction schemes 4, 6 to 9, 11, 12 and 14 below. The latter flow is shown in Example 8'7 below, and is particularly preferred when the compound contains a nitro group, because hydrogenation can convert the nitro group to an amino group. Selective hydration can be carried out using alternatively:

- hydrogen in the presence of a metal or metal oxide as a catalyst (eg palladium on carbon or platinum dioxide) in a protic solvent at 20-120°C (E.H. Rodd, Chemistry of Carbon Compounds, Vol. IVB, page 903, Elsevier, l959); or

- di(isobutyl)aluminum hydride in an aprotic solvent (eg tetrahydrofuran and/or dichloromethane) at -70 to 0°C (H. Sarges et al., J. Med. Chem., 33, 1859, 1990).

Compounds in which W represents a hydroxymethylene group and the 2,3-bond is saturated can be obtained by reduction with sodium borohydride of the corresponding compounds in which W represents a carbonyl group and the 2,3-bond is saturated, as shown in Example 123 below .

In some cases, compounds of general formula I can be prepared by conversion of other (parent) compounds of this invention. Such conversions include:

Process b: Fl-CO-Z-B → Fl-CH(OH)-Z-B

by the reduction shown in Examples 17 to 20 below,

Procedure c: Fl-CH(OH)-Z-B → Fl-CH(OAlkyl)-Z-B

by etherification as shown in Example 22,

Procedure d: Fl-(CH2)n-NH-Z-B → Fl(CH2)n-N(CH3)-Z-B

where n = 0 or 1, by N-methylation as shown in Example 35 below,

Process e: Fl-(CH2)n-NH-Z-B → Fl-(CH2)n-N(COCH3)-Z-B

where n = 0 or 1, by N-acetylation as shown in Example 36 below,

Procedure f: Fl-(CH2)n-NH-Z-B → Fl-(CH2)n-N(CONH2)-Z-B

where n = 0 or 1, by reaction with potassium isocyanate as shown in Example 50 below,

Procedure g: Fl-CH(OH)-Z-B → Fl-CO-Z-B

by oxidation, as shown in Example 51,

process h: Fl-Y-Z-B → Fl-Y-Z-B(N-oxide)

by oxidation, as shown in Examples 43 and 122 below,

Procedure i: H2N-Fl-Y-Z-B → CH3CONH-Fl-Y-Z-B

(where H2N-Fl represents the Fl group in which R6

an amino group or R 2 includes an amino group) using the N-acylation procedure described in Examples 36 and 95 below,

Process j: Fl(R6=NH2)-Y-Z-B → Fl(R6=CH3SO2NH)-Y-Z-B amidation, using the procedure described in Example 112 below,

Process k: Fl-Y-Z-NH-(CH2)n-[image] → Fl-Y-Z-N(Alk)-(CH2)n- [image]

or Fl-Y-Z-NH-CH2 [image] → FL-Y-Z-N(Alk)-CH2- [image]

or F1-Y-Z-NH-CH2 [image] → Fl-Y-Z-N(Alk)-CH2-[image]

by N-alkylation, using the procedure described in Examples 35 and 62 below.

Some compounds can be prepared by coupling reactions. For example, those in which Z contains a hydroxy substituent can be prepared by attachment via an epoxy group.

Procedure 1: Fl-Y-CH2-CH-CH2 [image] + H-B → Fl-Y-CH2-CH(OH)-CH2-B

as illustrated in Example 45 below.

It is also possible to bind via a double bond, e.g.:

Process m: Fl-Y-CH=CH2 + H-B → Fl-Y-CH2-CH2-B

as illustrated in Examples 37, 63 and 82 below.

Other synthesis schemes involve the formation of Y, Z or B during the reaction, for example:

Procedure n: Fl-(X)-(Q)-Cl+A-HN-Z-B → Fl-(X)-(Q)-N(A)-Z-B

where X= bond, CH2 or CH=CH, Q=CO or SO2, and A=H, alkyl or OPr where Pr denotes a protecting group), as illustrated in Example 12 (particularly preferred) and in Examples 60, 61, 64 , 67, 68, 72, 87, 88, 93, 98, 116, 129 and 130.

Some compounds can also be prepared by other processes including:

Fl-(X)-COOH + A-NH-Z-B in the presence of a binding agent (e.g. dicyclohexylcarbodiimide, N,N'-carbonyldiimidazole or diethyl cyanophosphonate), optionally in the presence of a reaction promoter (e.g. 4-dimethylaminopyridine or N- hydroxybenzotriazole) in an aprotic or chlorinated solvent (eg, dimethylformamide, chloroform) at -10/140°C (Albertson, Org. React., 12, 205-218, 1962; Doherty et al., J. Med. Chem., 35, 9, 1992; Staab et al., Newer Methods Prep. Org. Chem., 5, 61, 1968; Ishiara, Chem. Pharm. Bull., 39, 3236, 1991); as illustrated in Examples 80, 86, 89, 90, 92, 99 to 111, 113 to 115, 117 to 119 and 128.

Fl-(X)-COOH + A-NH-Z-B without solvent at 150-220°C (Mitchell et al., J. Am. Chem. Soc., 53, 1897, 1931) or in a high-boiling ethereal solvent ( eg diglime);

Fl-(X)-COO-Alk + A-NH-Z-B optionally in the presence of a binding agent (e.g. trimethylaluminum) in an aprotic and/or chlorinated solvent (e.g. hexane, dichloromethane) at -10/80°C, or without solvents at 80-180°C (S.M. Weinreb et al., Tetrahedron, 4171, 1977); M.F. Lipton et al., Org. Synth. 59, 49, 1979);

Fl-(X)-COOH + alkylchloroformate in the presence of a tertiary amine (eg triethylamine) followed by addition of A-NH-Z-B at 0-80°C; if desired, a reaction promoter (eg, 1-hydroxypiperidine) may be added prior to addition of the amine (Albertson, Org. React., 12, 157, 1962).

Process o: Fl-COCl + HS-Z-B → Fl-Y49-Z-B

Process p: Fl-COCl + HO-Z-B → Fl-Y2-Z-B

as illustrated in Example 10 below.

Procedure q: FlCHO +H2NO-Z-B → Fl-Y11-Z-B

as illustrated in Example 70 below.

Procedure r: Fl-CHO + A-HN-Z-B → Fl-CS-N(A)-Z-B

(where A=H or CH3) in the presence of sulfur in an aprotic solvent, eg DMF or pyridine, at 60-120°C (M.Carmack et al., Org. Reaction., 83, 1947; R. Benassi et al., Org. Magn. Res., 15, 25, 1981), as shown in Example 83 below.

Process with: Fl-NH2 + HCO-Z-B → Fl-Y29-Z-B

as shown in Example 34 below.

Process t: Fl-Y-CH3 + HO-CH2-CH2-B → Fl-Y-CH2-CH2-B

as shown in Example 4 below.

Process in: Fl-CH=CH-CONH2 + HOCH2-B → Fl-Y10-CH2-B

Procedure v: Fl-Y-Z-N3 + HCO-CH2-[image] → Fl-Y-Z-B3

with reducing conditions as illustrated in

Example 44 below.

Procedure w: Fl-Y-Z-NH2 + L-(CH2)n- [image] → Fl-Y-Z-B3

as illustrated in Examples 74, 75 and 76.

Fl-Y-Z-NH2 + L-CH2- [image] → Fl-Y-Z-B4

as illustrated in Example 52 below.

Procedure x: Fl-Y-Z-HN2 + [image] → Fl-Y-Z-B

as illustrated in Example 65 below.

Procedure y: Fl-Y-Z-CHO + HB → Fl-Y-Z-B

as shown in Example 53 below.

Those skilled in the art will know that the above synthesis procedures b) to y) can be simplified provided that the reacting intermediates do not carry further groups reactive to the reactants themselves (for example: CO, NH 2 , NHAlk or OH groups). Compounds of formula I bearing reactive groups can be prepared in the ways from b) to y) provided that the reactive groups present in the starting materials are protected and then, after the reaction, the protecting groups are removed, as shown in Example 71. Several examples of protection and deprotection for various reactive groups, can be found in T.W. Green, Protective Groups in Organic Synthesis, Wiley Interscience, 1981, (Second Edition, 1991).

Alternatively, non-reactive groups (eg NO 2 ) can be left during the first reaction and then converted to reactive ones (eg NH 2 ) as the final step of the process. See example procedure a).

Which synthesis technique will be preferred depends on the compound to be synthesized, but in general procedure n) is preferred for all compounds obtained by it. Other synthesis procedures will be apparent to those skilled in the art.

STARTING MATERIALS

Starting materials (Fl-Y-Z-L and Fl-Y-H and others) used in the previously described preparations can be prepared as such from simpler compounds such as Fl-COOH, Fl-CHO, Fl-COCl, Fl-NH2 and Fl-OH using transformation known to experts. Numerous such transformations are described in detail below. Many of these simple compounds are commercially available or their synthesis has been reported in the literature (Fl-COOH, Fl-CHO, Fl-COCl, Fl-NH2 and Fl-OH). Those that are not available can be synthesized according to one or more of the following reaction schemes from 1 to 16.

Reaction scheme 1 leads to compounds in which W represents a carbonyl group and X represents an oxygen atom.

SCHEME 1

[image]

A=CO2CH3, CO2C2H5, NO2, CH=CHCH3,

B=CO2H, NH2

Step 1a

Procedure without isolation of intermediate phenyl ester:

- R3CH2COCl or (R3CH2CO)2O and a Lewis acid (eg AlCl3 or ZnCl2), without solvent or in an aprotic solvent (eg nitrobenzene or chlorinated solvent) at 20-180°C.

Procedure for isolating the intermediate phenyl ester:

- R3CH2COCl or (R3CH2CO)2O is heated with the starting material or using other esterification processes, such as the Schotten-Buman process. The isolated ester is then heated in nitrobenzene or some other non-protic solvent (eg, a chlorinated solvent), or without any solvent, at 20-180°C, in the presence of a Lewis acid such as AlCl3 or ZnCl2 (A.M. Blatt, Org React., 1, 342, 1942).

Step 1b

- R2COCl or (R2CO)2O and R2COONa alone or in a non-protic solvent with a high boiling point (such as o-dichlorobenzene) at 150-220°C; this reaction also enables the direct transformation of compounds (2) into compounds (6), when compounds (2) have A=COOH;

- R2C(OAlk)3 in the presence of HClO4 at 20-40°C or in pridine in the presence of piperidine at 60-80°C;

- R2COCl or (R2CO)2O in a chlorinated solvent at -10 to 120°C in the presence of a base such as 1,8-diazabicycloundecene (DBU).

Step 1c

- R2COCl in pyridine at 20-100°C or in a non-protic solvent at 0-80°C, optionally in the presence of a base such as NEt3 or 4-dimethylaminopyridine.

Step 1d

- K2CO3 in acetone or methyl ethyl ketone at 20-80°C;

- NaH in DMSO or THF at 0-40°C;

- KOH or potassium t-butoxide in pyridine at 20-100°C.

Step 1e

- HCl or H2SO4 in AcOH at reflux or in alcohol (MeOH, EtOH, isopropanol) at 20°C up to the reflux temperature;

- CF3COOH in dichloromethane at 20-40°C;

- p-toluenesulfonic acid in benzene or toluene at reflux.

Step 1f

- R2COCl and K2CO3 or KOH in water and phase transfer catalyst in benzene or toluene at reflux;

- R2COOAlk and lithium bis(trimethylsilyl)amide or lithium diisopropylamide in THF at -78 to 0°C.

Step 1g

When A is a COOCH3 or COOC2H5 group:

- NaOH in aqueous EtOH at 0-75°C;

- LiOH in aqueous DMF, MeOH or THF or their mixture at 10-100°C;

- HCl in a protic solvent such as dioxane at 60-120°C.

When A, NO2:

- Reduction with a Ni-Raney catalyst in a protic solvent (eg isopropanol) or a mixture of protic solvents at 20-100°C;

- Reduction with hydrogen and a catalyst (eg Ni-Raney or Pd/C) in a protic solvent (eg MeOH, EtOH, isopropanol or their mixture) at 20-100°C;

- Reduction with SnCl2 in the presence of aqueous HCl in a protic solvent (eg AcOH) at 20-100C°;

- Reduction in the presence of Fe and aqueous HCl in a protic solvent at 20-100°C.

- When A is a CH=CHCH3 group:

- Oxidation with Na2Cr2O7 or another oxidizing agent such as KMnO4 in acetone/H2SO4 at

0-100°C.

Reaction Scheme 2 leads to compounds in which X represents a sulfur atom or a sulfinyl or sulfonyl group and W represents a carbon group. The starting o-mercaptobenzoates (1) are commercially available or can be prepared by known methods, for example by transformation of the corresponding o-alkoxycarbonylbenzene-nediazonium salts with treatment with potassium ethylxanthate (M.S. Cohen et al. J.Org. Chem., 18, 1394, 1953 ).

SCHEME 2.

[image]

Step 2a

- R2COCH(R3)CN or R2COCH(R3)COOAlk in polyphosphoric acid at 50-120°C;

- R2C≡C-CCOAlk and Al2O3 in an aprotic solvent (eg Et2O) at 0-40°C;

- R2C≡C-COOAlk and alkali in an aprotic solvent (eg THF or DMF) at 20-140°C.

Both of the last possibilities are followed by treatment with polyphosphoric acid at 50-120°C.

Step 2b

- NaOH in aqueous EtOH at 40-75°C;

- LiOH in aqueous DMF at 40-100°C.

Step 2c

- Stoichiometric 30% H2O2 in AcOH at 25-60°C;

- m-chloroperbenzoic acid in chloroform at 0-30°C.

Step 2d

- 30% H2O2 in AcOH at 50-80°C.

Reaction Scheme 3 leads to compounds in which R7 represents a methoxy group, W represents a carbonyl group and X represents an oxygen or sulfur atom. Compounds (1) can be prepared according to Reaction Schemes 1 and 2 starting from the corresponding phenols or thiophenols (which are not substituted in position 2 and 6 with COOAlk or NO2).

SCHEME 3

[image]

Step 3a

- HCHO and gaseous HCl in AcOH containing aqueous HCl (d=1.18) at 50-100°C (P. Da Re et al. Ann Chim., 46 904, 1956).

This procedure can be used when R3 is other than H or CH2OH.

The resulting intermediates 2 can be converted, using known procedures, to starting materials suitable for obtaining the desired compounds according to the invention (see intermediate LX1X).

Simple 2,3-dihydro intermediates (---- = single bond) can be prepared according to Reaction Scheme 4 provided that other groups that may be present (e.g. NH2, OH) are previously protected as described above . Thus obtained Compounds (4) can be converted into the corresponding derivatives having A=COOH or NH2 according to the procedure from Step 1g.

SCHEME 4

[image]

Step 4a

- R2-CHO, aqueous NaOH in EtOH or other protic solvent;

- R2-CHO, NaH or potassium t-butoxide in THF (or other dipolar aprotic solvent) at 0-150°C.

Step 4b

- Mineral acid (e.g. HCl or H2SO4) in water or other protic solvent (e.g. EtOH, AcOH) on

0-100°C.

Step 4c

- R2-CHO, 0.1 N to 1N aqueous NaOH or other suitable alkali in a protic solvent;

- R2-CHO, pyrrolidines in a protic (eg MeOH) or polar aprotic solvent at 0-100°C (H.J. Kabbe, Synthesis, 1978, p.886).

Step 4d

- Lithium diisopropylamide in THF at 0-20°C; then trimethylsilyl chloride and organic alkali (eg NEt3) (S.E, Kelly et al. J. Org. Chem., 56, 1325, 1991).

Step 4e

- R2-CHO in a chlorinated solvent (eg dichloromethane) at -78°C, then TiCl4 or another Lewis acid (S.E.Kelly et al. J. Org. Chem., 56, 1325, 1991).

Step 4f

- Lithium diisopropylamide in THF at -78°C, then R2-CHO (A. Banerij et al., Tetrahedron Letter, 1979, 3685).

Step 4g

- R2-CH=CR3COCl, Lewis acid (eg AlCl3) in a suitable solvent (eg nitrobenzene) or without solvent at 20-180°C.

Step 4h

- R2-CH=CR3COOAlk, triethylbenzylammonium hydroxide in an aprotic solvent (eg benzene) and without solvent at 50-150°C; then aqueous NaOH in MeOH at 20-50°C or LiOH in aqueous DMF. (In this case, compounds having A=COOCH3 or COOC2H5 are also hydrolyzed to compounds having A=COOH).

Step 4i

Concentrated H2SO4 or P2O5 or polyphosphoric acid or Lewis acid in nitrobenzene or toluene or without solvent at 0-180°C. (In this case, the hydrolysis of A=COOAlk to A=COOH also takes place).

Simple starting materials having R3=OH or OR8, where R8 is alkyl or aralkyl, can be prepared according to Reaction Scheme 5 where A has the same meaning as in Reaction Scheme 1. Compounds (1) and (2) (which are the same as (2) and (4) in Reaction Scheme 4, but so that R3=H) can be prepared according to the Reaction Scheme starting from the corresponding phenols and thiophenols having R3= H. Compounds (4) used in Reaction Scheme 5 can be prepared by known methods from the corresponding salicylates or thiosalicylates (see J. March, Advanced Organic Chemistry, 486, John Wiley and Sons, New York, 1985; L. René et al., Eur. J. Med. Chem.-Chim. Ter., 4, 385, 1977 and references therein). Substituent A in compounds (3) and (6) of Reaction Scheme 5 can be transformed by the process of Step 1g into substituent B as defined in Reaction Scheme 1.

SCHEME 5

[image]

Step 5a

- Aqueous NaOH in an alcoholic solvent (eg MeOH or EtOH) followed by 30% H2O2 at -10 to -78°C. (N.D. Meyer et al., J. Med, Chem., 34, 736, 1991 and references therein).(Not when A is CH=CH-CH3; when A=COOR, it is simultaneously converted to COOH).

Step 5b

When ---- - single connection:

- Amyl nitrate or another alkyl nitrate without solvent or in a suitable solvent (eg EtOH or benzene) in the presence of a catalyst such as 37% HCl (Org. React., 7, 327, 1953 and references therein); and then aqueous H2SO4 in a protic solvent (eg AcOH) at 10-100°C (Acheson R.M., An Introduction to the Chemistry of Heterocyclic Compounds, 347, John Wiley and Sons New York, 19'76).

When ---- - double bond:

- lithium diisopropylamide in dry THF at –78°C; and then AcOH and 30% H2O2 (B.D.M. Cunningham et al., Anti-cancer Drug Design, 7, 365, 1992).

Step 5c

- R2-CH=CH-NO2 (1 to 1.5 equivalent) in a suitable solvent (e.g. diisobutyl ether, DMSO or DMF) in the presence of alkali (e.g. KOH or NaOH) in catalytic or stoichiometric quantity at 20-150°C (see L. René, supra, and T. Sakakibara et al., Bull. Chem. Soc. Jpn., 51, 3059, 1978).

Step 5d

- 15% H2O2, NaOH or some other alkali (eg NEt3) in a protic solvent such as MeOH at 20-100°C (S.R. Deshpande et al., Synthesis, 835, 1983) or photolysis and alkaline hydrolysis (Rao T.S. and al., Heterocycles, 22, 1377, 1984) or KO2 in benzene containing 18-crown-6 ether at 20-100°C (Rao T.S., Heterocycles, 26, 2117, 1987). (Not when A is CH=CH-CH3; when A=COOR, it is simultaneously converted to COOH).

Step 5e

- R8L, where L represents a leaving group (e.g. alkylsulfate, halogen, tosyl) and a base (e.g. K2CO3, NaH, KOH, NaOE or LiOH) in a suitable solvent (e.g. THF, DMSO, DMF, benzene) in the presence of phase transfer catalyst (eg benzyltriethylammonium bromide) at 0-180°C.

Step 5f

- By the procedures of Step 1b.

Reaction Scheme 6, in which A has the same meaning as in Reaction Scheme 1, leads to compounds in which W represents a thiocarbonyl group. Compounds (1) and (2) of Reaction Scheme 6 can be prepared according to Reaction Schemes 1, 2, 4 and 5. Substituent A in compound (4) of Reaction Scheme 6 can be transformed by the process of Step 1g into Substituent B as determined in reaction Scheme 1.

SCHEME 6

[image]

Step 6a

- P2S5 in pyridine at 50-100°C (Stavaux et al., Bull. Soc. Chim. Fr., 2082, 1967).

Step 6b

- P2S5 or B2S3 or SiS2 or Lawesson's reagent in a chlorinated solvent (eg chloroform) or in an aromatic solvent (eg benzene, toluene, xylene) at reflux (Dean et al., J. Chem. Soc. C, 2192, 1963; R. K. Razdan et al., J. Med. Chem., 2l, 643, 1978; K. Clausen et al., Tetrahedron, 37, 3635, 1991).

Step 6c

- COCl2 without solvent or with an inert solvent (eg benzene) at 40-90°C (A. Schonberg et al., Chem. Ber., 101, 701, 1968).

Step 6d

- -Thioacetic or thiobenzoic acid or potassium diethylxanthogenate in a suitable solvent (eg benzene) at reflux (A.Schonberg, supra).

Reaction Scheme 7, in which A has the same meaning as in Reaction Scheme 1, leads to compounds in which W represents a methylene or hydroxymethylene group. Compounds (1), (2) and (4) of Reaction Scheme 7 can be prepared according to Reaction Schemes 1, 2, 5 and 6. Substituent A in compounds (7) of Reaction Scheme 7 can be transformed by the procedures of Step 1g into substituent B as which is determined in Reaction Scheme 1.

SCHEME 7

[image]

Step 7a

- 1,2-ethanedithiol or 1,3-propanedithiol in an aprotic solvent (eg dichloromethane or benzene or toluene) at 110°C in the presence of a catalyst (eg p-toluenesulfonic acid or boron trifluoride etherate).

Step 7b

- R2COCH2R3 in a suitable solvent mixture (eg EtOAc or dichloromethane plus EtOH or MeOH) saturated with gaseous HCl at 0-40°C; then aqueous HClO4 in AcOH at 20-100°C (L.Jurd, Tetrahedron, 28, 493, 1972).

Step 7c

- LiAlH4 in THF at reflux (if A is different from COOR and NO2);

- ZnI2 and sodium cyanoborohydride (6 equivalents) in a chlorinated solvent (eg 1,2-dichloroethane) at room temperature to reflux (C.K. Lau et al., J.Org. Chem., 51, 3083, 1986).

Step 7d

- Raney-Ni in an alcoholic solvent (eg isopropanol) at room temperature to reflux (Hilton et al., J.Am. Chem. Soc. 90, 6887, 1968).

Step 7e

- NaBH4 in a suitable solvent (eg MeOH or EtOH or DMSO) at -10 to 50°C (Z. Jurd, supra);

- LiAlH4 in THF (or some other suitable solvent) at 0-50°C (when A is different from COOR or NO2) (Degani et al., Ann.Chim. 61, 793, 1971; Kurosawa, Bull.Chem.Soc : Jpn., 51, 1175, 1978).

Step 7f

- Tertyl perchlorate in acetonitrile at room temperature (Degani et al., supra).

Step 7g

- Melting with P2O5 at 80-180°C (Hortmann et al., J.Am. Chem. Soc., 96, 6118, 1974).

Step 7h

- NaBH4 in EtOH or other suitable solvent at 0°C to reflux (K. Anaya, Bull. Chem. Soc. Jpn., 40, 1884, 1967).

- Hydrogen (1-10 atm) in EtOH (or other suitable solvent) in the presence of a catalyst such as 5% or 10% Pd/C or Raney-Ni or PtO2 at room temperature up to 80°C (K. Hanaya, supra) .

- Not when A is CH=CH3. When A=N02, it is simultaneously reduced to NH2.

- Aluminum triisopropoxide in isopropanol at room temperature up to 92°C.

Reaction Scheme 8 shows the preparation of simple starting materials such as (4), (5), (6) and (9), where A is the same as in Reaction Scheme 1. Compounds (1), (2), (3), (7), (8) can be prepared according to Reaction Scheme 1, 2, 4, 5, 7, 9, 11. Substituent A in compounds (4), (5), (6) and (9) of Reaction Scheme 8 can be transformed by the procedure of Step 1g into substituent B as determined in Reaction Scheme 1.

SCHEME 8

[image]

Step 8a

- Pb(OAc)4 in a suitable solvent (eg benzene, toluene) at reflux (G.A. Russell et al., J. Am. Chem. Soc., 1906, 1975).

Step 8b

- NaBH4 in alcohols (see Reaction Scheme 7, step 7a), then alkaline hydrolysis (when A=COOR, it is simultaneously converted to COOH);

- aluminum isopropoxide as described in reaction Scheme 7, step 7f;

- diborane in THF at -10°C to room temperature; then aqueous H2O2 in the presence of NaOH (not when A is CH=CH-CH3; when A=COOR, it is simultaneously converted to COOH). (Kirkia-charian et al., C.R.HEbd. Sessions Acad. Sci. C, 289, 227, 1979);

- LiAlH4 and AlCl3 in a suitable solvent (eg THF) at 0°C to reflux (not for A=COOR or NO2) (Bokadia et al., J. Chem. Soc., 4663, 1961).

Step 8c

- Hydrogen (100 atm), copper chromite in EtOH at 140°C., see M. A. Vickars, Tetrahedron, 20, 2873, 1964. When A=NO2, it is simultaneously converted to the NH2 group.

Step 8d

- KMnO4 in t-butanol (or other suitable solvent) in the presence of aqueous NaOH at -10 to 0°C. (K. Hanaya, Bull. Chem. Soc. Jpn., 40, 1884, 1967). (Not when A is CH=CH-CH3). (See also A.H. Haines, Methods for Oxidation of Organic Compounds Academic Press Inc, (London), 1985, paragraph 3.2.2).

- Osmium tetroxide (see A. H. Haines, supra, paragraph 3.2.1) in a suitable solvent (eg Et2O) at room temperature (Baraton et al., Bull. Soc. Chim. Fr., 4203, 1968) (not when A CH=CH-CH3);

- aqueous H2O2 in formic or acetic acid at -20 to -50°C;

- then NaOH, H2O, 45°C (Baraton et al., supra; A. H, Haines, supra; paragraph 3.2.7) (not when CH=CH-CH3; when A=COOR, simultaneously translates into COOH);

- silver acetate and iodine in moist AcOH at 0-20°C (K. Hanaya, supra; A. H. Haines, supra, paragraphs 3.2.3, 3.2.4, 3.2.9) (Not when A is CH=CH-CH3) .

Step 8e

- 30% H2O2 in the presence of NaHCO3 in benzonitrile at 0-110°C, then LiAlH4 in THF at 0-40°C (not for A=COOR and CH=CH-CH3) (Clark et al., Austr. Journ. of Chem., 27, 865, 1974).

Step 8f

- Hydrogen (1-50 atm) in a suitable solvent (eg EtOH) in the presence of a metal catalyst (eg PdCl2) at room temperature up to 78°C. (when A=NO2, it is simultaneously translated into NH2). (Bolger et al., Tetrahedron, 23, 341, 1967).

Step 8g

- see step 8b (Clark et al., supra).

Step 8h

- 0.4M cerium tsichloride heptahydrate in MEOH, in a suitable solvent (eg MEOH); then NaBH4 at 0° to 78°C. (WO 89/06650);

- NaBH4 in diglyme at 0°C until reflux (G. P. Thakar, Indian J. Chem., 3, 74, 1965) (when A=NO2, it is simultaneously converted to NH2);

- NaBH4 and AlCl3 in a suitable solvent (eg THF or benzene) at 0°C to reflux (not when A=COOR) (G.P. Thakar, supra);

- diboranes in THf at room temperature (not when A is CH=CH-CH3) (G.P. Thakar, supra).

Simple starting materials having W=CH2 and a single bond at position 2, 3 can be prepared according to Reaction Scheme 9 where A has the same meaning as in Reaction Scheme 1. Compounds (1) in Reaction Scheme 9 can be prepared according to Reaction Scheme 6. Compounds (1) in Reaction Scheme 9 can alternatively be obtained from compounds (2), by conversion to 4-toluenesulfonic ester or methanesulfonic ester and to a halogen derivative, which can be transformed into thioether derivatives (1) by nucleophilic substitution with a thiol. These simple conversions can be performed using techniques known to those skilled in the art. Compounds (2) in Reaction Scheme 9 can be prepared according to Reaction Scheme 7, Compounds (3) of Reaction Scheme 9, where P=OC(S)-aryl or OC(S)-heteroaryl or OC(S)O-alkyl or OC(S)O-aryl or OC(S)S-alkyl can be obtained by reacting compounds (2) with the corresponding chlorothioformate or chlorothiocarbonate or 1,1-thiocarbonyldiimidazole as described in J.Org.Chem., 55, 924, 1990 and Synthesis, 362, 1991 and references therein. Compounds (4) can be obtained from compounds (1) or (3) by simple elimination reactions with alkalis. Compounds (5) can be obtained according to Reaction Scheme 4. Substituent A in compounds (6) in Reaction Scheme 9 can be transformed by the procedure of Step 1g to Substituent B as determined in Reaction Scheme 1.

SCHEME 9

[image]

Step 9a

- Raney-Ni in a suitable solvent (eg isopropanol) at room temperature up to 100°C. When A is NO2, it is simultaneously converted to NH2;

- triethyltin hydride in benzene or other aromatic solvent at 30-150°C. For other methods such as nickel chloride and NaBH4 in MeOH or the borane-pyridine complex in trifluoroacetic acid or in dichloromethane in the presence of AlCl3, see J. March, Advanced Organic Chemistry, p. 728, J. Wiley and Sons, New York, 1992 and references therein. (not when A is CH=CH-CH3).

Step 9b

- Hydrogen with catalyst according to Reaction Scheme 8, step 8f.

When A is NO2, it is simultaneously converted to NH2.

Step 9c

- When P is an O-C derivative:

- tributylin hydride or tris(trimethylsilyl)silane in the presence of azaisobutyronitrile in a suitable solvent (eg toluene) at 80-150°C; (M. Drescher, Synthesis, 362, 1991; M. Sekine, J. Org. Chem., 55, 924, 1990);

- silane (eg triethylsilane or diphenylsilane) in a suitable solvent (eg dichloromethane) at -20°C to reflux in the presence of CF3COOH or BF3 (F.M. Mauser, J.Org. Chem., 55, 555, 1990);

- triethylchlorosilane, sodium iodide in acetonitrile; then Zn powder in AcOH and acetonitrile at room temperature up to 80°C (T. Morita et al., Synthesis, 32, 1981).

- When P is a halogen or an O-S derivative:

- a reducing agent (eg sodium cyanoborohydride in hexamethylphosphotriamides or NaBH 4 in DMSO) selected from those shown in J. March, Advanc. Org.Chem:, J. Wiley, New York, 1992, pp. 0-76, 0-77.

Step 9d

- Hydrogen (1-5 atm in a suitable solvent (e.g. EtOB) in the presence of a catalyst (e.g. 10% Pd/C at 50-78°C) (Sarcevic, Helv. Chim. Acta, 56, 1457, 1973). When A=NO2, it is simultaneously translated into NH2);

- Zn and gaseous HCl in Et2O, or Ac2O in toluene at 0-80°C. (Todan, Bull. Chem. Soc. Jpn., 45, 264, 1972) (not for A=NO2).

- Zn and gaseous HCl in a suitable solvent (eg EtOH) at 0-78°C;

- according to the previous step 9d (when A=NO2, it is simultaneously translated into NH2);

- hydrazine, NaOH in ethane-1,2-diol at 200°C (Chemical Abstracts, 74, (1971):22699) (not for A=COOR, NO2) or other methods from J. March, supra (not for A =COOR, NO2);

- according to Step 7c (not for A=NO2).

Reaction Scheme 10 shows the pathways to compounds where W represents a valence bond and X represents an oxygen atom or a sulfur atom:

SCHEME 10

[image]

Step 10a

- according to Step 1a, but using R3COCl or (R3CO)2O instead of R3CH2COCl or (R3CH2CO)2O, with or without isolation of the phenyl ester intermediate;

- hexamethylenetetramine in CF3COOH at reflux, followed by the addition of aqueous HCl. If A=COOAlk, it can be hydrolyzed to COOH under strongly acidic conditions, and thus requires re-esterification with an appropriate alcohol (eg, using thionyl chloride at reflux temperature) prior to Step 10c.

Step 10b

- R3COCH(R2)Hal in acetone or methyl ethyl ketone or dichloromethane or chloroform in the presence of a suitable alkali such as K2CO3, NEt3 or NaH, at 20-80°C.

Step 10c

- R2CH(HAL)COOAlk in an aprotic solvent, eg DMF, in the presence of a base, eg K2CO3, at '70-100°C, followed by hydrolysis of the crude intermediates with a strong base (eg KOH) in a protic solvent such as EtOH at reflux, and finally subjected to decarboxylation-dehydration conditions using a non-protic solvent (eg xylene) and an acid catalyst (eg p-toluenesulfonic acid) at reflux or simply by heating to 240°C in quinoline;

- R2CH2Hal and KOH in refluxing EtOH followed by cyclization of the isolated phenyl(thio)ether intermediate with sodium methoxide in boiling DMF/MeOH mixture. When A is COOAlk intermediates (4) having A=COOH are obtained.

Using ArCOCH2Br and K2CO3 in acetone at reflux, Compounds (4) are obtained with R2=ArCO.

Step 10d

- Vigorous mixing in preheated polyphosphoric acid at 90-140°C;

- Lewis acid (eg AlCl3) in chlorobenzene at 70-90°C. Cyclization is carried out on Compounds (3) having R3=Cl with a Lewis acid (eg AlCl3) in o-dichlorobenzene at 45°C or with BF3 in Et2O at 20-25°C to give compounds (4) where R3 is =OH, as shown by K. Davies, J. Chem. Soc.P.T.2624, 1957, for compounds having X=S and R 2 =H.

Step 10e

- sodium alcoholate (1 equivalent) in the same alcohol at 0-90°C; when A=COOAlk, the corresponding AlKOH may be conveniently used as the reaction solvent;

- When R2=COOAlk and X=S, Compounds (4) can be hydrolyzed to the corresponding R2=COOH with sulfuric-acetic acid mixture, (if A=COOAlk is present, it can also give A=COOH), and can selectively decarboxylate with copper in quinoline anhydride at 210-220°C to give Compounds (4) where R2=H according to J. Cooper et al., J. Chem. Soc. (C) 1971, 3405.

Step 10f

- R2CH2XH and one equivalent of sodium in EtOH at reflux or with NaHCO3 in EtOH:water at 60-90°C.

Step 10g

- When A=COOAlk or NO2, the procedures described in Step 1g can be used. It must be emphasized that the reduction of the NO2 group to the NH2 group, by catalytic hydrogenation, may simultaneously allow hydrogenation of the double bond at the 2-3 position, as described by S.L. Meisel et al., Heterocyclic Compounds, Ed. Interscience Publ.: "Compounds With Condensed Thiophene Rings", p. 34, (1954) and M. Ahmed, ibidem, Ed. Wiley-interscience: "Benzofurans", p. 56, (1974),

When A=NO2 and R2=COAr, the reduction is carried out with hydrogen in the presence of Pt on carbon as a catalyst, giving 2,3-dihydro compounds (5) where B=NH2 and R2=CH2Ar as shown in WO 86/ 07056;

when A=CH3 and R2, R3, R6 are not CH3 or R2 does not carry a CH3 group, the compounds must be translated into the corresponding:

A=CH2Br, by reaction with N-bromosuccimide in CCl and 2,2'-azobisiso-butyronitrile or benzoyl peroxide as a catalyst at reflux; A=CHO by reaction of the above compound with hexamethylenetetramine in refluxing chloroform, followed by acid hydrolysis of the salt in boiling AcOH or by reaction of compounds having A=CH3 with tetrabutylammonium dichromate in refluxing chloroform according to Valetta et al., Arzneim. Forsch., 40, 122 (1990);

A=COOH by oxidation of the above compounds (A=CHO) with silver oxide in a mixture of protic aqueous solvents (e.g. EtOH-DMF at 0-70°C according to H.R. Rodriguez et al. Tetrahedron 24, 6587 (1968) or with KMnO4 in t- butanol in the presence of NaH2PO4 aqueous solution at 70-75°C according to S. Maruz et al., Tetrahedron Letters 27, 4573 (1986).Compounds (4) of the above reaction scheme 10 having R3=C6H5 or t-butyl, R2=H and X=O, can be transformed into the corresponding intermediates having R2=C6H5 or t-butyl and R3=H by reaction with polyphosphoric acid at 132°C according to Davies et al., J. Chem. Soc., 1958, 822.

When X represents a nitrogen atom and W has the other required meanings except the valence bond, simple starting materials can be prepared according to the following Reaction Scheme 11:

SCHEME 11

[image]

Step 11a

- EtOC(R2)=C(COOEt)2 at 80-140°C without solvent or in a polar solvent (eg isopropanol).

Step 11b

- R2COC(R3)COOAlk and p-toluenesulfonic acid or methanesulfonic acid in a chlorinated solvent (eg chloroform or dichloromethane) or in an aprotic solvent (eg benzene) at reflux under azeotropic conditions.

Step 11c

- heating in Ph2O in the presence of p-toluenesulfonic acid or phosphoric acid or ZnO as a catalyst at 245-255°C according to Hung. Teljes 6251 (Chemical Abstracts, 79, 92026, 1973);

- heating in a high-boiling solvent (e.g. Ph2O), followed by hydrolysis of non-isolated Compounds (4) (R3=COOEt) with a strong acid (e.g. HCl) in a protic solvent (e.g. acetic acid at reflux) to give Compound (4) where R3=COOH.

Previously isolated acids can be decarboxylated by heating in a high-boiling solvent (eg, Ph 2 O) to give Compounds (4) where R 3 =H according to R. Albrecht et al., Ber. 105, 3118 (1972);

Step 11d

- heating in a high-boiling solvent (eg Ph2O) to 255°C;

- when R=Alk, Compounds (4) are obtained directly from Compounds (1), without isolation of Compounds (3), by condensation with R2COCH(R3)-COOAlk in polyphosphoric acid at 90-150°C, according to F. Piozza and co., Gazz. Chem. It., 100, 678, 1970.

Step 11e

- Al/Hg amalgam in EtOH aqueous solution at reflux, followed by acidification with a strong acid (eg HCl) and treatment with FeCl3 at reflux according to W. A. Denny et al., J. Med. Chem., 32, 396, 1989.

- When A=COOAlk, Compounds (4) must be hydrolyzed to the corresponding A=COOH, before proceeding to Step 11e.

- When A=NO2, intermediates (5) are obtained which have A=NH2.

Step 11f

- R2CH=CHCHO and arsenic acid in a strongly acidic medium (-eg concentrated H2SO4) and water at 105-115°C according to EP 0206802.

- When A=COO is Alk, Compounds (4) must be hydrolyzed to the corresponding A=COOH before proceeding to Step 11f. All compounds (1) have R=H and the resulting Compounds (5) have R3=H.

Step 11g

- R2CH(Hal)-CH(R3)COOH in a protic solvent (e.g. water) in the presence of a strong alkali such as NaOH at 10C-125°C, followed by cyclization of the isolated compounds of anilinopropionic acids with preheated polyphosphoric acid at 120 -125°C or with phosphorus pentoxide in a high-boiling aprotic solvent (eg xylene) at 120-140°C. In some cases, it is useful to start with Compound (1), where R=tosyl or some other suitable protecting group, and the resulting Compounds (6), where R=tosyl, can be easily translated into Compounds (6), where R= H by hydrolysis with a strong acid (eg HC1) in a protic o-solvent (eg AcOH) at reflux.

When A=COO is Alk, compounds are obtained that have A=COOH.

Step 11h

- R2CHO and ethylene in AcOH and HCl at 25-30°C according to K.D. Hesse, Liebigs Ann. Chem. 741, 117 (1970). When Compounds (1) have R=H in starting materials (7), compounds R=R3,=H are obtained.

- Epichlorohydrin, followed by cyclization of isolated anilinopropanol derivatives in refluxing N,N-diethylaniline or o-dichlorobenzene in the presence of a proton acceptor (eg NEt,) according to S.D. Boyd et al., J. Org. Chem. 30, 2801 (1965). In this case, Compounds (7) are obtained which have R=R2=H and R5=0H.

Step 11i

- by hydrogenation in the presence of a catalyst (eg platinum oxide) in a protic solvent (eg EtOH) at 20-30°C and 2-4 atm according to G. M. Coppola, J. Eeter. Chem. 15, 645, 1978. When A=NO2, Compounds (7) with A=NH2 are obtained. Thus obtained Compounds (4), (6) and (7) can be converted into the corresponding derivatives having A=COOH or NH2, according to the procedures of Reaction Scheme 1, Step 1g.

The synthesis of simple Compounds (7) of Reaction Scheme 11 having R=H and A=COOH can also be carried out using the procedures shown in Reaction Scheme 12:

SCHEME 12

[image]

W = CH2 or bond

W=CH2 or bond

Step 12 a

- oxalyl chloride in a polar solvent (e.g. THB1) at reflux, followed by an internal Friedel-Craft acyclization of the crude chlorooxalylamide with a Lewis acid (e.g. AlCl3) in a non-polar solvent (e.g. CS2) at reflux, according to EP 0402859}

Step 12b

- 30-35° aqueous H2O2 and a strong alkali (e.g. NaOH) in a polar solvent (e.g. water) at 20-30°C followed by the addition of a strong acid (e.g. HCl), as reported in EP 0402859.

Reaction Schemes 13 and 14 lead to simple starting materials in which X represents an imino group and W represents a valence bond. In these two Reaction Schemes, A has the same meaning as in Reaction Scheme 1.

SCHEME 13

[image]

Step 13a

- ClCH2C(Cl)=CH2 in the presence of K2CO5 at 40-80°C according to L. Purdie, J. Chem. Soc. (C) 1970, 1126.

Step 15b

- R2CO Hal in pyridine or in a chlorinated solvent (e.g. dichloromethane) in the presence of a proton acceptor (e.g. NEt,) at 20-100°C or in a polar solvent (e.g. acetone) in the presence of K2CO3u at 20-80°C .

Step 13c

- BF3, in MeOH at 130-155°C

- heating to 100 to 110°C.

Compounds (5) obtained by Step 13c always have R2=CH-

Step 13d

- R2COCH(O Alk)2 in a non-polar solvent (e.g. toluene) in the presence of iodine as a catalyst at reflux under azeotropic conditions followed by reduction of isolated (or non-isolated) imino compounds with NaBH4 in a polar solvent (e.g. MeOH) in the presence of NaOH as a catalyst at reflux. If A=COO is Alk, it will be nidrolyzed to COOH.

Step 13e

- sodium amides in a high-boiling solvent (eg N,N-diethylaniline) at 220-250°C according to F. Piozzi et al. , Gazz. Chim.lt., 93, 1382, 1963.

- potassium t-butoxide in a polar solvent (eg DMF) at 20-100°C according to EP 0042298

Step 13f

- BF3, in an apolar solvent (eg benzene) at 5 to 10°C,

Step 13g

- Zn or Fe powder in an acid medium (eg AcOH) and water at 70-100°C. If A=NO2, it will be reduced to NH2

Step 13h

- thionyl chloride at reflux. The resulting acyl chlorides are isolated, reacted with sodium azide in an acidic medium (eg AcOH) at 10-20°C, later heated to 50-70°C.

Step 13i

- diazotization with NaNO2 in concentrated H2SO4, followed by the addition of aqueous ZnCl2 at 5-10°C and the reaction of isolated diazonium salts with CH2=C(R2)COOH in a polar solvent (e.g. acetone) in the presence of a copper salt (e.g. CuCl2) at 25-30°C. Examples of steps 13g 13h and 13i are presented by A. Allais et al., Eur. J. Med. Chem., 10, 187, 1975.

Step 13j

- R2CH2NO2 in a polar solvent (eg EtOH) in the presence of a base (eg n-butylamine) and a catalytic amount of acid (eg AcOH) at reflux.

Compounds (5) thus obtained can be converted into the corresponding derivatives having A=COOE or NH2 according to the procedures of Reaction Scheme 1 step lg.

Referring to Reaction Scheme 14, Compounds (4) having R3=H correspond to Compounds (5) of Reaction Scheme 13.

SCHEME 14

[image]

R= Alkyl

Step 14a

- NaNO2 in an aqueous acidic medium (e.g. HCl) at -5 to +5 C

- isoamyl nitrite in a polar solvent (eg EtOH) at 5-10°C

Step 14b

- aqueous solution of SO2 at 0-10°C, press Pfannstiel et al., Ber. 75,1096, 1942;

- triphenylphosphine and heating the isolated phosphonium salt in an aqueous-alcoholic HCl solution at reflux according to Horner et al., Ber. 85, 1073, 1953.

Step 14c

- R2COCH(R3)Hal in alkaline solvent: high boiling point (e.g. N,N-diethylaniline) at 160-180°C or simply by heating without solvent at 180°C

- R3COCHC(R2)Hal in a polar solvent (e.g. acetone) in the presence of a suitable proton acceptor (e.g. K2CO3) at reflux, followed by cyclization of the isolated α -anilinoketone intermediates with freshly melted ZnCl2 in a protic solvent (e.g. EtCH) at reflux ;

- R2CH(Hal)CN in the presence of BCl3, and a Lewis acid (e.g. TiCl4) in an apolar solvent (e.g. benzene) at reflux, followed by cyclization of the isolated 2-amino-á-haloacetophenone Compounds with a suitable reducing agent (e.g. .NaBH4) in a polar medium (eg dioxane-water) at reflux, according to T. Sagusawa et al. J. Crg. Chem., 44, 5?8, 1979. Compounds (4) with R3=H are obtained by the previous method;

Step 14d

- R2COCH2R3, by heating at 100°C without solvent or at reflux in a polar solvent (e.g. KeGH), followed by cyclization of the isolated hydrazone Compounds with polyphosphoric acid at 100-130°C or simply by heating in ethyleneglycol or aqueous formic acid or ethanolic formic acid acid.

- Cyclization can also be carried out by heating ethanolic HCL at reflux or in an AcOH/HCl mixture at reflux or in orthophosphoric acid at 95-105°C or simply by heating with anhydride ZnClp at 100-220°C. When A=COO is Alk, Compounds (4-) are obtained which have A=COOH.

Step 14e

- borane-pyridine complex at 0-300C, followed by the addition of a proton agent (eg HC1);

- tin or zinc and aqueous HCl at 50-100°C;

- Na3BH4 in the presence of a Lewis acid (eg AlCl3) in pvridine at 0-30°C or alternatively in the presence of salts such as cobalt or zinc chloride;

- sodium borocyanohydride in AcOH at 20-80°C;

- hydrogen in the presence of a catalyst (eg Pt) in a polar solvent Cnpr. EtOH) at 20-80°C.

Other general methods are presented by Zoulihan in Heterocyclic Compounds, Part I, Ed. Wiley-Interscience: "Indoles", p. 462 (1972). When A=NO2, Compounds (4) can be reduced to the corresponding Compounds (5) having A=NH2

Step 14f

- NaH and RHal in an anhydride polar solvent (eg DMF) at 20-80°C and

- RHal in the presence of potassium carbonate in a polar solvent (eg acetone) at reflux;

- sodium amide and RHal in a polar anhydride solvent (eg THF) at a low temperature (-70°C).

Compounds (4), which carry other reactive groups such as NH2 or CH, must be protected using suitable protecting groups that can be selectively removed at the end of the process;

Step 14

-RHal in the presence of alkali metal carbonates (eg potassium carbonate) as shown by Houlihan in Heterocyclic Compounds, Part Two, Ed. Wiley-Interscience: "Indoles", p. 90 (1972) and references therein.

- Compounds (5), which carry other reactive groups such as NH2 or OH, must be protected as previously stated;

Step 14h

- tetrachloro-/1,4-/-benzoquinone in a polar solvent (eg ethylene glycol monomethyl ether) at reflux;

- copper (II) chloride in pyridine at reflux according to Kikugawa et al. J. Heather. Chem., 16, 1325, 19^9.

Compounds (6) having R2 and R3 other than H can be reduced to the corresponding starting materials (7) using lithium aluminum hydride according to H.C. Printy et al., J. Am. Chem. Soc. 71, 3205, 194-9.

Compounds (4) of Reaction Scheme 14 having R2=OH and R3,=OH can be obtained from Compounds (7) of Reaction Scheme 11 having R=R2=H and R3=OH by ring closure using an oxidant (e.g. sodium periodate) and alkali (e.g. NaOH) in aqueous EtOH at reflux according to S.D. Boyd et al., Org. Chem., 30, 2801, 1965.

Starting materials (4), (5), (6) and (7) can be converted into the corresponding A=COOH or NH2, according to the methods of Reaction Scheme 1, step 1g, and from these into alternative final products. When NH is present and can interfere in the following reactions, it can be shielded as shown from I,W. Green in Protective Gro-ups in Organic Synthesis, Wiley Interscience, 1981. Alternatively, non-reactive groups (eg NOp) can be converted to reactive ones (eg NH2) as a final step in the process. Starting materials in which W represents a valence bond, X represents an imino group and the 7-substituent is a carboxymethyl group can be obtained according to Reaction Scheme 15.

SCHEME 15

[image]

Step 15a

-Hydrogen in the presence of 10% Pd/C as a catalyst at 451bs in water containing one equivalent of NaOH, followed by diazotization with sodium nitrite in HCl at 0-5°C and stannous chloride. Cyclization is carried out during acidification of the tin salt with H2S and is completed by refluxing in xylene, see H.E.Baumgarten et al., T. Am. Chem. Soc, 82, 3977, 1960.

Step 15b

- R3CH2COR2 in the presence of an acid (eg acetic acid) in a polar solvent (eg EtOH) at reflux as shown by w.J.VWelstead et al., J.Hed. Chem., 22, 1C74- (1979) for R2=CH3, and R3=C6BH5 where step 15c and 15d are also shown;

Step 15c

- lower alcohol (eg MeOH, EtOE) at reflux in the presence of a current of hydrogen chloride

Step 15d

- strong alkali (eg KOH) in a polar solvent (eg water) at reflux.

The preparation of simple starting materials that have R3=hydroxy-alkyl and/or corresponding ethers can be carried out by reacting either Compounds (3) Reaction Scheme 1, Compounds (2), (4) or (5) Reaction Scheme 2, Compounds (4) of Reaction Schemes 5,10,11 and 15, Compounds (5) of Reaction Scheme 13 and Compounds (4) and (5) of Reaction Scheme 14 which have R3=H CH3 according to Reaction Scheme 16, where A and B have the same meanings as in Reaction Scheme 1 and R5Hr represents H or an alkyl group, and R4 represents an alkyl or aralkyl group:

SCHEME 16

[image]

R4=Alk, Aralk

R5 = H, Alk

Step 16a

R3=H, W=CO, CS (and no activated phenyl ring is present):

- Formaldehyde and HCl in water, EtOH or AcOH at 50-100°C,

- Chloromethyl methyl ether and fuming sulfuric acid at 50-70°C (H. Nakarumo et al., Buli. Chem. Soc. Jap,, 57, 2323, 1984),

R3=CH3, W=CO, CS, bond, and there are no other methyl groups in the molecule:

- N-bromosuccinimide in the presence of benzoyl peroxide or 2,2-azo-bisisobutyronitrile in CCl4 at 50-80°C

Step 16b

R3=H, W=bond, X=O, S, NH or N-Alk and no electron donating groups or other rings in the molecule:

- Phosphorus oxychloride and DMF at 50-140°C, or some other Vilsmeyer-Haack reagent (see Jutz, Adv. Ore. Chem., 9, 225, 1976);

R3=CH,, W=bond, X=O, S, NH or N-Alk and no other CIL, groups:

- Irradiation with a Hg high-pressure lamp in a protic solvent (eg, AcOE) at 20-100°C as shown by Frasco et al. Tetrahedron, 23, 603, 1973.

Step 16c

- Sodium or potassium acetate in an aprotic solvent (eg acetone, DMF) at 40-120°C.

Step 16d

R5 in Compounds (5) =H:

- Reducing hydride (eg NaBH4) in a polar solvent (eg MeOH or EtOE or dioxane) at 0-80°C

R5 in Compounds (5) =alkyl:

- Alkyl magnesium bromides in aprotic solvents (eg Et2O, THF) at 0-60°C

Step 16e

- NaOH or LiOH in protic solvents (eg alcohols, water) or their mixture at 25-50°C. (In the case when A=COO is Alk, it is simultaneously hydrolyzed to COOH)

Step 16f

- The same procedures as described in step 1g of Reaction Scheme 1, but with the oxidation of CH=CHCH3, to COOH for compounds (5)

Step 16

- Strong alkali (e.g. NaE) and R4-L reagent (where L is a halogen atom or a tosyloxy group) in anhydride aprotic solvents (e.g. DMF or THF) at 20-14C°C

Step 16h

-R4OH and alkali (eg Na, NaH) in excess R4OH or in aprotic solvents (eg DMF or THF) at 20-140°C.

Simple Compounds (5) having a hydroxyalkyl group at position 3 obtained in this way can react as such or, alternatively, be derivatized on the hydroxymethyl group using known reagents and procedures, so that said group does not interfere in the following reactions necessary to prepare such compounds of formula (I) bearing protected hydroxyalkyl groups such as R3. The protected final products are finally translated by deprotection procedures to compounds of formula (I) having R3=hydroxyalkyl group.

Prodrugs, as previously defined, can be prepared from the corresponding hydroxy compounds by Method 1, below, or from the corresponding amido compounds by Method 2, described below.

Method 1

- by reaction with chloroform, isocyanate or isothiocyanate, carbonyl chloride or bromide or some other activated acid derivative (e.g. anhydride) in a suitable solvent (e.g. chlorinated solvent, DMF, TEF, diosane, acetonitrile, pyridine) in the presence or absence of alkali (e.g. NEt,, pyridine, 4-di-methylaminopyridine, NaOH, potassium carbonate or 1,10-diazabicyclo-undecene or some others) at -20/100°C

- by reaction with carboxylic acid in the same solvents as before, in the presence of a condensing agent such as N,N-carbonyldiimidazoles, carbodiimides or some others known to experts

- by reaction with dialkyl or diaryl chlorophosphate or dialkyl cyanophosphate under the same conditions described above (for example, see the procedures of Example 114- hereinafter and S.O. Thorberg et al., J. Med. Chem., 30, 2008, 1987.

Method 2

Prodrug derivatives of "acidic" NH groups according to "Compounds of the Invention" can be synthesized from compounds of formula I by preparing N-hydroxy(substituted)methyl derivatives and reacting under exactly the same conditions as previously described for oxygen derivatization.

Intermediate N-hydroxy(substituted)methyl derivatives can be isolated or directly reacted to give the desired compound.

N-hydroxy(substituted)methyl derivatives of the type Ny-CH(R1)OH, where R1=H or CCl3, can be obtained by reacting the corresponding compounds of formula I with formaldehyde or CCl3CHO as described in H.E. Zaugg, Organic Reactions, 14, Chapter 2, 52 J Wiley and sons Few Tork, 1965 or J.P. Chupp, J.Crg. Chem., 28, 2592, 1965. In the case when R1=phenyl, the mentioned compounds can be synthesized by reaction with benzaldehyde or a cyclic amine (eg morpholine) in MeOH or dichloromethane:MeOH 1:1 at 0°C at reflux and hydrolyzing intermediate with 0.1N HCl at pH 4. (O. Jacobseen, Annalen, 157,243, 1884; H. Bundgaard et al. Int. J. Pharm., 22, 45, 1984).

The previously described reaction pathways and steps are shown by way of example and are not limiting from the point of view of the invention. Real experts in this field will know that the mentioned chemical transformations take place on polyfunctional substrates and that the reagents used can interfere, reacting. also with other groups present in the molecules. For example, catalytic hydrogenation can transform a nitro group into an anino, as desired, but isolated double bonds can also be hydrogenated, and halogen atoms can be removed; lithium aluminum hydride can reduce conjugated ketones to alkanes, as desired (e.g. step 7c in Reaction Scheme 7), but also COO Alk groups to CH2CH or NO2 to -N=N-, etc. Undesired side reactions can be avoided or minimized by choosing appropriate conditions or by using alternative reagents or by using other synthetic routes. If these "alternatives" would give negative results, the unwanted intermediates must be transformed into useful ones, using methods known to experts.

Detailed description of intermediate preparation

8-(3-bromopropoxycarbonyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate I)

30 g of 1,3-dibromopropane is added dropwise, at room temperature, to a suspension of 30 g of sodium 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylate in 150 ml of dimethylformamide and 35 ml of water. The reaction mixture was stirred at room temperature for 5 days. Then 100 ml of water is added and the mixing is continued for another 15 minutes. The precipitate is filtered with suction, washed with water and purified by light chromatography on silica gel, eluting with chloroform methyl acetate 95:5. The collected fractions were evaporated to dryness in vacuo and the residue was recrystallized from ethanol to give 27.7 g of the title compound, m.p. 114-115°C.

The 3-enzopyran carboxylate salt used in the above synthesis was prepared by dissolving 104 g of the corresponding acid in 560 ml of hot methanol and adding 280 ml of an aqueous solution of 31 g of sodium hydrogen carbonate. 850 Kl of acetone was added to the solution to precipitate the desired salt, which was collected by suction filtration (62 g, m.p. >280°C). The corresponding acid was prepared according to Da He, P. et al., J. Med. Pharm. Chem., 2, 263, 1960.

8-hydroxymethyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate II)

467 ni of a 1.4-8N solution of sodium borohydride in anhydrous dimethylformamide is added during 30 minutes, with stirring at room temperature, to a solution of 100 g of 3-methyl-4oxo-2-phenyl-4-H-1-benzopyran-3-carbonyl chloride in 1 liter of anhydrous dimethylformamide. The reaction mixture is stirred for 2.5 hours at room temperature. Add 88 ml of 2N hydrochloric acid while maintaining the temperature at 0-5°C. Then 102 ml of 12.7N sodium hydroxide solution is added. The mixture is poured into 6 liters of water, stirred for three hours, and filtered through a Buchner funnel. The filter residue is washed with 4-N sodium hydroxide solution and then with water. The resulting white solid crystallized from methanol to give 50g of the title product, m.p. 14-5-147°C.

E-8-(2-carboxyvinyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate III)

A mixture of 7.92 g of 8-formyl-3-methyl-4-oxo-2-phenyl-4-H-1-benzopyran (prepared as described in Uneyama, K. et al., Buli. Chem. Soc. Jap., 58, 2361, 1985), 3.75 g of malonic acid and 0.4-6 ml of piperidine in 15 ml of anhydrous pyridine were mixed for 3 hours at 100°C. After cooling to 20-25°C, the reaction mixture is poured into a mixture of 9Cg of crushed ice and 33 ml of hydrochloric acid (d=1.18). The resulting precipitate was collected by suction filtration, washed with water and crystallized twice from ethanol to give 5.5 g of the title compound, m.p. 226-229°C

E-8-(2-chlorocarbonylvinyl)-5-methyl-4-xo-2-phenyl-4-E-1-benzopyran (Intermediate IV)

A solution of 9.2 g of Intermediate III and 7.8 g of thionyl chloride in 75 ml of toluene is refluxed for 3 hours. After cooling to 2°C-25°C, the resulting crystals were collected by suction filtration, washed with acetone and dried in vacuo to give 6.8g of the title product, m.p. (190) 196-198°C after recrystallization from toluene.

8-acetyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate V)

1.17 g of magnesium, 7.4 ml of anhydrous ethanol and 0.2 ml of anhydrous carbon tetrachloride are placed in a round bottom flask under a stream of nitrogen. When the temperature begins to rise, 7.5 ml of anhydrous chlorobenzene is added, followed by a slow dropwise (25 min) solution of 5.28 ml of anhydrous diethylmalonate and 3.5 ml of anhydrous cyclochlorobenzene in 16 ml of anhydrous ethanol. The reaction flask is heated to 75°C for two hours , then cooled to 25°C and a solution of 8.8 g of 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carbonyl chloride in 53 ml of anhydrous chlorobenzene was added slowly, without exceeding 35 °C. The reaction mixture was further stirred for two hours at 35°C and then cooled to 0°C. Add 13 ml of water and 1.9 ml of sulfuric acid (d=1.84?). The resulting solution is decanted from insoluble inorganic substances and dried in a vacuum.

The obtained crude acyl malonate is refluxed for six hours with 10.4 ml of acetic acid, 7 ml of water and 1.3 ml of sulfuric acid (d=1.84). After cooling, the solution is poured into ice water and the precipitate is collected by suction filtration and washed with aqueous sodium carbonate. Crystallization from 90% ethanol gives 6.5 g of the title compound, m.p. 159-161°C.

8-bromoacetyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate VI)

During two hours at 20-25°C, a solution of 11.2 g of bromine in 250 ml of chloroform is added to a solution of 19.5 g of Internier V in 700 ml of chloroform. After stirring for one hour at 20-25°C, the solution is washed with 400 ml of 2N aqueous sodium hydroxide solution and then several times in a row with water, dried using anhydrous sodium sulfate and then in a vacuum. The crude product was treated with diethyl ether, collected by suction filtration and crystallized from acetone to give 16 g of the title product, m.p. 134-135°C

8-(2-hydroxyethylcarbamoyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate VII)

The title product is prepared in the same way as Intermediate XXXVI, but using 2-aminoethanol instead of 3-aminopropanol, m.p. 206-208°C.

3-methyl-4-oxo-2-phenyl-4-H-1-benzopyran-8-sulphonylchloride (Intermediate VIII)

A solution of 4.55 g of sodium nitrite in 12 ml of water is added dropwise to a mixed solution of 15.1 g of 8-amino-5-methyl-4-oxo-2-phenyl-4-H-1-benzopyran (prepared as described in Da Re, P. and sur, II. 7annaco (Ed. Sci.), 11, 670, 1956) in 150 ml of hydrochloric acid (d=1.18) at -5°C. Stirring was continued at 0°C for 30 minutes. The solution is placed, during 10 minutes at -5 to 0°C, in 120 ml of a 30% weight solution of sulfur dioxide in acetic acid containing 1.53 g of copper chloride dihydrate and 13 ml of water. After one hour at 0°C and one hour at 20-25°C, 300 ml of ice water is added to the mixture. The formed precipitate is collected by suction filtration, washed with water and dried in a desiccator over sodium hydroxide to constant weight, obtaining 18 g of the crude title product, m.p. 165-17C°C, for use without further purification.

8-(3-chloropropoxy)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate IX)

This compound was prepared in the same manner as Intermediate XI, but using 1-bromo-3-chloropropane instead of 1-bromo-2-chloroethna.m.p. 98-102°C after washing with petroleum ether diethyl ether 7:3

8-acetamido-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate X)

A solution of 1.75 g of acryloyl chloride in 15 ml of anhydrous tetrahydrofuran is added dropwise at -10°C to a mixed solution of 5 g of 8-amino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran and 3 ml of triethylamine in 60 ml of anhydrous tetrahydrofuran. After stirring at 0°C for one hour and at room temperature for one hour, the reaction mixture is poured into water and filtered with suction. After filtering, the precipitate is washed with water. Desiccation gives 5.5 g of the title compound, m.p. 229-230°C.

8-(2-chloroethoxy)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XI)

A mixture of 7.52 g of 8-hydroxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran prepared in the manner described in Da Re, P. et al., Ann. Chim., 1962, p. 506 etc.), 6.22 g of anhydrous potassium carbonate and 25.5 ni of l-bromo-2-chloroethane in 70 ml of dimethylformamide were stirred at 60°C for 25 hours. The mixture is cooled to 20-25 C and poured into 500 ml of water. The organic solution, obtained by extraction with dichloroethane, is washed with an aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Solvents and excess 1-bromo-2-chloroethane were evaporated in vacuo to give 8.8 g of the title product, m.p. 141-142°C after crystallization from chloroformhexane.

8-(2-azidoethoxy)-3-methyl-4-oxo-2-phenyl-4-H-1-benzopyran (Intermediate XII)

A mixture of 15.2 g of Intermediate II and 6.24 g of sodium azide in 150 ml of anhydrous dimethylformamide was stirred for 12 hours at 70-75°C. After cooling to 20-25°C, the reaction mixture is poured into 1.5 1 of water and extracted with dichloromethane. The organic solution is washed with aqueous sodium chloride and dried over anhydrous sodium sulfate.

Solvents are evaporated under vacuum.

The residue is taken up with water, collected by suction filtration and dried to obtain 14 g of the title product, m.p. 119-120°C.

8-[N-(2-hydroxyethyl)-N-methyl-1-carbamoyl]-3-methyl-4-oxo-2-phenyl-4-H-1-benzopyran (Intermedier XIII)

A solution of 1.6 ml of 2-methylamino-ethanol in 10 ml of water is added dropwise over 5 minutes to a suspension of 6 g of 8-chlorocarbonyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran and 1.52 g of potassium carbonate in 60 ml of acetone. After stirring for 2.5 hours at 20-25°C, the solvent is removed in vacuo and the residue is taken up in 150 ml of acetone. The mixture is refluxed for 15 minutes and then filtered. The solvent is evaporated from the filtrate and the residue is dissolved in 20 ml of dimethylformamide, treated with 14 ml of 1,4-th sodium carbonate solution, stirred for 30 minutes at 20-25°C and diluted by adding 150 ml of water. The mixture was extracted with chloroform and the organic layer was washed with 0.5N hydrochloric acid and then with water. The solution is dried over anhydrous sodium sulfate and the chloroform is evaporated. The resulting oil is taken in 200 ml of diethyl ether and stirred for two hours at 20-25°C. The solids were collected by suction filtration and crystallization from ethyl acetate gave 4.92 g of the title product, m.p. 128-130°C.

8-(2-chloroethylcarbamoyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XIV)

The title product was prepared in the same manner as Intermediate XXXVII, but using Intermediate VII in place of Intermediate XXXVI and carrying out the reaction at room temperature. T.t. 181-182°C (ethyl acetate).

8-(N-methyl-2-chloro-ethylcarbamoyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XV)

A solution of 1.1 ml of thionyl chloride in 2 ml of dichloromethane is added to a solution of 3.37 g of Intermediate XIII in 20 ml of dichloromethane, and the mixture is stirred for four hours at room temperature. Removal of the solvent gives an oil which is taken up in diethyl ether. The title product precipitates as a white solid, and is collected by suction filtration and used without further purification. T.t. (118) 126-128°C (diethyl ether).

8-(4-bromobutoxy)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XVI)

A mixture of 5 g of 8-hydroxy-3-ethyl-4-oxo-2-phenyl-4H-1-benzopyran, 4.2 g of anhydrous potassium carbonate and 43.6 g of 1,4-dibromobutane in -5 ml of dimethylformamide was stirred at 75°C during two o'clock. The mixture is cooled to 20-25°C, poured into 100 ml of water and extracted with dichloromethane. The organic solution is washed with an aqueous solution of sodium chloride and dried in anhydrous sodium sulfate. Solvents and excess 1,4-dichlorobutane are evaporated in vacuo. The residue is taken up with 55 ml of petroleum etherdiethyl ether 7:4, collected by suction filtration to give 5.6 g of the title product, m.p. 91-92°C.

5-(5-bromopentyloxy)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intennedier XVII)

This compound is prepared in the same way as Intermediate IVI- but using 1,5-dibromopentane instead of 1,4-dibromobutane and purifying the crude product by chromatography on a silica gel column (with elution with dichloromethane:ethyl acetate 99:1) m.p. 75-76°C, after taking in petroleum ether diethyl ether 30:4.

5-(2-chloroethoxymethyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XVIII)

6 ml of thionyl chloride in 18 ml of chloroform is added at 0°C to a mixed solution of 23 g of Intermediate XXII and 11 ml of triethylamine in 185 ml of chloroform. The reaction mixture is heated to 70°C and stirred for two hours. After cooling to room temperature, it is poured into water. The organic layer is separated, washed with sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness under vacuum. Yield: 24 g of the title product. By simple crystallization from ethanol, a product with a melting point of 102-103°C is obtained.

8-chloromethyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XIX

53.4 g of Intermediate II and 38.5 ml of anhydrous triethylamine are dissolved in 440 ml of chloroform. A solution of 19.8 ml of thionyl chloride in 80 ml of anhydrous chloroform is added dropwise to this solution, keeping the temperature at -10 to -2°C. The reaction mixture is stirred at room temperature for four hours, and then diluted with 400 ml of water. The aqueous phase is extracted with chloroform and the extracts are added to the chloroform phase. The chloroform solution is washed with salt water, dried over anhydrous sodium sulfate and evaporated to dryness under vacuum. Yield: 56 g of the title product, which after recrystallization from ethanol shows a melting point of 112-113°C

8-methylaminomethyl-5-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XX)

A solution of 15.1 g of anhydrous zinc chloride and 14.5 g of sodium cyanoborohydride in 400 ml of anhydrous methanol is added dropwise at 0°C to a mixed solution of 55.8 g of 8-formyl-3-methyl-4-oxo-2-phenyl-4-H-l- benzopyran, 60.7 g of methylamine hydrochloride and 125 ml of triethylamine in 600 ml of anhydrous methanol. After stirring for 5 hours at 2u-25°C, the solvent is evaporated in vacuo and the residue is taken up in 200 ml of water and collected by suction filtration. The crude product is dissolved in aqueous acetic acid, washed with ethyl acetate and precipitated by adding cold 6N sodium hydroxide solution. 4-9 g of the title product are obtained, m.p. 97-99°C, after crystallization from 75% ethanol.

8-(2-chloroethylthiomethy)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intemedijer XXI)

A solution of 37 g of Intermediate ZIX and 10.5 g of thiourea in 370 ml of ethanol is refluxed for one hour. The reaction mixture was cooled to room temperature, and 4-2 g of 3-amidi-nothiomethyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran crystallized spontaneously. Simple recrystallization from ethanol yields a product with a melting point of 233-235°C.

48 ml of a 35/5 aqueous solution of sodium hydroxide is added to a strongly stirred suspension of 35 g of the compound thus obtained and 1.05 S of benzyl triethylammonium chloride in 44u ml of 1,2-dichloroethane. The mixture is stirred for 2.5 hours and then poured into 300 ml of water. The aqueous layer is extracted with 1,2-dichloroethane and the extracts are added to the organic layer which is washed with sodium chloride solution, dried with anhydrous sodium sulfate and evaporated to dryness in vacuo. The residue was recrystallized from methanol to give 22 g of the title product, m.p. 82-83°C.

8-(2-hydroxyethoxymethyl)-5-methTl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XXII)

Prepare a solution of 2.5 g of Intermediate XIX in 25 ml of xylene and 3 ml of dioxane. 0.15 g of sodium is dissolved in 3.10 ml of anhydrous ethylene glycol, and this solution is added dropwise to the solution of Intermediate III at room temperature. After refluxing for 5.5 hours, the reaction mixture was cooled to room temperature and poured into 50 ml of water. It is extracted with dichloromethane, and the extract is washed with sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness in a vacuum. The solid residue crystallized from ethanol to give 2.1 g of the title product, m.p. 132-133°C

8-trifluoroacetamido-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XXIII)

Ctorine 9.5 ml of trifluoroacetic anhydride in 20 ml of anhydrous dichloromethane is added dropwise at -5 to 0°C to a solution of 5 g of 6-amino-3-methyl-4-oxo-2-phenyl-4H--benzopyran in 50 ml of anhydrous dichloromethane. dichloromethane. The reaction mixture is stirred for two hours at 20-25°C and then poured onto crushed ice. The organic layer obtained by extraction with dichloromethane is washed with a cold 5% sodium bicarbonate aqueous solution and water, and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue crystallized from ethanol to give 5.2 g of the title product. d.p. 175-176°C.

8-aminoethyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XXIV)

A mixture of 21 g of Intermediate XXIX and 19 g of triphenylphosphine in 160 ml of tetrahydrofuran is stirred at room temperature for 8 hours. Thin layer chromatography shows the disappearance of Intermediate XXIX. Add 3 ml of water and continue mixing for another 24 hours. The solvents are removed on a rotary evaporator and the residue is dissolved in water as its acetate. The aqueous solution is washed with ethyl acetate, made alkaline with a 37% sodium hydroxide solution and filtered through a Buchner funnel. The residue after filtration is washed with water and desiccation yields 18 g of the title product. The hydrochloride, recrystallized from ethanol, has a melting point of 256-258°C

8-(2-chloroethylsulphonylmethyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XXV)

41.6 ml of aqueous 30% hydrogen peroxide is added dropwise at 40°C for 20 minutes to a solution of 26.2 g of Intermediate XXI in 300 ml of glacial acetic acid. The mixture is heated to 60°C and stirred at that temperature for 4.5 hours, cooled to room temperature and poured into 60 ml of water. Filtration through a Buchner funnel gave a residue which was washed with water and dried to give 29.4 g of the title product. Simple crystallization from ethanol gives the product m.p. (89) 159-161°C.

8-(2-chloroethylsulphinylmethyl)-3-methyl-4-oxo-2-pheny-4H-1-benzopyran (Intermediate XXVI)

36 ml of aqueous 300% hydrogen peroxide is quickly added dropwise at 10°C to a solution of 12 g of Intermediate XXI in 84 ml of glacial acetic acid. The reaction mixture is stirred for 4 hours at room temperature and then poured into 220 ml of water. The title product is collected by suction filtration, washed with water and dried. Yield 12.4 g, m.p. 142-145°C (methanol).

8[N-methyl-N-(2-chloroethyl)-aminoethy]-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XXVII)

A mixture of 22 g of Intermediate XI, 66 ml of 1-bromo-2-chloroethane and 11 g of anhydrous potassium carbonate in 88 ml of dimethylformamide is stirred for 12 hours at 20-25°C. The reaction mixture is then poured into 600 ml of water and extracted with dichloromethane.

The organic layer is washed with water, dried over anhydrous sodium sulfate and acidified with ethanolic hydrogen chloride. The solvent and excess 1-bromo-2-chloro-ethane are removed in vacuo at 70-80°C. The residue is taken up in cold 1N sodium hydroxide solution and extracted with dichloromethane. The organic solution is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in a vacuum at 25-30°C.

The crude title product was purified by light chromatography on silica gel eluting with ethyl acetate petroleum ether 7:3, giving 15 g of the title product, melting point 115-120°C after crystallization from ethanol.

1-(2-hydroxy-2-methylpropyl)-(methoxyphenyl)-piperazine (Intermediate XXVIII)

A mixture of 7 g of 1-(2-methoxyphenyl}-piperazine, 7.33 g of anhydrous potassium carbonate, 1.75 g of potassium iodide and 5.6 ml of 1-chloro-2-methyl-2-propanol is stirred for about 90 minutes at 70°C and during further 6 hours at 90°C. The reaction mixture is poured into ice water and extracted with ethyl acetate. The organic layer is washed with an aqueous sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The title product is obtained as an oil, and is characterized by the fact that its dihydrochloride crystallized from ethanol has a melting point of 225-227°C.

8-azidomethyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XXIX)

A mixture of 22.8 g of Intermediate XIX 6.8 g of sodium azide in 110 ml of dimethylformamide was stirred for three hours at 100°C. After cooling to room temperature, 130 ml of water and 88 ml of ethanol were added to the reaction mixture. After one hour, the crystals are collected by vacuum filtration, washed with water and dried. Yield: 22 g of title product. The product obtained by simple recrystallization from ethanol has a melting point of 132-134°C.

8-[N-(2-hydroryethyl)-aminoethy]-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XXX)

A solution of 2.38 g of anhydrous zinc chloride and 2.30 g of sodium cyanoborohydride in 71 ml of anhydrous methanol is added dropwise with stirring to a mixture of 9.2 g of 8-formyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran and 9.12 g of ethanolamine in 90 ml of anhydrous methanol. Stirring was continued at 20-25°C for 5 hours, before the solvent was removed in vacuo. 250 ml of water is added to the residue and the insoluble substances are collected by suction filtration and washed with water. The crude product is dissolved in 1N acetic acid, and the solution is washed with ethyl acetate. The aqueous solution is then made alkaline by adding 2N sodium hydroxide solution and the precipitate is collected by suction filtration and washed with water to give the title product in an amount of 3.5 g, m.p. 117-121°C after drying at 60°C.

8-(N-methyl-N-chloroacetyl-aminomethyl)-3-methyl-4-oxo-2-phenyl--4-E-l-benzopyran (Intermediate XXXI)

A solution of 6 ml of chloroacetyl chloride in 60 ml of 1,2-dichloroethane is added dropwise at -5 to 0°C to a solution of 20 g of Intermediate XX and 10 ml of triethylamine in 200 ml of 1,2-dichloroethane. After stirring at 20-25°C for two hours, 15 ml of water was added to the reaction mixture and the phases were separated. The organic phase is washed with water and dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue crystallized from ethanol to give 22.5 g of the title product, m.p. 146-148°C.

5-chloroacetafflidomethyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XXXII)

A solution of 3.2 ml of chloroacetyl chloride in 32 ml of 1,2-dichloroethane is added dropwise with stirring at -5°C to a mixture of 10 g of Intermediate HIV and 5.5 ml of triethylamine in 80 ml of 1,2-dichloroethane. The reaction mixture was stirred at room temperature for one hour and then 150 ml of water was added. The phases are separated; the aqueous phase is extracted with 1,2-dichloroethane and the extracts are added to the organic phase which is then washed with saturated sodium bicarbonate solution, washed with water and dried over anhydrous sodium sulfate and evaporated to dryness under vacuum. The residue was crystallized from ethanol to give 10.7 g of the title product, m.p. 152-155°C.

8-['N-acetyl-N-(2-chloroethyl)-amnoethyl]-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XXXIII)

8.65 g of Intermediate XXX and 4.15 ml of triethylamine are dissolved in 70 ml of tetrahydrofuran. A solution of 2.35 ml of acetyl chloride in 23 ml of tetrahydrofuran was then added dropwise to this solution at -10°C over 40 minutes. After stirring for 3 hours at 0-10°C and for 2 hours at 20-25°C, the solvent is evaporated under vacuum. 100 ml of water is added to the residue, and extraction with dichloromethane is carried out, successive organic extracts are combined and the solvent is removed in vacuo. The residue is dissolved in 50 ml of methanol and 3 g of potassium carbonate and 10 ml of water are added. After stirring at 50°C for 20 minutes, in order to hydrolyze the N,O-diacetyl derivative that was formed, the solvent was removed in vacuo and the residue was treated with water and dichloromethane as already described. The dichloromethane solution is evaporated again to dryness, and 5.9 g of 8-[N-acetyl-N-(2-hydroxyethyl)-aminoethy]-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran are obtained, m.p. 171-172°C. A solution of 3.6 g of thionyl chloride in 30 ml of dichloromethane is added dropwise to a solution of 6.1 g of the thus obtained compound in 70 ml of dichloromethane at 0°C. After stirring for 90 minutes at 20-25°C, the reaction mixture is washed with water and dried.

The solvent was removed in vacuo to give the crude title product for use without further purification.

8-(3-chloropropylthio)-3-methyl-4-oxo-2-phenyl-4-H-1-benzopyran (Intermediate XXXIV)

A solution of 20.1 g of stannous chloride dihydrate in 18 ml of hydrochloric acid (d=1.18) is added during 5 minutes at 65°C to a solution of 6 g of Intermediate VIII in 70 ml of acetic acid, the reaction mixture is cooled to 30-35°C and the solvent remove under vacuum. The rest is taken in water, and the insoluble substances are collected by suction filtration, washed with water and dried. Yield 3.2 g of 8-mercapto-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, melting point 115-118°C after crystallization from ethanol.

A mixture of 8 g of the thus prepared compound, 27 ml of 1-bromo-3-chloropropane, 0.2 g of tetrabutylaronium bromide and 6.2 ml of 35% sodium hydroxide in 30 ml of benzene is vigorously stirred for 4 hours at 20-25°C. Add 100 ml of water and 40 ml of dichloromethane. The organic layer is separated, washed with water and dried over anhydrous sodium sulfate. Solvents and excess l-bromo-3-chloro-propane are removed in vacuo. The residue was purified by column chromatography on silica gel, eluting with petroleum ether ethyl acetate 9:1, and 5.7 g of the title compound was obtained. After crystallization from methanol, it shows a melting point of 34-86°C.

8-(3-chloropylsulphonyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XXXV)

7 ml of 30% hydrogen peroxide is added at 20-25°C to a solution of 3.4-5 g of Intermediate XXXIV in 35 ml of acetic acid. After stirring for 4 hours at 60°C, the reaction mixture was cooled to 20-25°C. Add 30 ml of water. A precipitate is formed, collected by suction filtration, washed with water and dried, yielding 3.4 g of the title product. After crystallization from acetone, it shows a melting point of 160-163°C.

8-(3-hydroxypropylcarbamoyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XXXVI)

A solution of 7.6 ml of 3-aminopropanol in 50 ml of water is added dropwise over 30 minutes to a suspension of 30 g of 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carbonyl chloride and 15.2 g of potassium carbonate in 400 of acetone. The thick suspension is stirred for three hours at 20-25°C. The solvents are removed in vacuo and the residue is taken up in 300 ml of water. After mixing for one hour, the precipitate is collected by suction filtration and washed with water. The crude product was purified by crystallization from 95% ethanol to obtain 23.8 g of the title product, m.p. 191-195°C An additional 4.7 g of the title product was obtained by concentrating the crystallization filtrate in vacuo.

8-(3-chloropropylcarbamoyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XXXVII)

A solution of 1.1 ml of thionyl chloride in 2 ml of chloroform is added to a boiling solution of 3.37 g of Intermediate XXXVI in 20 ml of chloroform. After stirring for 90 min under reflux, the solvent was removed in vacuo and the residue was crystallized from acetonitrile to give the title product in an amount of 3 g, m.p. (188) 193-194°C.

8-[1-hydroxy-4-(4-methylphenylsulphonyloxy)-butyl]-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate

XXXVIII)

1.12 g of sodium cyanide in 3 ml of water at 20-25°C was added, to the mixed mixture 3.96 g of 8-formyl-3-methyl-4-oxo-2-phenyl-4H-1-benzo-pyran, 2.61 g morpholine and 4.-3 g of p-toluenesulphonic acid in 20 ml of tetrahydrofuran and 30 cl of 1,2-dichloroethane. The reaction mixture is refluxed for 4 hours, and then 10 ml of cold water is added. Tetrahydrofuran is distilled off at normal pressure, and 10 ml of 1,2-dichloromethane and 10 ml of chloroform are added. The organic phase is separated, washed with an aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and evaporated to dryness under vacuum. The residue is suspended in diethyl ether, filtered and crystallized from chloroform:ethylacetate. Yield 3.55 g of 8-(morpholino-cyano-methyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, m.p. 236-238°C 3.5 ml of a 30% solution of potassium hydroxide in anhydrous methanol is added with stirring at room temperature to a suspension of 22.8 g of the thus prepared compound in 520 ml of anhydrous tetrahydrofuran. 6.3 ml of acrylonitrile in 20 ml of tetrahydrofuran is added dropwise to this suspension, and the reaction mixture is stirred at room temperature for one hour.

Solvents evaporate in vacuum. Crystallization of the residue from methanol gives 23.22 g of 8-(1,3-dicyano-1-morpholino-propyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran. 23.2 g of the thus prepared compound is dissolved in 250 ml of dioxane, 250 ml of 6M hydrochloric acid is added and the mixture is refluxed for 2.5 hours. After cooling to room temperature, the mixture is poured into 700 ml of aqueous sodium chloride solution and extracted with ethyl acetate. The extracts are washed with an aqueous sodium chloride solution and treated with 700 ml of a 1M sodium hydroxide solution. The aqueous layer is washed with ethyl acetate and acidified with 37% hydrochloric acid. The precipitate is collected by suction filtration and crystallization from ethanol gives 10.2 g of 8-(3-carboxy-1-oxopropyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran m.p. 191-192°C. Diborane, obtained by dropping a solution of 2.1 ml of freshly distilled boron trifluoride diethyl etherate in 10 ml of anhydrous diglyme in 19 ml of a 0.66M solution of sodium borohydride in diglyme, is introduced into a suspension of 2.28 g of the thus prepared compound in 23 ml of anhydrous tetrahydrofuran, and is stirred at 0° C under a stream of nitrogen. Stirring was continued for 20 minutes at 0°C and for a further 20 minutes at room temperature. Carefully drop methanol into the mixture at 0°C to quench the reaction. Solvents were removed by evaporation in vacuo.

The residue is purified by light chromatography on silica gel, eluting with petroleum ether: ethyl acetate 3:7. The collected fractions are evaporated in vacuo to give 2 g of 8-(1,4-dihydroxybutyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, m.p. 133-134°C. 2.8 g of p-toluenesulphonyl chloride was added at 0°C to a mixed solution of 3.17 g of the thus prepared compound in 32 ml of anhydrous pyridine. The mixture is stirred for 6 hours at 0°C and left overnight at -4°C without stirring. It is then poured into 200 ml of aqueous sodium chloride solution, acidified with 10 ml of 125 hydrochloric acid and filtered with suction. The residue after filtration is dissolved in chloroform, and the solution is washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, the solvent is distilled on a rotary evaporator. The residue is purified by light chromatography on silica gel, eluting with petroleum ether: ethyl acetate 1:1. the collected fractions were evaporated to dryness in vacuo to give 3.04 g of pure title product, m.p. 123-124°C.

4-[4(2-methoxyphenyl)-1-piperazinyl]-butyraldehyde (Intermediate XXXIX)

A solution of 5.4 g of 2-(3-chloropropyl)-dioxolane and 15.9 g of 1-(2-methoxy-phenyl-piperazine) in 60 ml of dimethylformamide was stirred for 4 hours at 80°C. After cooling to 20-25°C, the reaction mixture is poured into 50 ml of ice-cold 0.5N sodium hydroxide solution and extracted with dichloromethane. The organic phases are washed with water and dried over anhydrous sodium sulfate. The solvent is removed in vacuo, and the residue is purified by light chromatography on silica gel, eluting with dichloromethane :ethanol 95:5.9.3 g of 2-(3-[4-(2-methoxyphenyl)-1-piperazinyl-propyl-dioxolane were obtained as an oil.

NMR CDCl3 (δ) 1.5-2.0 (4H, m, CH2CH2CH) 2.2-5.2 (1H, m, 5 x CH2N) 3.7-4.0 (7H, m, OCH5 and 2 x OCE2) 4.8 (IH, t, OCHO) 6.7 -6.9 (4H, m, aromatic protons)

A solution of 12.8 g of the thus prepared compound in 200 ml of tetrahydrofuran and 420 ml of 1N hydrochloric acid solution is kept at 20-25°C for 24 hours. It is then alkalized using a 5N sodium hydroxide solution and immediately extracted with dichloromethane. The organic layer is washed with water and dried over anhydrous sodium sulfate. The solvent is evaporated in a vacuum, and the residue is purified by light chromatography on silica gel, eluting with dichloromethane-ethanol 97:3. 6.4 g of the title compound are obtained as an oil.

NMR CDCl3, (δ) 1.5-2.0 (2H, m, CH2CH2CH2) 2.2-2.8 (8H, m, 3 xCH2N and CE2CHO) 2.0-3.2 (4H, m, 2 x CH2NAr) 3.3 (3H, s, OCH3) 6.8 (4H, s, aromatic protons) 9.3 (1H, s, CHO).

8-(2,3-epoxypropoxy)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XL)

7 ml of 2,3-epoxypropyl chloride is added dropwise at 20-25°C to a mixed solution of 5 g of 8-hydroxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran and 9.7 ml of 2N sodium hydroxide in 10 ml of ethanol. After 5 hours at 20-25°C, the reaction mixture is poured into 100 ml of water and the formed precipitate is collected by suction filtration. After drying and purification by light chromatography on silica gel (eluting with petroleum ether:ethyl acetate 65:35), 4.45 g of the title compound were obtained, m.p. 128-129°C.

8-(N-methyl-2-(4-methylphenylsulphonyloxy)-ethylsulphamoy)-3-methyl-4-oxo-2-phenyl-4-H-1-benzopyran (Intermediate XLI)

A solution of 5 g of Intermediate VIII in 60 ml of dichloromethane and 20 ml of tetrahydrofuran is added dropwise at 0°C to a mixture of 2.5 ml of 2-methyl-aminoethanol and 2.1 ml of triethylamine in 20 ml of dichloromethane. after stirring for two hours at 20-25°C, 100 ml of water and 100 ml of dichloromethane are added to the reaction mixture. The precipitates are separated and the organic solution is dried over anhydrous sodium sulfate. The solvent is removed in vacuo, and the residue is purified by chromatography on a silica column eluting with petroleum etherethyl acetate 3. Thus, 4.5 g of 8-(N-methyl-2-hydroxy ethyl sulphamyyl-5-methy-4-oxo-2- phenyl-4H-1-benzopyran, melting point 146-147°C after crystallization from ethanol.

The thus obtained compound was converted into the title compound by p-toluene-sulphonylation according to the second step of the procedure described below for the preparation of Intermediate XLII. The title product is used without purification.

8-[2-(4-methylphenylsulphonyloxy)-ethylsulphamoyl]-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XLII)

A solution of 5 g of Intermediate VIII in 37 ml of tetrahydrofuran is added dropwise at 0°C to a mixture of 2.5 ml of ethanolamine and 2.5 ml of triethylazine in 25 ml of tetrahydrofuran. After mixing at 20-25°C, the reaction mixture is poured into 40°C ml of water. The formed precipitate is collected by suction filtration, washed with water and air-dried, yielding 4.6 g of 8-(2-hydroxyethyl sulphamoyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, melting point 186-187°C after crystallization from ethyl acetate.

2.1 g of p-toluenesulphonyl chloride is added in portions at 0°C to a solution of 3.6 g of the thus prepared compound in 25 ml of pyridine.

After 6 hours at 20-25°C, the reaction mixture is slowly poured into crushed ice containing a small excess of hydrochloric acid. The formed precipitate is collected by suction filtration and washed with water. 4.9 g of the title compound were obtained, melting point (163) 166-169°C after crystallization from ethyl acetate.

8-(3-aminopropylcarbamoyl)-5-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride (Intermediate XLIII)

A solution of 21.6 g of 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carbonyl chloride in 250 ml of anhydrous tetrahydrofuran is added dropwise to a mixed solution of 17 g of 3-(2-methyl-2-propoxycarbamoyl)-propylamine. (prepared as described by Sari, W.S. et al., J. Med. Chem., 33 97, 1990) and 15 ml of triethylamine at 0-10°C. After stirring for two hours at room temperature, the reaction mixture was poured into water and filtered to give 12.3 g of 3-(2-methyl-2-propoxycarbamoyl)-propyl-3- methyl-4-oxo -2-phenyl-4H -1-benzopyran-8-carboxamide which is re-crystallized from ethanol. T.t. 178-180°C.

A solution of 4.3 ml of trifluoroacetic acid in 15 ml of anhydrous dichloromethane is added dropwise at -5°C with stirring to 3.3 g of the thus prepared compound in 35 ml of anhydrous dichloromethane. After heating to room temperature, the mixture is stirred for 8 hours. Dichloromethane and excess trifluoroacetic acid are evaporated at 20-25°C using a rotavaporator. The oily residue was dissolved in dichloromethane and 1N sodium hydroxide solution was added. The organic layer is washed with water, dried over anhydrous sodium sulfate and filtered. Excess ethanolic hydrogen chloride is added to the filtrate and the solvent is removed in vacuo. The residue crystallized from ethanol to give 1.5 g of the title compound, m.p. 253-255°C.

8-(2-chloroethylureido)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XLIV)

4 ml of 2-chloroethyl isocyanate was added, with stirring at room temperature, to a solution of 3.9 g of 8-amino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran in 52 ml of anhydrous dimethylfonnamide. Mixing is continued for 5 hours at 70°C. Water is added to the reaction mixture, and extraction with ethyl acetate is carried out. The organic phase is evaporated to dryness under vacuum. The residue is suspended in diethyl ether with stirring. The title product is then filtered and recrystallized from methanol. Yield: 3.74 g, m.p. 213-214°C.

(Z,E)-8-(4-[2-(1,3-dioxanyl)-1-butenyl]-3-ethyl-4-oxo-2-phenyl-4H-1-benzopyrain (Intermediate XLV)

1.6 ml of 2.5N butyllithium in hexane was added dropwise at -20°C to a solution of 1.53 g of 2-[2-(1,3-dioxanyl)]-ethyl triphenyl phosphonium bromide in 10 ml of anhydrous tetrahydrofuran. The mixture is stirred for 20 minutes at -20°C. A solution of 0.8 g of 8-formyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran in 11 ml of anhydrous tetrahydrofuran is added dropwise to the mixture, which is then heated to 0°C for 90 minutes and then to room temperature during 30 minutes. The reaction is quenched by the addition of methanol. The solvents are evaporated in vacuo and the residue is purified by light chromatography on silica gel, eluting with ethyl acetate: petroleum ether 3.7 to give the title compound as a mixture of diastereoisomers S and Z, m.p. (93) 93-100°C. The ratio of the two isomers was determined by NMR spectroscopy and results in E:Z=65:35

NMR, CDCl3, (δ)

8.1-8.2 (m, 1E, CH in position 5 of the benzopyran ring) 7.2-7.8 (m, 7E, other aromatic CH groups of the benzopyran and phenyl ring) 6.9 (dt, 1H, Fl-CH Eisomer)

6.8 (dt, IH, Fl -CH of the Z isomer) 6.4 (dt, IH, Fl -CH=CH of the E isomer)

5.9 (dt, IH, Fl-CH=CH of the Z isomer) 4.6-4.7 (m, 1E, OCHO)

3.6-4.2 (m, 4H, CCH2O dioxane ring) 2.4-2.7 (i, 2H, CHCH2CH)

1.9-2.3 (m 5H, ĆE-, and CH2 in position 5 of the dioxane ring)

8-(4-[2-(1.3-dioxanyl)-butyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XLVI)

A mixture of U.2 g of 1035-ton palladium on carbon, as a catalyst, and 1 g of Intermediate 1LV in 24 ml of methanol is hydrogenated in a Farr apparatus at room temperature with a hydrogen pressure of 1.5 atmospheres. After the theoretical amount of hydrogen has been consumed, the catalyst is filtered and the solvent is removed by evaporation in vacuo. The residue is crystallized from cyclohexane to give the title product, m.p. 118-119.5°C

8-carboxymethyl-5-methyl-4-oxo-2-phenyl-4E-1-benzopyran (Intermediate XLVII)

4.5 g of potassium permanganate is added, in portions during one and a half hours with stirring at 0-10°C, to a mixture of 2.76 g of 8-allyl-3 methyl-4-oxo-2-phenyl-4E-1-benzopyran (P. Da Re, U3 3350411), 0.17g Aliaot 336, 1.12 ml acetic acid, 56 ml dichloromethane, 3.2 ml sulfuric acid (d=1.84) and 60 ml water. Mixing is continued at room temperature for 5 hours. 3.4 g of sodium metabisulphite is added in portions over 15 minutes at 0-5°C. The organic layer is separated, washed with water and extracted with 60 ml of 1N aqueous sodium hydroxide solution. The aqueous phase is acidified by the addition of dilute hydrochloric acid and extracted with ethyl acetate.

The organic phase is washed with water, dried over anhydrous sodium sulfate and, after filtration, evaporated to dryness under vacuum. The residue is treated with carbon tetrachloride, and the solid is collected by suction filtration to give 1 g of the title product, m.p. 191-192°C (acetonitrile).

8-(4-chlorobutyramido)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XLVIII)

The title product was prepared in the same manner as Intermediate X, but using 4-chlorobutyryl chloride instead of acryloyl chloride. The resulting solid is filtered from water and dried, and taken up in hot diethyl ether and collected by suction to give the title compound. The sample, crystallized from 50% aqueous ethanol and washed with diethyl ether, melts at (153) 162-164° C.

8-methylamino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XLIX)

A solution of 0.5 g of Intermediate XXIII in 1.5 ml of anhydrous dimethylformamide is added dropwise with stirring, at -5°C, to a suspension of 0.045 g of sodium hydride (80% in mineral oil).

After stirring for one hour at room temperature, 0.092 ml of methyl iodide in 0.6 ml of anhydrous diethylformamide was added dropwise. Then the reaction mixture is stirred at 50°C for one hour, cooled to 20°C, poured into water, filtered with suction and dried at 60°C for 3 hours to obtain 0.6 g of 8-(N-methyl trifluoro acetamido)- 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran.

NMR (δ)

8.15 (d-i IH, benzopyran CH in 5)

7.10-7.60 (m, 7H, other benzopyran and phenyl CHs)

3.30 (s, 3H, CH3-N)

2.10 (s, 3H, benzopyran OH, in 3)

A mixture of 0.44 g of the above compound and 0.05 g of sodium borohydride in 4 ml of ethanol and 1 ml of dimethylsulphoxide is stirred at room temperature for one hour, and then quenched with an excess of 4N hydrochloric acid. After removal of ethanol by vacuum evaporation, the residue is taken up with water, then with 3N sodium hydroxide and extracted with ethyl acetate. the organic layer is washed with water, dried over sodium sulfate and evaporated to dryness under vacuum. The solid residue crystallized from ethanol to give 0.22 g of the title compound, mp 145-146°C

8-(N-methylacrylamido)-5-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate L)

This compound is prepared in the same manner as Intermediate X, but using Intermediate ZLIX instead of 8-amino-3-methyl-4-oxo-2-pienyl-4H-1-benzopyran. Instead of diluting with water, the THF was removed by evaporation in vacuo, and the solid residue was dissolved in ethyl acetate and washed with water. The organic solution was dried over anhydrous sodium sulfate and evaporated to dryness in vacuo to give the title compound. The sample, purified by chromatography on a silica gel column (with elution with ethyl acetate/petroleum ether 4:6) and crystallized from cyclohexane, melts at 136-137°C.

1-[2-(1,3-dihydro-1,3-dioxo-2H-isoinlol-2-yloxy)-ethyl]-4-(2-methoxyphenyl)-piperazine (Intermediate LI)

A mixture of 6.73 g of N-hydroxyphthalimide, 3.73 g of sodium acetate and 10 g of 1-(2-chloroethyl)-4-(2-methoxyphenyl)-piperazine in 100 ml of anhydrous dimethylsulphoxide was stirred at 100°C for 4 hours. The reaction mixture is then cooled to room temperature, poured into water and extracted with ethyl acetate. The combined organic layers were washed with 1N sodium hydroxide, dried over sodium sulfate and evaporated to dryness in vacuo to give 7.58 g of the title compound. A sample was crystallized from cyclohexar and found to melt at (76) 80-83°C

l-(2-aminooxyethyl)-4-(2-methoxyphenyl)-piperazine hydrochloride (Intermediate LII)

A solution of 5.59 g of Intermediate LI and 1.10 ml of 85% hydrazine hydrate in 13C ml of 95% ethanol is refluxed for 4 hours. Ethanol is removed by evaporation in vacuo. The residue is taken up with water and then with an excess of 37% hydrochloric acid, and filtered. The acidic aqueous solution was made alkaline with 5% sodium hydroxide solution and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness in vacuo to give 4.3 g of the title compound as an oil. The sample was converted to hydrochloride by salification using ethanolic hydrogen chloride in dichloromethane. The solvents were removed by evaporation in vacuo and the crude residue was crystallized from ethanol to give the title compound, mp 208-209°C.

3-(4-chlorobutylthio)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate LIII)

The title compound was prepared in the same manner as Intermediate XXXIV, but using 1-bromo-4-chlorobutane instead of 1-bromo-3-chloropropane. T.t. 81-84°G (ethanol).

8-(4-chlorobutylsulphinyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate LIV)

The title compound was prepared in the same manner as Intermediate XXVI, but using Intermediate LIII instead of Intermediate XXI. The sample, crystallized from cyclohexane:benzene 0.5:1 melts at 124-125°C.

8-carboxy-4-oxo-3-phenyl-4H-1-benzopyran (Intermediate)

A solution of 38.22 g of silver nitrate in 75 ml of water is added dropwise, with stirring, at 20-25°C, to a solution of 22.5 g of 8-formyl-4-oxo-3-phenyl-4H-1-benzopyran (prepared as described by G. A-tassi et al., Eur. J. Med. Che.-Chim. Ter., 20, 393 (1985)) in 150 ml of 85% ethanol and 4-50 ml of dimethylformamide. Then, a solution of 32.67 g of 35% potassium hydroxide in 195 ml of water is added dropwise with stirring at 15-20°C. After additional mixing at room temperature, the reaction mixture is filtered by suction and the initial liquid is acidified with 37% hydrochloric acid and diluted with 1.2 liters of water. By filtration with suction and washing with water until neutralization, the title product is obtained as raw material. It is suspended in 150 ml of ethyl acetate and mixed with 444 ml of 0.3 M sodium hydrogen carbonate until clear layers are obtained. The aqueous layer is washed with 75 ml of ethyl acetate, then acidified with 37% hydrochloric acid, filtered and dried at 60-65°C to give 19.12 g of the title compound, melting point (215) 218°C. The sample, crystallized from ethanol, has the same melting point.

8-chlorocarbonyl-4-oxo-5-phenyl-4H-1-benzopyran (Intermediate LVI)

A mixture of 15.97 g of Intermediate LV and 15.6 ml of thionyl chloride in 75 ml of anhydrous toluene is mixed at 80-85°C for 4 hours. After removal of the solvent under vacuum, the residue is taken up twice in 20 ml of toluene and evaporated to dryness giving, after drying, 16 g of the title compound melting at (126) 138-140°C, and used without further purification. T.t. (130) 138-140°0 (toluene).

8-(N-acetylcarbamoyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate LVII)

A mixture of 3.5 g of 8-carbamoyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (described in JP 61-238783), 4-.8 ml of acetic anhydride and 0.25 ml of sulfuric acid (d=1.098) is stirred at 140°C for three minutes. The reaction was cooled to room temperature, diluted with water and suction filtered to give, after washing with water and drying, 3.88 g of the title compound

NMR (CDCl3)

10.50 (bs, 1H, imidic NH)

8.35-8.70 (m, 2H, CE in position 5 and 7 in the benzopyran ring) 7.45-8.00 (m, 6H, other aromatic CHs) 2.60 (s, 3H, CE3CO)

2.20 (with 3H, CH3 in position 3 of the benzopyran ring)

2-(2-methylthiophenoxy)-acetaldehyde diethyl acetal (Intermediate LVIII)

A mixture of 15.2 ml of 97% 2-bromoacetaldehyde diethylacetal, 14 g of 2-(methylthio)-phenol, 13.7 g of anhydrous potassium carbonate and 3.13 g of tricaprylmethylammonium chloride in 140 ml of anhydrous dimethylformamide was stirred at 95°C for 38 hours. At the end of this period, the reaction mixture is cooled to room temperature, poured into 1 liter of water and extracted with diethyl ether. The organic layer is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness under vacuum. The oily residue is purified by chromatography on a silica gel column eluting with petroleum ether:ethyl acetate 99:1. Evaporation in vacuo of the collected fractions gave 12.9 g of pure title compound. The sample was crystallized from n-hexane and melted at 50-52°C

2-(2-methylthiophenoxy)-acetaldehyde (Intermediate LIX)

A mixture of 10.5 g of Intermediate LVIII and 14 ml of 2N hydrochloric acid in 85 ml of anhydrous tetrahydrofuran is stirred at 50 C for 2 hours. The organic solvent is then removed by evaporation in vacuo, and the aqueous residue is extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo to give 9.5 g of the title compound as a solid which was used without further purification. The sample was crystallized from cyclohexane to give the pure title product, m.p. 102-104°C.

8-(4-chlorobutylsulphonyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate LX)

The title product was prepared in the same manner as Intermediate XXV, but using Intermediate LIII instead of Intermediate XXI. It is crystallized from diisopropyl ether and melts at 112-115°C.

8-ethoxycarbonyl-4-oxo-4H-1-benzopyran (Intermediate LXI)

4.35 g of sodium metal is added piecewise at room temperature to a solution of 9.85 g of ethyl 3-acetyl-2-hydroxy benzoate (synthesized from 3-acetyl-2-hydroxybenzoic acid (prepared as described in R.E. Ford, J.Med.Chem .,29, 538, (1986)) by refluxing in 6N ethanolic hydrogen chloride for one and a half hours, evaporating to dryness in a vacuum and purifying the crude compound by silica gel column chromatography (eluent is ethyl acetate-petroleum ether 8:2) -m.p. 47°C (hexane)) in 98 ml of ethyl formate.

The reaction mixture spontaneously reaches reflux in 2u minutes; then it is stirred at room temperature for 4 hours and the ethyl formate is removed by evaporation to dryness in vacuo. The crude solid is taken up in 120 ml of ethanol and 67 ml of 5.5 M ethanolic hydrogen chloride. The mixture is stirred at reflux for 30 minutes, after which time it is cooled to room temperature and evaporated to dryness under vacuum. The residue was purified by chromatography on a silica gel column eluting with ethyl acetate: petroleum ether 3:7 to 6:4 to give 8.31 g of the title compound. The sample crystallized from cyclohexane melts at 88-89°C.

8-carboxy-4-oxo-4H-1-benzopyran (Intermediate LXII)

30 ni of 6N hydrochloric acid is added to a solution of 4.0 g of Intermediate LXI in 30 ml of dioxane, and the resulting mixture is refluxed for 5 hours. The reaction mixture is cooled to room temperature and poured into 200 ml of water. After 12 hours at 0 to 5°C, the title product is suction filtered. Washing with water and diethyl ether gives, after drying, 2.8 g of the title product, which is used without further purification. The sample that was washed with hot acetonitrile:methanol 25:1 , filtered and crystallized from acetic acid melts at 253-254°C.

8-carboxy-6-hydroxy-5-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate LXIII)

A mixture of 1.5 g of 8-carboxy-S-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (prepared as described in JP 61-15880) and 28 ml of 57% hydroiodic acid in 47 ml of acetic acid is stirred at reflux for 18 hours. The reaction mixture was cooled to room temperature and poured into water, 1N sodium hydroxide was added to adjust the pH to 4 to 5. 2 g of sodium thiosulphate was added and stirring was continued for 15 minutes. After this period, the crude title product is filtered with suction and dissolved in 0.5M sodium hydroxide; the basic solution is washed with ethyl acetate and acidified to pH 1 by adding 375% hydrochloric acid. The title compound is collected by suction filtration and dried. Yield: 1.12 g of the title compound, which is used without further purification and melts at 279-281°C after crystallization from 50% ethanol.

2-hydroxy-5-nitro-5-propionyl-benzoic acid (Intermediate LXIV)

97.1 g of 2-hydroxy-3-propionyl-benzoic acid, prepared as described in Erit. 1, 34-3, 119 (1974), is added in 5 minutes to 500 ml of sulfuric acid (d=1.84) and stirred at -25°C. A mixture of 40 ml of 65% nitric acid and 100 ml of sulfuric acid (d=1.84) was added in 40 minutes, keeping the temperature of the reaction mixture between -20 and -13°C. The mixture was stirred at -18°C for a further 30 minutes. After this time, 2.0 kg of crushed ice and 500 ml of water are carefully poured into the mixture, stirred for 10 minutes and filtered to obtain the title compound, after washing with water and drying at 50°C for 6 hours. Crystallization from 50% ethanol gives 91.5 g of the title compound, which melts at 186-189°C, and is used without further purification. A sample which. was recrystallized from 50% ethanol, melting at 189-191°C.

ethyl 2-hydroxy-5-nitro-3-propionyl-benzoate (Intermediate LXV)

A solution of 93.3 g of Intermediate LXIV and 25 ml of sulfuric acid (.d= 1.84) in 490 ml of ethanol is refluxed for 17 hours» After cooling to room temperature, 47.7 g of sodium carbonate is added in portions and the ethanol is evaporated under vacuum. The residue is taken in 1.2 liters of water, alkalized by adding 37% sodium hydroxide and stirred for 15 minutes. 37% hydrochloric acid was added to this suspension to adjust the pH to 6. Filtration gave 85.4 g of the title compound, which was used without further purification, (m.p. 75-77°C). The sample, crystallized twice from ethanol, melts at 76-77°C.

8-ethoxycarbonyl-3-methyl-6-nitro-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate LXVI)

A mixture of 48.1 g of Intermediate LXV, 63 ml of benzoyl chloride and 85.6 g of sodium benzoate is mixed at 180°C (bath temperature) for 8 hours. The pasty mixture is cooled to 60-70°C; 700 ml of 50% ethanol is added and the resulting mixture is again stirred at 50°C for 30 minutes. Add 60 ml of 35% sodium hydroxide at 50°C, ensuring that the temperature does not exceed 15°C.

Filtration with suction, followed by washing with 50% ethanol and water, gives the crude product which is purified by double passage on a silica gel chromatography column, eluting first with dichloromethane petroleum ether gradation 8:2 to 9:1, then with dichloromethane and finally with dichloromethane :ethyl acetate 95:5. Evaporation of the collected fractions in vacuo gives the title compound, which is washed with 140 ml of ethanol. Yield: 43 g, m.p. 152-133°C (ethanol).

8-carboxy-3-methyl-6-nitro-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate LXVII)

A mixture of 15.9 g of Intermediate LXVI and 48 ml of 1N sodium hydroxide in 320 ml of ethanol is stirred at reflux for 30 minutes. The organic solvent is removed by evaporation in vacuo and the resulting suspension is diluted with 200 ml of water and acidified with 37% hydrochloric acid. Filtration and washing with diethyl ether gave 11.1 g of the title compound melting at (258) 286-292°C and used without further purification. After crystallization from dimethylformamide water 6:4, the title compound shows the same melting point.

8-chlorocarbonyl-3-methyl-6-nitro-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate LXVIII)

A mixture of 6.2 g of Intermediate LXVII, 5.2 ml of thionyl chloride and 0.1 ml of anhydrous dimethylformamide in 60 ml of toluene was stirred at 90°C for 2 hours. Evaporation to dryness in vacuo and desiccation gave 6.5 g of the title compound, m.p. 161-162°C, which is used without further purification. A sample crystallized from toluene has the same melting point.

8-carboxy-7-methoxy-5-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate LXIX)

216 ml of a 0.3 M solution of potassium permanganate in water is added dropwise over 4-0 minutes to a mixture of 7.94 g of 8-formyl-7-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (prepared as is described in Da Re et al., J. Org. Chem., 25, 1097, 1960) and 54 ml of % sodium hydrogen phosphate in 162 ml of t-butanol, and is stirred at 75 C. After a further two and a half hour of mixing at the same temperature, the reaction mixture is cooled to room temperature and 81 ml of IM sodium dithionite is slowly added to it. The mixture is extracted with ethyl acetate. the organic layer is washed four times with 160 ml of 0.5N sodium hydroxide, the collected basic aqueous layers are washed with diethyl ether and acidified with 37% hydrochloric acid. The title compound precipitates. It is filtered and washed with water, giving after desiccation 3.3 g of the title compound, which is used in further reactions without purification, and melts at 180-181°C after crystallization from 95% ethanol.

Ethyl 3-propionyl-2-(4-trifluoromethylbenzoyloxy)-benzoate (Intermediate LXX)

A solution of 6.7 g of 4-trifluoromethylbenzoyl chloride (prepared from the corresponding benzoic acid and thionyl chloride in benzene at reflux and used without purification) in 50 ml of chloroform is added dropwise to a solution of 7.13 g of ethyl 2-hydroxy-3-propionyl-benzoate and 4.9 ml of triethylamine in 50 ml of chloroform. The mixture is stirred for two hours at room temperature, the solvent is then evaporated in vacuo and the residue is purified by chromatography on a silica gel column eluting with petroleum ether:ethyl acetate 85:15. Evaporation in vacuo to dry, collected fractions gives 7.4 g of the title compound as oil.

NMR spectrum at 60 MHz (CDCl3)

7.6-8.5 (m, 6H, aromatic CHs)

7.5 (t, 1H, phenol ring, CH in 5) 4.2 (q, 2H, COOCH2) 2.9 (q, 2H, COCH2) 1-1.3 (2t, 6E, 2x CH3)

8-ethoxycarbonyl-3-methyl-4-oxo-2-(trifluoromethvlphenyl)-4H-1-benzopyran (Intermediate LXXI)

A mixture of 6.96 g of Intermediate LXX and 2.58 g of potassium t-butoxide in 35 ml of pyridine was stirred at 100°C for two hours. After this time, the reaction mixture is cooled to room temperature, poured into a solution of 50 ml of acetic acid in 600 ml of water and extracted with ethyl acetate. The organic layer is washed with 10% hydrochloric acid and water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo to give 6.9 g of l-(2-hydroxy-3-ethoxycarbonyl)- -2-methyl-3-(4- trifluoromethylphenyl)-1,3-propanediones. A solution of the thus prepared compound and 2.2 ml of 37% hydrochloric acid in 35 ml of glacial acetic acid was stirred at 100°C for 1.5 hours. After cooling to room temperature, the mixture is poured into 630 ml of 1N sodium hydroxide and extracted with ethyl acetate. The organic layer is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The crude product is purified by chromatography on a silica column eluting with petroleum ether: ethyl acetate 85:15. Evaporation in vacuo to dryness gave 2.95 g of the title compound, melting at 111-113°C after crystallization from cyclohexane.

8-carboxy-3-methyl-4-oxo-2-(4-trifluoromethylphenyl1-4H-1-benzopyran (Intermediate LXXII)

A mixture of 2.95 g of Intermediate LXXI and 0.43 g of lithium hydroxide mono-hydrate in 12.5 ml of methanol and 12.5 ml of tetrahydrofuran containing 8 ml of water is stirred at room temperature for one and a half hours. The mixture is poured into a solution of 30 ml of 1N hydrochloric acid in 300 ml of water, and filtered with suction to give 2.4-7 g of the title product, which is used without further purification. The sample crystallized from 60% ethanol melts at 253-254°C.

8-ethoxycarbonyl-2-(4-benzoylphenyl)-3-methyl-4-oxo-4H-1-benzopyran (Intermediate LXXIII)

The title compound is synthesized following the procedure of Intermediates LXX and LXXI in the order described, but starting from 4-benzoylbenzoyl chloride instead of 4-trifluoromethylbenzoyl chloride and reacting this compound in 1,2-dichloroethane instead of chloroform and in the presence of 4-dimethylaminopyridine instead of triethylanine.

After the usual procedure, the residue is purified by chromatography on a silica column eluting with dichloromethane:ethyl acetate 9:1. Evaporation in vacuo to dryness of the collected fractions gave the title product which was used without further purification. The sample crystallized from cyclohexane melts at 125-136°C (dec.).

8-carboxy-2-(4-benzoylphenyl)-3-methyl-4-oxo-4H-1-benzopyran (Intermediate LXXIV)

The title sequence is prepared in the same way as Intermediate LXXII, but starting from Intermediate LXXIII instead of Intermediate LXXI. It is purified by dissolving the crude product in 0.5M sodium hydroxide, the aqueous layer is washed with ethyl acetate and the pure title compound is precipitated with the addition of 37% hydrochloric acid. The sample crystallized from acetic acid melts at 260-262°C,

ethyl 2-(4-phenoxybenzoyloxy)-5-propionyl-benzoate (Intermediate LXXV)

The title compound was prepared in the same manner as described for Intermediate LXX, but starting from 4-phenoxybenzoyl chloride instead of 4-trifluoromethylbenzoyl chloride. Evaporation of the solvent gave the pure title product.

NMR spectrum at 200 MHz (CDCl3, δ) 8.17 (dd, 3H, phenyl CHs in position ortho to carboxylate groups)

7.92 (dd, 1H, phenyl CH in the position ortho to the CO group)

7.38-7.48 (m, 3H, phenyl CHs in the position of meta to carboxylate groups)

7.25 (d, 1H, CH in the position of the 4-phenoxy ring)

7.05-7.10 (2d, 4H, other CHs of the phenoxy ring)

4-.25 (q, 2H, CH2O)

2.90 (q, 2H, CH2CO)

1.05-1.20 (m, 6H, 2 x CH3)

8-ethorycarbonyl-3-methyl-4-oxo-2-(4-phenoxyphenyl)-4H-1-benzopyran (Intermediate LXXVI)

The title compound is prepared in the same way as Intermediate LXXI, but starting from Intermediate LXXV instead of Intermediate LXX. Purification was carried out on a silica column with elution with petroleum ether:ethyl acetate 6:4. Evaporation in vacuo gave the pure title compound, m.p. 98-100°C.

8-carboxy-5-methyl-4-oxo-2-(4-phenoxyphenyl)-4H-1-benzopyran (Intermediate LXXVII)

This compound was obtained in the same way as Intermediate LXXII, but starting from Intermediate LXXVI instead of Intermediate LXXI.

8-carboxy-2-(t-butyl)-3-methyl-4-oxo-4H-1-benzopyran (Intermediate LXXVIII)

6 ml of pivaloyl chloride is added dropwise to a mixed solution of 8.9 g of ethyl 2-hydroxy-3-propionyl-benzoate in 20 ml of anhydride pyridine. The reaction mixture is stirred at 30°C for 6 hours, cooled to room temperature and 200 g of crushed ice and 30 ml of 10N hydrochloric acid are poured into the mixture. After extraction with diethyl ether, the organic phases are washed with solvent, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo, yielding 11.4 g of crude ethyl 2-pivaloxyloxy-3-propionyl-benzoate. 2.4 g of this compound is dissolved in 4 ml of anhydrous pyridine and 1 g of anhydrous potassium t-butoxide is then added to the solution. The resulting mixture is heated for 15 minutes at 100°C, cooled to room temperature and poured into 50 g of ice water containing 8 ml of 10N hydrochloric acid. After extraction with diethyl ether, the organic phases are washed with brine, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo, yielding 2.1 g of crude ethyl 2-hydroxy-3-(pivaloylpropionyl)-benzoate, which is used in the next step without further purification. . 2 g of the compound thus prepared is heated for 15 minutes at 100°C after dissolving in a mixture containing 15 ml of acetic acid and 1-.5 ml of 37% hydrochloric acid.

After cooling to room temperature, the mixture is poured into 100 ml of water and extracted with diethyl ether. The organic phase is washed with 5% aqueous sodium hydrogen carbonate and then with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo, yielding 1.6 g of crude 8-ethoxycarbonyl-2-(t-butyl)-3-methyl -4-oxo-4H-1-benzopyran.

1.5 g of the previous ester is dissolved in 2 ml of methanol, then 3 ml of 10 N sodium hydroxide is slowly added, keeping the temperature between 25 and 35°C. After 1.5 hours at room temperature, the reaction mixture is diluted with 100 ml of water and extracted with ethyl acetate. The aqueous layer is acidified with 3N hydrochloric acid. The precipitate was collected by suction, washed with water and crystallized from ethazol to give 0.8 g of the title compound, melting at 225-228°C.

8-carboxy-2-cyclohexyl-3-methyl-4-oxo-4H-1-benzopyran (Intermediate LXXIX)

This compound is prepared according to the reaction scheme and procedures described in 2a Intermediate LXX7III, but starting from cyclohexylcarboxyl chloride instead of pivaloyl chloride, and with some other differences. In fact, ethyl 2-cyclohexylcarbonyloxy-3-propionyl-benzoate was obtained after 5 hours of stirring in pyridine at room temperature and converted to ethyl 2-hydroxy-3-(2-cycloie-xylcarbonyl-propionyl)-benzoate by heating with potassium t -buroxidone for 2.5 hours at 100°C. The cyclization of 8-ethoxycarbonyl-2-cyclohex-1-3-methyl-4oxo-4H-1-benzopyran was carried out by heating in a mixture of acetic and hydrochloric acid at 100°C for 1.5 hours and the title compound was obtained by hydrolysis (it was carried out during 20 minutes at room temperature). The title compound melts at 224°C after crystallization from 40% ethanol.

8-ethoxycarbonyl-2-(2-furyl)-5-methyl-4-oxo-4H-1-benzopyran (Intermediate LXXX)

A mixture of 3.2 g of Intermediate XC and 1.3 g of anhydrous potassium t-butoxide in 8 ml of anhydrous pyridine is stirred at 60°C for 15 minutes, cooled to room temperature and poured into 60 ml of ice water containing 15 ml of 10 N hydrochloric acid. After extraction with ethyl acetate, the organic phases are washed with an aqueous 5% solution of sodium bicarbonate and water and dried over anhydrous sodium sulfate. After evaporation in a vacuum, 2.5 g of crude ethyl 3-(2-furoyl-propionyl)-2-hydroxy-benzoate are obtained. 2.5 g of the thus obtained compound is mixed at 100°C for 30 minutes with 10 ml of acetic acid and 0.7 ml of 57% hydrochloric acid. After cooling to room temperature, the mixture is poured into 180 ml of water. The title compound precipitates and is collected by suction filtration, washed with water and crystallized from isopropanol. Yield: 1.5 g, m.p. 137-139°C

8-carboxy-2-(2-furyl)-5-methyl-4-oxo-4H-1-benzopyran (Intermediate LXXXI)

A mixture of 3.5 g of Intermediate LXXX and 6 ml of 10 N sodium hydroxide in 40 ml of methanol is mixed at room temperature for one hour and poured into 500 ml of water. After extraction with ethyl acetate, the aqueous layer is acidified with 3N hydrochloric acid. The title compound precipitates and is collected by suction filtration, washed with water and crystallized from a 7:3 methanol:chloroform mixture. Yield: 2.55 G, T.T. 272-277°C

8-ethoxycarbonyl-3-methyl-4-oxo-2-(2-thienyl)-4H-1-benzopyran (Intermediate LXXXII)

This compound was prepared in two steps according to the procedures described for Intermediate LXXX, but using Intermediate XCI in place of Intermediate XC. The title compound melts at 116-118°C after crystallization from isopropanol.

8-carboxy-3-methyl-4-oxo-2-(2-thienyl)-4H-1-benzopyran (Intermediate LXXXIII)

This compound is prepared according to the procedures described for Intermediate LXXXI, but using Intermediate LXXXII instead of Intermediate LXXX. The melting point was 287-294-°C after crystallization from a 7:3 mixture of methanol and chloroform.

8-carboxy-4-oxo-2-phenyl-4H-1-benzothiopyran (Intermediate LXXXIV)

A mixture of 1 g of 8-methoxycarbonyl-4-oxo-2-phenyl-4H-1-benzothiopyran (Intermediate XCII), 2.2 ml of 12.5 N sodium hydroxide, 15 ml of methanol and 5 ml of dioxane was stirred at room temperature for 2.5 hours. After evaporation from vacuum, water is added until complete dissolution, and this solution is extracted with chloroform. The separated aqueous phases are acidified with dilute hydrochloric acid until complete precipitation of the crude compound, which is then filtered and purified by crystallization from acetic acid. Yields 0.62 g, wt.t. 302°C

(E)-8-ethoxycarbonyl-5-methyl-4-oxo-2-(2-styryl)-4H-1-benzopyran (Intermediate LXXXV)

This compound is prepared in three steps according to the procedures described with Intermediate XC (first step) and Intermediate LXXX (second and third steps).

In the first step, (E)-cinnamoyl chloride is used instead of 2-furoyl chloride and the resulting (3)-ethyl 2-hydroxy-3-(2-styryl-popionyl)-benzoate is used without further purification for the second step. The title compound melts at 129-130°C after crystallization from isopropanol.

(E)-8-carboxy-3-methyl-4-oxo-2-styryl-4H-1-benzopyran (intermediate LXXXVI)

This compound is prepared according to the procedures described for Intermediate LXXXI, but starting from Intermediate LXXXV instead of Intermediate LXXX, and keeping the reaction at room temperature for 10 hours. The title compound melts at 284-286°C after crystallization from ethanol.

8-carboxy-3-methyl-2-(4-methylphenyl)-4-oxo-4H-1-benzopyran (Intermediate LXXXVII)

A mixture of 1.9 g of 2-hydroxy-3-propionyl-benzoic acid (prepared as described in Brit. 1, 34-343 119 1974). 5.2 g of anhydrous sodium 4-methylbenzoate and 3.9 m)-4-methylbenzoyl chloride are mixed at 155-195°C for 8.5 hours. After cooling to room temperature, the solidified mass is left to stand overnight with 100 ml of chloroform. The mixture is then shaken with a 5% aqueous sodium carbonate solution, which is added until the pH of the aqueous phase is 8.9. The organic phase is extracted with 3% sodium carbonate and the aqueous phases are combined, repeatedly extracted with diethyl ether and acidified with 10 N hydrochloric acid. The precipitate is purified by light chromatography on silica gel eluting with chloroformmethanol 100:2 to 100:20. The title compound, obtained by vacuum evaporation of the combined fractions containing it, melts at 249-251°C, after crystallization from ethanol.

8-ethoxycarbonyl-2-(4-fluorophenyl)-3-methyl-4-oxo-4H-1-benzopyran (Intermediate LXXXVIII)

This compound is prepared in three steps according to the procedures described for Intermediate XC (first step) and Intermediate LXXX (second and third steps). In the first step, 4-fluorobenzoyl chloride is used instead of 2-fluoroyl chloride, and the reaction lasts for 20 hours at room temperature, giving ethyl 2-(4-fluorobenzoyloxy)-3-propi-onyl-benzoate. This compound is used in the second step without further purification. The title compound melts at 128-130°C after taking up in diethyl ether and crystallization from ethanol.

8-carboxy-2-(4-fluorophenyl)-3-methyl-4-oxo-4H-1-benzopyran (Intermediate LXXXIX)

A solution of 3.3 g of Intermediate LXXXVIII and 0.6 g of lithium hydroxide hydrate in 50 ml of tetrahydrofuran, 10 ml of methanol and 10 ml of water is kept at room temperature for 5 hours and then poured into 300 ml of 1N hydrochloric acid. The precipitate formed is collected by suction filtration, washed with water and dried to give 2.3 g of the title compound, which melts at 249-250°C after crystallization from 95% ethanol.

ethyl 2-(2-furoyloxy)-5-propionyl benzoate (Intermediate XC)

4.35 ml of 2-furoyl chloride is added dropwise with iodine at 10-15°C to a mixed mixture of 8.9 g of ethyl 2-hydroxy-3-propionyl-benzoate and 5.4 g of 4-dimethylaminopyridine in 25 ml of dichlorosethane. After two hours at room temperature, the reaction is quenched with 200 ml of water. The organic layer is washed with a 5% solution of sodium bicarbonate, dried over anhydrous sodium sulfate and evaporated in vacuo, the residue is purified by light chromatography on silica gel eluting with petroleum ether ethyl acetate 4:1, obtaining 9.4 g of the title spray as a solid of low melting point, which is used in a further step without purification. NMR spectrum at 60 MHz (CDCl3, δ)

8.2 (1H, dd, CH in position 4 of the benzene ring)

8.0 (1H, dd, CE in position 6 of the benzene ring)

7.7-7.5 (1H, dd, CH in position 5 of the furan ring)

7.43 (1H, t, CE in position 5 of the benzene ring)

7.45 (1H, s, CH in position 3 of the furan ring)

6.6-6.8 (1H, m, CH in position 4 of the furan ring)

4.3 (2H, q, COOCH2CH3) 2.9 (2H, q, COCH2CH3)

0.95-1.35 (6H, m, 2 x CH3)

ethvl 5-propionyl-2-(2-thienylcarbonyloxy)-benzoate (Intermediary XCI)

This compound was prepared in the same manner as Intermediate XC, but using 2-thienylcarboxyl chloride instead of 2-furoyl chloride.

NMR spectrum at 60 MHz (CDCl3, δ)

7.1-8.35 (6H, m, aromatic CHs)

4.25 (22H, q, CCOCH2CH3)

2.9 (2H, q, COCH2CH3)

0.95-1.3 (6H, m, 2 x CH3)

8-methoxycarbonyl-4-oxo-2-phenyl-4H-1-benzothiopyran (intermediate XCII)

A mixture of 16.5 ral of methyl thiosalicylate1, 25.6 ml of ethyl benzoylacetate and 350 g of polyphosphoric acid is stirred at 90°C for 3 hours. After cooling to room temperature, the mixture is poured into crushed ice and the raw material is collected by filtration, washed with water and purified by crystallization from ethanol. T.t. 170-171°C.

Analysis of elements for C17H12O3S:

Calculated (%): 0.68.90, H, 4.08 S, 10.82.

Found (+) C, 68.59; H, 4.13 S, 10.69.

NMR spectrum at 200 MHz (CDCl3, δ)

8.83-8.95 (dd, 1H, benzothiopyran CH in 5)

S.4-5-8.53 (dd, IH, benzothiopyran CH in 7)

7.68-7.80 (m, 2H, 2-phenyl CHs in 2 and 6)

7.55-7.65 (t, 1H, benzothiopyran CH in 5)

7.45-7.55 (m 3H, 3H, 2-phenyl CHs in 3,4 and 5)

7.24 (s, 1H, benzothiopyran CH in 3)

4.00 (s, 3H, COOCH5)

8-ethoxycarbonyl-3-bromomethyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XCIII)

A mixture of 9.2 g of 8-ethoxycarbonyl-3-aethyl-4-oxo-2-phenyl-4H-1-benzopyran (prepared as described by Da Re, P. et al., T. Med. Pharm. Chem., 2 , 253, 1960), 6.4 g of N-bromosuccinimide and 0.04 g of benzoyl peroxide in 80 ml of anhydrous carbon tetrachloride are mixed at reflux for 1.5 hours. After cooling to room temperature, the formed succinimide is collected by suction and washed with cold carbon tetrachloride.

The base liquid was evaporated to dryness in vacuo, and the residue was taken up in diethyl ether and collected by suction filtration to give 9.2 g of the title compound, melting at 133-134°C after crystallization from acetone:n-hexane.

8-ethoxycarbonyl-3-acetoxymethyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XCIV)

A solution of 10.2 g of sodium acetate trihydrate in 3.0 ml of water is added dropwise, at room temperature, to a solution of 29 g of Intermediate XCTII in 300 ml of dimethylformamide. After stirring at 50°C for 1.5 hours, the reaction mixture is poured into 2 liters of water and the precipitated title product is collected by suction filtration and crystallized from acetone to give 20 g (two "yields" collected). T.t. 151-152°C.

8-carboxy-3-hydroxymethyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XCV)

116 -1 1N sodium hydroxide is added over 10 minutes to a mixed suspension of 14.8 g of Intermediate ZCIV in 300 ml of 95% ethanol. The reaction mixture was then heated to 60-65°C for 15 minutes, giving a clear solution which was kept at room temperature for a further hour. After evaporation in vacuo, the residue is dissolved in 200 ml of water and the solution is acidified by slowly adding 10 ml of hydrochloric acid (d=1.18). After stirring for one hour at room temperature, the title compound is collected by suction filtration, washed with water and crystallized from isopropanol, giving 9.3 g, mp (225) 237-240°C.

ethyl-2-(4-nitrobenzoyloxy)-3-propionyl-benzoate (Intermediate XCVI)

The title product was prepared according to the procedure described for Intermediate XC, but using 4-nitrobenzoyl chloride instead of 2-furoyl chloride. The product was obtained as a low melting point solid. (m.p. (40) 78-80°C).

NMR spectrum at 60MHz (CDCl3, δ)

7.85-8.50 (m, 6H, aromatic CHs)

7.50 (t, IH, CHs in position 5 of the phenol ring)

4.25 (q, 2H, CH2O)

3.95 (q, 2H, CH2)

0.95-1.30 (m, 6H, CH3)

8-ethoxycarbonyl-5-methyl-2-(4-nitrophenyl)-4-oxo-4H-1-benzopyran (Intermediate XCVII).

A mixture of 29.7 g of Intermediate XCVI and 10.15 g of anhydrous potassium t-butoxide in 59 ml of anhydrous pyridine was stirred at 100°C for 13 hours. The reaction mixture is cooled to room temperature, poured into 400 ml of 4N hydrochloric acid and extracted with dichloromethane. The organic layer is washed several times in a row with water, then with 2.5% sodium hydrogen carbonate, dried over anhydrous sodium sulfate and evaporated to dryness in a vacuum.

The crude product is purified by chromatography on a silica gel column eluting with hexane:ethyl acetate 7:3. Evaporation in vacuo of the collected fractions gives 7 g of the title compound, which melts at (130) 145-148°C.

8-carboxy-3-methyl-2-(4-nitrophenyl)-4-oxo-4H-1-benzopyran (Intermediate XCVIII)

A suspension of 0.38 g of Intermediate XCVII in 4.75 ml of dioxane and 4.75 ml of methanol is stirred at 50°C. 1.29 ml of 1N sodium hydroxide is added and stirring is continued for three hours at the same temperature. The reaction mixture is cooled to room temperature and 3N hydrochloric acid is added to pH 1. The suspension is filtered with suction to give 0.13 g of the title compound, which melts at 320 -321°C after crystallization from dioxane.

8-ethoxycarbonyl-3-methyl-4-oxo-2-trifluoromethyl-4H-1-benzopyran (Intermediate XCIX)

3.16 ml of 1,S-diazobicyclo (5.4.o)undec-7-ene was added dropwise at 0°C using a needle to a mixed mixture of 3 g of ethyl 2-hydroxy-3-propionyl-benzoate and 5.53 ml of trifluproacetic anhydride. The reaction mixture was stirred at 60°C for 4 hours after that period, cooled to room temperature and diluted with ethyl acetate and water. The organic layer is washed with 1N sodium hydroxide and water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The residue was purified by chromatography on a silica gel column eluting with petroleum ether:ethyl acetate 95:5 to give 0.8 g of the title compound.

NMR spectrum at 200 MHz (CDCl3, δ)

8.41, 8.37 (2dd, 2H, CHs in positions 5 and 7 of the benzopyran ring)

7.51 (t, 1H, CH in position 6 of the benzopyran ring)

4.46 (q, 2H, COOOH2)

2.22-2.27 (m, 3H, JH-F=2.16 Hz, CH3, in position 3 benzopyran. finger.)

1.39 (t, 3H, CH2CH3)

8-carboxy-3-methyl-4-oxo-2-trifluoromethyl-4H-1-benzopyran (Intermediate C)

The title compound was prepared in the same manner as Intermediate LXII, but using Intermediate XCIX instead of Intermediate LXI, and after diluting with water, extracting with ethyl acetate instead of filtering. After drying over anhydrous sodium sulfate and evaporating the organic layer to dryness in vacuo, the title compound is obtained as a solid melting at 175-178°C.

3-[4-(2-methoxyphenyl)-1-piperaziny]-N-methyl-propylazine (Intermediate CI)

42 ml of 35% aqueous methylamine was added to a solution of 8.2 g of 3-[4-(2-methoxyphenyl)-1-piperazinyl]-propyl chloride in 48 ml of dimethylformamide. The mixture is heated to 60°C in a closed flask for 5 hours, and then cooled to 30°C. The solvent is evaporated in a vacuum, and the residue is mixed for 30 minutes with 100 ml of diethyl ether. The solids collected by suction filtration are dissolved in 200 ml of chloroform: 5N methanolic ammonia 100:3. After 30 minutes of mixing at room temperature, the solution is adsorbed by column chromatography and eluted using chloroform: 5N methanolic ammonia 100:5 to 100:15. Fractions containing the title compound were combined and evaporated in vacuo to give 3 g of Intermediate CI as a thick oil.

NMR spectrum at 60 MHz (DMSO-d6, δ)

6.80 (s, 4H, aromatic CHs)

3.75 (s, 3H, OCH3)

3.20-2.75 (m, 4H, piperazine-CH2s in positions 3,5)

2.75-2.10 (m, 8E, piperazine CH2s in positions 2,6 and : CH2 CH2CH2)

2.40 (s, 1H, NH)

2.30 (s, 3H, NCH3)

1.80-1.40 (m, 2H, CH2CH2CH2)

ethyl 2-benzoyl-3-ethylbenzo[b]furan-7-carboxylate (Intermediate CII)

A mixture of 11.1 g of ethyl 2-hydroxy-3-propionyl-benzoate, 9.9 g of phenacyl bromide, 6.9 g of anhydrous potassium carbonate and 200 ml of acetone is stirred at reflux temperature for 7 hours. After cooling to room temperature, the inorganic salts are separated by filtration, and the solution is evaporated in a vacuum. The residue is purified by light chromatography on a silica gel column eluting with toluene. The title compound, obtained by vacuum evaporation of the combined fractions containing it, is crystallized from 90% ethanol. Yield: 9.8 g, m.p. 64-66°C.

7-carboxy-2-benzoyl-3-ethyl-benzo [b] furan (Intermediate CIII)

A mixture of 7 g of Intermediate CII, 275 ml of 0.95N sodium hydroxide and 400 ml of dioxane is stirred at reflux temperature for 4 hours. After cooling to room temperature, dioxane is evaporated in vacuum and replaced with the same volume of water. After filtering through charcoal, the solution is acidified with dilute hydrochloric acid and the precipitate is filtered and purified by crystallization from acetone. Yield: 4.94 g, m.t. 193-195°C.

methyl 3-methyl-2-(4-methylphenyl)-4-oxo-4H-1-benzopyran-8-carboxylate (Intermediate CIV)

This compound is prepared in three steps according to the procedures described for Intermediate XC (first step) and Intermediate LXXX (second and third steps). In the first step, 4-methylbenzoyl chloride is used instead of 2-furanecarbonyl chloride and methyl 2-hydroxy-3-propionylbenzoate instead of ethyl 2-hydroxy-3-propionylbenzoate. The reaction lasts for 4 hours at room temperature, giving methyl 2-(4-methylbenzoyloxy)-3-propionylbenzoate. This compound is used without purification on column chromatography for the second step which lasts 1.5 hours at 100°C. In the third step, 96% sulfuric acid is used instead of 37% hydrochloric acid.

The title compound melts at 174-175°C after crystallization from ethanol.

ethyl 2-(4-biphenylyl)-3-methyl-4-oxo-4H-1-benzopyran-8-carboxylate (Intermediate CV)

This compound is prepared in three steps according to the procedures described for Intermediate XC (first step) and Intermediate CIV (second and third steps). In the first step, 4-phenylbenzoyl chloride is used instead of 2-furanecarbonyl chloride and the reaction lasts 20 hours at room temperature and 13 hours at reflux temperature. Purification is carried out by chromatography on a silica gel column with elution with petroleum ether: ethyl acetate graduations from 100:5 to 100:10, giving ethyl 2-(4-biphenyl)-3-propionylbenzoate.

The title compound melts at 165-167°C after taking up in 95% ethanol.

2-(4-biphenyl)-3-methyl-4-oxo-4H-1-benzopyran-8-carboxylic acid (Intermediate CVI)

A mixture of 4.3 g of Intermediate CV and 35 ml of 35% hydrochloric acid in 50 ml of 1,4-dioxane and 15 ml of water was mixed at reflux for 16 hours. After cooling, the mixture is poured into 200 ml of water and extracted with ethyl acetate. The organic layer is separated and extracted with a 20% aqueous sodium carbonate solution. The precipitate is formed after acidifying the aqueous layer with dilute hydrochloric acid, collected by suction, washed with water and dried to give 2.5 g of the title compound melting at 242.5- 244°C.

2-(4-hydroxyphenyl)-5-methyl-4-oxo-4H-1-benzopyran-8-carboxylic acid (Intermediate CVII)

A mixture of 3 g of ethyl 2-(4-methoxyphenyl)-3-methyl-4-oxo-4H-1-benzopyran-8-carboxylate (prepared as described in JP 58,225,083 C.A. 100, 191648b. (1984)) and 60 ml 48% hydrobromic acid in 80 ml of acetic acid is stirred at reflux for 8 hours. After cooling, the mixture is poured into 500 ml of water and the precipitate is collected by suction and washed with water. The crude product is purified by light chromatography eluting with chloroform-isopropyl alcohol gradation from 9:1 to 7:3, followed by elution with methanol, thus obtaining 1 g of the title compound, which melts at 300°C.

1-(2-methoxyphenyl)-4-(4-methylaminobutyl)piperazine (Intermediate CVIII)

A solution of 3.8 ml of trifluoroacetic anhydride in 25 ml of anhydrous dichloromethane is added dropwise with stirring at 0°C to a solution of 2.53 g of 4-[-(2-methoxyphenyl)-1-piperazinyl]butylamine in 25 d of anhydrous dichloromethane. After two hours of stirring at room temperature temperature, the reaction mixture is diluted with dichloromethane and washed with water. The organic layer was dried over sodium sulfate and evaporated to dryness in vacuo, yielding 3.3 g of pure 1-(2-methoxy-phenyl)-4-(4-trifluoroacetyl amino)butylpiperazine as per NMR spectrum.

NMR spectrum at 60 MHz (CDCl3, δ)

7.70-8.00 (bs, 1H) NH

6.80-7.20 (m, 4H) aromatic CHs

3.85 (s, 3H) CH 5 O

2.0-3.80 (m, 12H) piperazine CH2s,CH2N and CH2NHCO

1.50-2.05 (m, 4H) C-CH2CH2-C

0.88 g of 50% sodium hydride is added in portions with stirring at 0°C to a solution of 3.3 g of the above intermediate in 46 ml of anhydrous dimethylformamide. After stirring for 1 hour at the same temperature, 0.57 ml of methyl iodide was added. The reaction mixture was stirred at 0°C for a further 1.5 hours, then poured into water and extracted with ethyl acetate.

The organic layer is washed with water, dried over sodium sulfate and evaporated to dryness in vacuo to give 1.13 g of crude 1-(2-methoxyphenyl)-4-[4-(N-methyltrifluoroacetylamino)butylpiperazine which is used in the next step without further purification. 0.18 g of sodium borohydride is added to a solution of 1.13 g of this intermediate in 30 ml of ethanol and the resulting mixture is stirred at 60°C for one hour. After cooling to room temperature, the reaction mixture is poured into water, extracted with dichloromethane. The organic layer was washed with water, dried over sodium sulfate and evaporated to dryness in vacuo to give 0.82 g of pure title compound,

NMR spectrum at 60 MHz (CDCl3, δ)

6.80-7.20 (m, 4-H) aromatic CHs

3.85 (s, 3H) CH 3 O

2.90-3.20 (m, 4H ) piperazine CH2s, positions 3 and 5

2.30-2.80 (m, 8H) piperazine CH2s, positions 2 and 6

2 x CH2N

2.50 (s, 3H) CH3N

1.80 (s, IH) NH

1.40-1.80 (m, 4H) C-CH2-CH2-C

1-(3-amino-2,2-dimethylpropyl)-4-(2-methoxyphentyl)-piperazine

The title compound can be prepared by treating 1-(2-methoxyphenyl)-piperazine with isobutyraldehyde, 37% formaldehyde in water and acetic acid at 90-150°C or with ethanolic hydrogen chloride (Mannich reaction) to give 1-( 2-phenyl-2-methyl-propyl)-4-(2-methoxyphenyl)-piperazine, which is then aminated with excess ammonia under reducing conditions. The latter may be hydrogen or a catalyst (for example, palladium on carbon, Raney nickel or platinum dioxide) in a solvent (for example, ethanol, methanol, isopropanol, dichloromethane, chloroform or dimethyl-formamide) between room temperature and 80°C, or alternatively a metal hydride (for example, sodium borohydride, sodium or potassium cyanoborohydride or potassium triacetoxyborohydride) in a solvent (for example, methanol, ethanol, chloroform, benzene or 1,2-dichloro-ethane) in the presence of an acid (for example, hydrogen chloride gas or acetic acid), 8-chlorocarbonyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran can be reacted as described in Example 12 below to give 8-(2,2-dimethyl-3 -[4-(2-methnoxyphenyl)-1-piperazinyl]-propyl-carbamoyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran.

8-trifluoroacetamidomethyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran

This compound can be prepared according to the procedure described for Intermediate XXIII, but using Intermediate XXIV instead of 8-amino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran. It can be used as starting material instead of Intermediate XXIII, in the reaction described in Example 32 to give 8-{2-[4-(2-methoxy-phenyl)-1-piperazinyl]-ethylaminomethyl}-3-methyl-4- oxo-2-phenyl-4H-1-benzopyran.

8-(2-chloroethylureidomethyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran

This intermediate can be prepared by the procedure described for the preparation of Intermediate XLIV, but using Intermediate XXIV instead of 8-amino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran. It can react with a compound of formula H-B, according to Path (a) to give the desired final compound.

8-ethenylsulphonylaminomethyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran

This compound is prepared by reacting Intermediate XXIV with 2-chloroethylsulphonyl chloride in a halogenated solvent such as dichloromethane in the presence of triethylamine at 0-40°C, according to A.A. Goldeberg, J. Chem. Soc, 464, 1945. It can react with the corresponding compounds H-B, according to Path (m) to give the corresponding final compound.

Proceeding as described above, but starting from 8-amino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, the final compounds are F1-Y36-(CH2)2-B.

8-chlorosulphonylmethyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran

This intermediate can be prepared by reacting 8-amidinothiomethyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (the synthesis of which is described in Intermediate XXI) with chlorine gas in water at -10 to +10°C according to T.B. Johnson et al., J. Chem. Soc, 61, 2548, 1939. By reacting this intermediate with the corresponding compounds A-NH-Z-B according to Path n, the desired compounds can be obtained.

Examples

Example 1

8-{2-(4-(2-methoxyphenyl)-1-piperazinyl)-1-oxoethyl}-3-methyl-4-oxo-2-phenvyl-4H-1-benzopyran hydrochloride

A solution of 11.5 g of 1-(2-methoxyphenyl)-piperazine in 30 ml of methanol is added dropwise at 20-25°C to a stirred mixture consisting of 21.4 g of Intermediate VI and 4.1 g of potassium carbonate in 120 ml of methanol. After stirring for 4 hours at the same temperature, the reaction mixture is placed in a vacuum. The residue is extracted with chloroform and the organic layer is washed with water, dried over anhydrous sodium sulfate/calcium chloride, filtered and dried in vacuo.

The obtained crude product is dissolved in acetone and an excess of ethanolic hydrogen chloride is added. After collection by suction filtration and recrystallization from 95% ethanol, 16.3 g of the title compound are obtained, m.p. (189) 195-199°C.

Example 2

8-{2-[4-(2-methylphenyl)-1-piperazinyl]-1-oxoethyl}-3-methyl-4-oxo-2-phenyl-4H-41-benzopyran hydrochloride

This compound is prepared according to Example 1, but using 1-(2-methylphenyl)-piperazine instead of 1-(2-methoxy phenyl)-piperazine and carrying out the reaction in dimethylformamide for 1 hour instead of methanol for 4 hours, M.p. (194) 203-206°C (isopropanol).

Example 3

8-(2-[4-{2-ethoxyphenyl)-1-piperazinyl}-1-oxoethyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride

This compound was prepared according to Example 1, but using 1-(2-ethoxyphenyl)-piperazine instead of 1-(2-methoxy phenyl)-piperazine and conducting the reaction in dimethylformamide for two hours instead of methanol for four hours. T.t. 208-210°C (isopropanol).

Example 4

8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-1-oxopropyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride

A solution of 10 ml of 37% formaldehyde in 15 ml of methanol is added dropwise, during 3 minutes at 0°C, to a solution of 5.75 g of 1-(2-methoxyphenyl)-piperazine in 10 ml of methanol. After 12 hours at 0°C, the mixture was dried in vacuo and redissolved in 15 ml of methanol. At 0°C, 20 ml of 3.6N hydrogen chloride in diethyl ether is added. After drying in vacuum, the residue is suspended in 15 ml of 1,4-dioxane. With stirring at 20-25°C, add a solution of 8.3 g of Intermediate V in 100 ml of 1,4-dioxane. After stirring for 8 hours at reflux, the reaction mixture is cooled to 30-40°C. 50 ml of methanol was added and the mixture was refluxed for a further two hours. After cooling to 20-25°C, the resulting solution is diluted with 300 ml of diethyl ether. Stirring is continued for a further three hours at the same temperature. The title compound is collected by suction filtration and recrystallized from ethanol. Yield: 4 g, m.p. 209-210°C.

Example 5

8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propoxycarbonyl}3-methyl-4-oxo-2-phenyl-4H-1benzopyran dihydrochloride

A mixture of 4.24 g of 8-carboxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran and 6.3 g of anhydrous potassium carbonate in 60 ml of dimethylformamide was stirred at 80°C for 30 minutes. Then 5.23 g of 1-(3-chloropropyl)-4-(2-methoxyphenyl)-piperazine was added and stirring was continued at 80 C for three and a half hours. The reaction mixture was cooled to room temperature, poured into ice water and extracted with ethyl acetate. The organic extracts are washed with an aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and evaporated to dryness in a vacuum. The residue is then taken up in ethanol and an excess of ethanolic hydrogen chloride is added to the solution. Yield: 8.16 g of the title compound, m.p. 198-203°C.

Example 6

8-(2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethoxycarbonyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran dihydrochloride

Proceeding as described in Example 5, but using 1-(2-chloroethyl)-4-(2-methoxyphenyl)-piperazine instead of 1-(3-chloropropyl)-4-(2-methoxyphenyl)-piperazine, the title compound is obtained compound, m.p. 200-203°C from ethanol.

Example 7

3-(3-(4-(2-chlorophenyl)-1-piperazinyl]-propoxycarbonyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran dihydrochloride

A mixture of 2.8 g of 1-(2-chlorophenyl)-piperazine hydrochloride and 4.2 g of anhydrous potassium carbonate in 25 ml of dimethyl formamide was stirred at room temperature for 15 minutes. 4.81 g of Intermediate I is added, and the mixing is continued for 2 days. The reaction mixture is then poured into 200 ml of cold water, extracted with diethyl ether and ethyl acetate.

The organic extracts are washed with an aqueous solution of sodium chloride, 0.1N acetic acid, an aqueous solution of sodium chloride, an aqueous 4% solution of sodium carbonate and water, and then dried over anhydrous sodium sulfate. After evaporation to dryness in vacuo, the residue is dissolved in 160 ml of acetonitrile and an excess of hydrogen chloride in diethyl ether is added. The insoluble title compound is recrystallized from acetonitrile. Yield: 3.6 g, m.p. 138-143°C.

Example 8

8-[3-(4-phenyl-1-piperazinyl)-propoxycarbonyl]-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran dihydrochloride

The title compound was prepared using the procedure described in Example 7, but using 1-phenyl-piperazine in place of 1-(2-chloro-phenyl)-piperazine hydrochloride. Recrystallization is carried out from methanol; melting point is 229-231°C.

Example 9

8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propoxycarbonyl}3methyl-4-oxo-2-phenyl-4H-1-benzopyran dihydrochloride

Proceeding as described in Example 7j but using 1-(2-methoxyphenyl)-piperazine hydrochloride instead of 1-(2-chlorophenyl)-piperazine hydrochloride, the title compound is obtained. This represents an alternative route to the product from Example 5.

Example 10

8-{3-[4(2-methoxyphenyl)-1-piperazinyl]-2-methyl-2-propoxy-carbonyl}-5-methyl-4-oxo-2-phenyl-4H-1-benzopyran dihydrochloride

5.29 g of Intermediate XXVIII in 25 ml of 1,2-dichloroethane is added dropwise at 60°C to a solution of 6 g of 8-cyclocarbonyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran in 22 ml of 1,2 -dichloroethane. The reaction mixture is refluxed for 16 hours, then cooled to room temperature and poured into a cold 0.5 sodium hydroxide solution. Add water and dichloromethane. The organic phase is separated, washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvents are evaporated and the oily residue is purified by light chromatography on silica gel, eluting with petroleum ether:ethyl acetate 55:15. The collected fractions were evaporated to dryness in vacuo and the residue was dissolved in ethanol. An excess of ethanolic hydrogen chloride was added to give 6.71 g of the title compound, m.p. 203-204°C.

Example 11

8-{3-[4-(2-ethoxyphenyl)-1-piperazinyl]-propylcarbamoyl}-3-methyl-4oxo-2-phenyl-4H-1-benzopyran dihydrochloride

hemihydrate

A mixture of 6.23 g of 1-(2-methoxyphenyl)-piperazine and 5.34 g. Intermediate XXXYII is heated to 180°C for 5 hours. After cooling, the dark mass is purified by light chromatography on silica gel, eluting with dichloromethane:methanol 100:3. Fractions containing the title compound are combined. The solvents are removed in vacuo and the residue is dissolved in boiling ethanol. The solution is filtered, acidified with ethanolic hydrogen chloride, and left to stand overnight at 20-25°C. The crude product is collected by filtration and crystallization from ethanol yields 5 g of the title compound, m.p. (177) 182-186°C.

Example 12

8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylcarbamoyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran dihydrochloride henihydrate

A solution of 4.48 g of 8-chlorocarboyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran in 40 ml of chloroform is added dropwise over 10 minutes at room temperature to a solution of 3.74 g of 3- 4-(2-methoxyphenyl )-1-piperazinyl propylamine, prepared as described in GB 2161807, and 1.97 g of triethylamine in 50 ml of chloroform. After stirring for two hours, the solution is washed first with 0.5N hydrochloric acid, then with a saturated aqueous sodium bicarbonate solution and finally with water. The chloroform solution is dried over anhydrous sodium sulfate and the solvent is evaporated in vacuo. The residue was treated as described in Example 11 to give the title compound 6.67 g, m.p. (177) 182-185°C. This represents an alternative route to the product from Example 11. The following salts were also prepared:

monohydrochloride hydrate, m.p. 151-154°C,

monomethanesulphonate, m.p. 162-164°C, and

(+)-hemimalate hydrate, m.p. 110-112°C.

This example describes the condensation of an amine, 3-(4-(2-methoxyphenyl)-piperazinyl]-propylamine, with a carbonyl chloride, 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carbonyl chloride.

It should be noted that the amine can be condensed with the corresponding free acid or the corresponding ethyl ester by heating equimolar amounts with or without solvent. If a solvent is used, a suitable hydrophilic or hydrophobic solvent with a high boiling point is suitable. The amine can also be condensed at room temperature with an equimolar amount of the appropriate free acid in the presence of N,N'-dicyclohexylcarbodiimide and 4-dimethylaminopyridine in a solvent such as dichloromethane, chloroform, tetrahydrofuran or dimethylformamide.

Example 13

8-{2-[4(2-methoxyphenyl)-1-piperazinyl]-ethylcarbamoyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran monohydrochloride hemihydrate

The title compound was prepared by the procedure described in Example 16, but using Intermediate XIV instead of Intermediate XV and heating at 55-60°C for 32 hours. Also, the procedure is varied as follows. After collection of the base by filtration, purification was carried out by light chromatography on silica gel with elution with chloroformethanol 100:0.5 and then 100:1. Fractions containing the title compound were combined and the solvents were removed in vacuo. The residue is crystallized from ethanol. After filtration, the solids are taken up in boiling water and enough dilute hydrochloric acid is added to make a solution. Crystal salts are separated by cooling and collected by filtration. T.t. 119-123°C.

Example 14

8-(3-[2-(2-methoxyphenoxy)-ethylamino]-propylcarbamoyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzoryran hydrochloride

Proceeding as described in Example 11, but using 2-(2-methoxyphenoxy)-ethylsine (prepared according to Augstein, J. et al., J.Ked.Chem., 8, 356, 1965) instead of l-(2- methoxyphenyl)-piperazine, by heating for two hours instead of five hours, and using dichloromethanemethanol 100:5 as eluent, the title spectrum is obtained. T.t. 200-202°C (ethanol).

Example 15

8-[3-4-phenyl-1-piperazinyl)-propylcarbamoy]-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran monohydrochloride

hemihydrate

Proceeding as described in Example 11, but using 1-phenylpiperazine instead of 1-(2-methoxy phenyl)-piperazine, heating for 2 hours instead of 5 hours, and using dichloromethane:methanol 100:4 as eluent, the title compound is obtained. T.t. (251) 255-258°C with decomposition (87% ethanol).

Example 16

S-{N-methyl-2-4-(2-methoxyphenyl-1-piperazinyl)-ethylcarbamoyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran monohydrochloride

A mixture of 3.56 g of Intermediate XV, 2.35 g of l-(2-methoxyphenyl)-piperazine, 2.76 g of anhydrous potassium carbonate and 1.66 g of potassium iodide in 25 ml of dimethylformamide was stirred at 100°C for 6 hours. After cooling, the solvent is removed in vacuo and the residue is taken up in 50 ml of water, stirred for one hour at room temperature, collected by filtration, washed with water and crystallized from 95% methanol in the presence of a small amount of activated carbon (to remove color). The base is dissolved in 105 ml of boiling 0.086N hydrochloric acid. After cooling, the crystallized salt was collected by filtration to give 4.3 g of the title compound (mp 201-203°C).

Example 17

8-(1-hydroxy-2-[4-(2-methoxyphenyl}-1-piperazinyl)-ethyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride

1.36 g of sodium borohydride is added in portions at 0 to 5°C to a solution of 15.5 g of the compound prepared in Example 1 in 1500 ml of methanol. After stirring for 90 minutes at 0 to 5°C, 3N hydrochloric acid was added to slightly acidify the reaction mixture, and then dried in vacuo. The residue is shaken with 2N aqueous sodium hydroxide solution and extracted with chloroform. The organic layer is dried over anhydrous sodium sulfate/calcium chloride, filtered, acidified with ethanolic hydrogen chloride and dried in a vacuum. After washing with diethyl ether, the crude product crystallized from ethanol to give 9.5 g of the title compound, m.p. 248-249°C.

Example 18

8-(1-hydroxy-2-[4-(2-methylphenyl)-1-piperazinyl]-ethyl}-3-methyl)-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride

This compound is prepared according to Example 17, but starting from the compound prepared in Example 2, which is more convenient than the compound from Example 1. T.p. 257-258°C (ethanol).

Example 19

8-[1-hydroxy-2-[4-(2-ethoxyphenyl)-1-piperazinyl]-ethyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride

This compound was prepared according to Example 17, but using as starting compound that was prepared in Example 3 rather than the one prepared in Example 1. M.p. 241-242°C (methanol).

Example 20

3-{1-hydroxy-3-[4-(2-methoxphenyl)-1-piperazinyl]-propyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride

This compound was prepared according to Example 17, but starting from the compound prepared in Example 4 rather than from the one prepared in Example 1. The crude base was purified by light chromatography (silica gel, eluants-ethyl acetate-chloroform 4:1). The fractions containing the pure base are combined, acidified with ethanolic hydrogen chloride and dried under vacuum. The residue crystallizes from ethanol. T.t. (126) 156-16°C.

Example 21

3-{1-hydroxy-4-[4-(2-methoxyphenyl)-1-piperazinyl]-butyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride monohydrate

A solution of 3.04 g of Intermediate ZXXVIII and 2.45 g of 1-(2-methoxyphenyl)-piperazine in 21 ml of anhydride dimethyl formamide was stirred for 5 hours at room temperature. A further 1.22 g of 1-(2-methoxyphenyl)-piperazine was added, and the mixture was stirred for 4 hours, poured into 300 ml of water and extracted with ethyl acetate. The combined organic extracts are washed with an aqueous solution of sodium bicarbonate and then with an aqueous solution of sodium chloride, and evaporated to dryness in a vacuum. The residue is purified by light chromatography on silica gel eluting with ethyl acetatermethanol 95:5. The collected fractions are dried in a rotaevaporator, and the residue is dissolved in 0.81 M ethanolic hydrogen chloride and dried again in a vacuum. The solid residue was crystallized from a mixture of water:ethenol 9:1 to give 2.4-3 g of the title compound, m.p. 144-146°C

Example 22

8-{1-ethoxy-2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride

6 ml of anhydrous dimethylsulphoside is added to 6.55 g of sodium hydride (50% in mineral oil, washed several times in a row with hexane) under a stream of nitrogen. A solution of 5 g of the compound prepared in Example 17 in 50 ml of anhydrous dinethylsulphoxide is added to the mixture at 20-25°C. After stirring for 1 hour at 20°C, 0.66 g of ethyl bromide is added. The reaction mixture was stirred for an additional 20 minutes at the same temperature and then poured into ice water. The crude product obtained after suction filtration is purified by light chromatography (silica gel, eluants-chloroform:ethyl acetate 8:2). Fractions containing the pure title compound were collected, acidified with ethanolic hydrogen chloride and dried in vacuo. The residue was crystallized from chloroform:diethyl ether and dried in vacuo at 140°C to give 1.6 g of the title compound, m.p. (155) 209°.

Example 23

8-{N-methyl-2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethylamino-methyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran dihydrochloride hemihydrate

A mixture of 5.2 g of Intermediate XXVII, 3.1 g of 1-(2-methoxyphenyl)-piperazine and 2.2 g of anhydrous potassium carbonate in 50 ml of diethylformamide was stirred at 70°C for 7 hours. After cooling to 20-25°C, the reaction mixture is poured into 500 ml of water, extracted with dichloromethane. The organic phase is washed with water and dried over anhydrous sodium sulfate. The solvent is removed in vacuo. The residue is purified by light chromatography on silica gel, eluting with a mixture of ethyl acetate and petroleum ether 98:2. The title compound is obtained by salification with ethanolic hydrogen chloride. T.t. 217-219°C

Example 24

8-(N-acetyl-2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethylamino-methyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride

A mixture of 5 g of Intermediate XXXIII and 5.3 g of 1-(2-methoxypbenyl)-piperazine in 75 ml of dimethylformamide was stirred at 95°C for two hours. After cooling to 20-25°C, the reaction mixture is poured into 200 ml of water, alkalized with potassium carbonate and extracted with ethyl acetate. The organic phase is washed with water and dried over anhydrous sodium sulfate. The solvent is removed in vacuo. The residue is purified by light chromatography on silica gel, eluting with a mixture of dichloromethanemethanol 100:0.2. By salification of the pure base with ethanolic hydrogen chloride and recrystallization from methanol, 4.4 g of the title compound is obtained, which melts at (200) 227-228°C and contains an equivalent of methanol.

Example 25

8-[4-(2-methoxyphenyl)-1-piperazinylacetamidomethyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride

A mixture of 3.42 g of Intermediate XXXII, 2.74 g of l-(methoxyphenyl)-piperazine and 0.71 g of anhydrous potassium carbonate in 34 ml of anhydrous dimethylformamide was stirred for 2 hours at 0°C. The reaction mixture is poured into water and filtered under suction. The resulting solid is purified by light chromatography on silica gel, eluting with ethyl acetate:petroleum ether 6:4. The collected fractions are evaporated to dryness in vacuo, and the residue is crystallized from ethyl methyl ketone. The resulting base is treated in an ethanolic solution with a molar equivalent of aqueous 2.25N hydrochloric acid to give the title compound, m.p. 168-170°C.

Example 26

S-{N-methyl-N-[4-(2-methoxyphenyl)-1-piperazinyl}-acetamidomethyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride hydrate

A mixture of 5 g of Intermediate XXXI, 2.9 g of 1-(2-methoxypienyl)-piperazine and 2 g of anhydrous potassium carbonate in 50 ml of dimethylformamide was mixed at 20-25°C for 3 hours. The reaction mixture is then poured into 500 ml of water and extracted with dichloroethane. The organic phase is washed with water and dried over anhydrous sodium sulfate. The solvent is removed in vacuo. The residue is purified by light chromatography on silica gel eluting with a mixture of ethyl acetate:petroleum:ether 6:4, and crystallized from acetone giving 3.6 g of the base of the title compound, which melts at 144-145°C. The base was dissolved in ethanol and 8N hydrochloric acid and water were added to give the title compound, m.p. 218-220°C, after drying at 100°C in a vacuum.

Example 27

8-[2-(4-(2-methoxyphenyl)-1-piperaziny]-ethoxyphenyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran dihydrochloride

A mixture of 4 g of Intermediate XVIII, 2.4 g of 1-(2-methoxyphenyl)-piperazine, 1.96 g of potassium iodide and 1.65 g of anhydrous potassium carbonate in 40 ml of anhydrous dimethylformaniide was stirred at 90°C for 7 hours. After cooling to the juice temperature, the mixture is poured into water and extracted with dichlorcrethane. The combined extracts are washed with an aqueous sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness in a vacuum. The residue crystallized from ethyl acetate giving crystals which were collected and dissolved in ethanol, and treated with excess ethanolic hydrogen chloride to give 5.21 g of the title compound, m.p. 199-201°C.

Example 28

8-{2-[2-(2-ethoxyphenoxy)-ethylamino]-ethoxymethyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride

Proceeding as described in Example 27, but using 2-(2-ethoxyphenoxy)-ethylamine in place of 1-(2-methoxyphenyl)-piperazine and including a purification step by light chromatography on silica gel eluting with ethyl acetate methanol 97:3, 4.25 g of the title compound is obtained. T.t. 191-193°C.

Example 29

8-{2-[4-(2-nethoxyphenyl)-1-piperazinyl]-ethylthiomethyl]-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride

2.5 g of potassium carbonate, 2.13 g of potassium iodine and 3.15 g of 1-(2-methoxyphenyl)-piperazine were added to a solution of 5 g of Intermediate XXI in 50 ml of dimethylformamide, and the mixture was stirred at 90°C for 4.5 hours. After cooling to room temperature, the reaction mixture is poured into 4-50 ml of water and extracted with ethyl acetate. The organic extracts are washed with water, dried over anhydrous sodium sulfate and evaporated to dryness under vacuum. A solution of the residue in acetone was treated with a molar equivalent of 3.8N hydrogen chloride in diethyl ether, filtered and recrystallized from ethanol to give 6.15 g of the title compound, m.p. (218) 223-224°C.

Example 30

8-(2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethylsulphinylmethyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran dihydrochloridhemihydrate

The title compound was prepared by the procedure described in Example 29, but using Intermediate XXVI instead of Intermediate XXI and mixing for 2.5 hours, which is preferable to mixing for 4.5 hours. After the usual procedure, the residue is purified by light chromatography on silica gel with elution with a mixture of ethyl acetate:r:ethanol 97:3. The collected fractions are acidified with an excess of ethanolic hydrogen chloride, and evaporation is carried out in a vacuum to dryness. The residue was crystallized from ethanol to give 5.2 g of the title compound, m.p. 170-172°C. This compound contains one equivalent of ethanol.

Example 31

8-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethylsulphonylmethyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride •

A mixture of 4.5 g of Intennedijer XXV, 2.36 g of 1-(2-methoxyphenyl)-piperazine and 0.84 g of potassium carbonate in 45 ml of anhydrous dimethyl-formamide was stirred at room temperature for 2.5 hours. The reaction mixture is poured into 300 ml of water and filtered with suction, and washed with water. The solid base crystallizes from ethanol and has a melting point of 143-146°C. The crystals are dissolved in 1,2-dichloroethane and the solution is acidified with ethanolic hydrogen chloride. Recrystallization from a mixture of methanol:water 1:5.5 gives 4.4 g of the title compound, m.p. 229-233°C.

Example 32

8-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethylamino}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran dihydrochloride

A solution of 3.7 g of Intermediate XXIII in 10 ml of dimethylformamide is added dropwise at 0°C to a suspension of 0.9 g of sodium hydride (50% in mineral oil) in 9 ml of dimethylformamide. The cold bath is removed, and after 30 minutes at 20-25°C, a solution of 4.1 g of 1-(2-chloroethyl)-4-(2-methoxyphenyl)-piperazine in 10 ml of dimethylformamide is added. The mixture is stirred at 90°C for 5 hours and then cooled to 20-25°C. Then 0.25 g of sodium hydride (50 ml in mineral oil) is added, followed by 1.36 g of 1-(2-chloroethyl)-4-( 2-methoxyphenyl)-piperazine in 5 ml of dimethylformamide. The mixture is stirred at 90°C for 8 hours and cooled again to 20-25°C. Carefully add 200 ml of water and extract the mixture with ethyl acetate. The organic layer is washed with water and dried over anhydrous sodium sulfate. The solvent is evaporated in vacuo and the residue is purified by light chromatography on silica gel eluting with n-hexaneethyl acetate 3:2. This gives a mixture of the base of the title compound and the corresponding N-trifluoroacetyl compound.

3.8 g of this mixture is dissolved in 35 ml of ethanol and 35 ml of dimethylsulphoxide. 0.55 g of sodium borohydride is added to this solution in portions at 20-25°C. The mixture is stirred for three hours at that temperature and then poured into 200 ml of water and extracted with ethyl acetate. The organic extracts are washed with water, dried over anhydrous sodium sulfate and evaporated to dryness under vacuum. The residue is dissolved in dichloromethane. 2 equivalents of ethanolic hydrogen chloride are added to give the title compound which is recrystallized from ethanol. Yield: 3.8 g, m.p. 231-234°C

Example 33

8-(3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylamino}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride

2.75-hydrate

Using 1-(3-chloropropyl)-4-(2-methoxyphenyl)-piperazine in place of 1-(2-chloroethyl)-4-(2-methoxyphenyl)-piperazine, but proceeding otherwise as in Example 32, the title compound was obtained. T.t. 206-208°C (10% ethanol).

Example 34

8-{4-[4-(2-methoxyphenyl)-1-piperazinyl]-butylamino}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride

hemihydrate

A mixture of 3.8 g of Intermediate XXXIX, 3.9 g of 8-amino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8.3 g of sodium triacetoxyborohydride and 3.4 ml of acetic acid in 40 ml of 1,2-dichloroethane is stirred under 6 hours at 20-25°C. Then 15 ml of a 5% aqueous solution of sodium bicarbonate is added and the mixture is stirred for 10 minutes. The mixture is then alkalized by adding 0.5N sodium hydroxide solution and extracted with dichloromethane. The organic extracts are washed with water and dried over anhydrous sodium sulfate. The solvent is evaporated in vacuo and the residue is purified by light chromatography on silica gel, eluting with ethyl acetate: petroleum ether 9:1. The obtained base is dissolved in dichloromethane and 1 equivalent of ethanolic hydrogen chloride is added. After removal of the solvent in vacuo, the residue was crystallized from 50% ethanol to give 1.6 g of the title compound, m.p. (14-0) 151-153°C.

Example 35

8-{N-methyl-3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylamino}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride hemihydrate

A mixture of 4 g of the compound prepared in Example 33, in the form of a base, 4.35 ml of 37% aqueous formaldehyde and 1.15 g of sodium cyanoborohydride in 25 ml of acetonitrile is stirred at 20-25°C, keeping the pH in the range 5-6 by adding acetic acid for reaction time. After 4 hours, the solvent is evaporated in vacuo. 80 ml of ethyl acetate and 200 ml of ice-cold 1N sodium hydroxide solution were added to the residue. The organic phase is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness under vacuum. The residue is purified by light chromatography on silica gel, eluting with ethyl acetate/petroleum ether 3:1. The obtained pure base is dissolved in diethyl ether. 1 equivalent of ethanolic hydrogen chloride was added and the solvent was removed in vacuo. The residue crystallizes from water to give 2 g of the title compound, m.p. 186-137°C.

Example 36

8-{N-acetyl-3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylamino}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride hydrate

A mixture of 4.8 g of the compound prepared in Example 33, in the form of a base, 2.8 ml of acetic anhydride and 33 ml of pyridine was stirred at 80°C for 4 hours. After cooling to 20-25°C, the reaction mixture is poured into 200 g of ice water, acidified with 10 N hydrochloric acid and extracted with dichloromethane. The organic extracts are washed with water, dried over anhydrous sodium sulfate and evaporated to dryness under vacuum. The residue is purified by light chromatography on silica gel, eluting with ethyl acetate:methanol 95:5. The pure compound as a base that is obtained is dissolved in dichloromethane. 1 equivalent of ethanolic hydrogen chloride was added and the solvent was removed in vacuo. The residue crystallized from acetonitrile to give 3 g of the title compound containing 0.33 equivalents of acetonitrile, m.p. 208.5-210.5°C.

Example 37

8-(3-[4-(2-ethoxyphenyl)-1-piperazinyl]-propionamido)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride

A mixture of 3.9 g of Intermediate X and 3.07 g of 1-(2-methoxyphenyl)-piperazine in 40 ml of dimethylformamide was stirred at 60°C for 6 hours. The reaction mixture is then cooled to room temperature and poured into water. After extraction with dichloromethane, the organic phase is washed with water and dried over anhydrous sodium sulfate. The solvent is removed in vacuo. The crude residue crystallizes from ethanol to give the base of the title compound, which is then dissolved in hot etharol. 1 molar equivalent of 0.81M ethanolic hydrogen chloride is added to the solution. 4 g of the title compound are obtained, m.p. 255-257°C.

Example 38

8-{2-[4-(2-methoxyphenyl)-1-piperasinyl]-ethylureido}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methanesulphonate

A mixture of 3.34 g of Intermediate XLIV and 7.22 g of 1-(2-methoxyphenyl)-piperazine was stirred at 100°C for 5 hours. Then a further 1.8 g of 1-(2-methoxyphenyl)-piperazine was added and the stirring continued for a further two hours at 100°C. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer is washed with aqueous sodium hydroxide solution, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The crude residue is purified by light chromatography on silica gel eluting with ethyl acetate: ethanol 98:2. The collected fractions are evaporated to dryness in a vacuum and crystallized from a mixture of water:ethanol 4:6. The crystals are redissolved in dichloromethane and treated with 1 molar equivalent of methanesulphonic acid. The crude methane sulphonate obtained (obtained by evaporation in a vacuum) crystallizes from a mixture of ethyl acetate:ethanol 1:1 giving 2.35 g of the title compound, which melts at 191-193°C.

Example 39

8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethoxy}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride hydrate

A mixture of 6.61 g of Intermediate XI, 8.34 g of 1-(2-methoxyphenyl)-piperazine and 1.26 g of sodium iodide in 70 ml of dimethylformamide was stirred at 80°C for 17 hours. After cooling to 20-25°C, the reaction mixture is poured into 600 ml of water, made alkaline with a 5% aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic extracts are washed with an aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and evaporated to dryness in a vacuum, the residue is purified by light chromatography on silica gel with elution with a mixture of dichloromethane methanol 99:1, then 98:2. Fractions containing the base of the title compound were combined and the solvent was removed in vacuo. The residue is purified in ethanol and ethanolic hydrogen chloride is added. The title compound crystallizes and is collected by suction filtration. Recrystallizes from 95% ethanol. Yield: 6.5 g, m.p. 224-225°C. Analysis of elements:

Found %: C=66.38, E=6.34, N-5.35, Cl=6.76, H2O=3.35

Calculated %: 55.34, 5.14, 5.33, 6.75, 3.43

NMR spectrum at 60 MHz (CDCl3-CD3OD)

7.8-7.1 (m, 8H, aromatic protons of the benzopyran ring)

7.1-6.5 (m, 4H, aromatic protons of the 2-methoxyphenyl group)

4.8-4.4 (m, 2H, OCH2)

4.4-4.1 (m, 3H, Hp2O and N+E)

3.9-3.0 (m, 10E, 5 x CH2N)

3.8 (s, 3H, OCH3)

2.1 (s, 3H, CH3)

Example 40

8-{3-[4-(2-nethoxyphenyl)-1-piperazinyl]-propoxy}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran dihydrochloride

This compound was prepared by the procedure described in Example 39, but using Intermediate IX instead of Intermediate XI. Purification by light chromatography was omitted as unnecessary in this case. T.t. 225-227°C.

Example 41

8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-butoxyl}-3-methyl)-4-oxo-2-phenyl-4H-1-benzopyran dihydrochloride.

A mixture of 7.75 g of Intermediate XVI, 4.7 g of 1-(2-methoxyphenyl)-piperazine, 3.3 g of potassium iodide and 2.8 g of anhydrous potassium carbonate in 78 ml of dimethylformamide was stirred at 75°C for 2 hours. After cooling to 20-25°C, the reaction mixture is poured into 600 ml of water and extracted with dichloromethane. The organic extracts are washed with water and dried over anhydrous sodium sulfate, and the solvent is removed by evaporation in a vacuum. The residue is purified by chromatography on a silica column, eluting with ethyl acetate. The pure title compound thus obtained as a base is transformed into its dihydrochloride by treatment with ethanol and hydrogen chloride. After crystallization from ethanol, 6.5 g of the title compound is obtained. T.t. 217-219°C.

Example 42

8-{5-(4-(2-methoxyphenyl)-1-piperazinyl)-pentoxy}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride

This compound was prepared by the procedure described in Example 4-1, but using Intermediate XVII instead of Intermediate XVI. 173°C (ethanol). The corresponding base melts at 117-118°C (ethanol).

Example 43

8-{3-[4-(2-methoxyphenyl)-1-oxo-1-piperazinyl]-propoxy}-3-methyl-4-oxo-phenyl-4H-1-benzopyran 1.75-hydrate

2.93 g of magnesium monoperoxyphthalate in 10 ml of water is added dropwise at -15°C to a solution of 4.34 g of the compound prepared in Example 40 and 0.1 g of benzyl(triethyl)ammonium chloride in 20 ml of dichloromethane and 20 ml of methanol. The mixture is stirred for two hours at 0°C and then warmed to room temperature. It is poured into water and made alkaline by adding an aqueous solution of sodium hydroxide. Extraction with dichloromethane gives, after the usual procedure, a solid which is purified by light chromatography with elution with a mixture of dichloromethane and methanol 9:1. The collected fractions containing the pure compound were evaporated to dryness in vacuo and the residue crystallized from acetonitrile to give 0.5 S of the title compound, m.p. 89-92°C.

Example 44

8-{2-[2-(2,6-dimethoxyphenoxy)-ethylaziino]–ethoxy}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride

A mixture of 4.5 g of Intermediate XII, 3.7 g of triphenylphosphine and 2.85 g of 2,6-diaethoxyphenoxyacetaldehyde (prepared according to Nelson, W.L-. et al., J.Med.Chem.,. 22, 1125,1979) in 4-5 ml of benzene is stir at 20-25°C for 18 hours and reflux for 5 hours. The solvent is evaporated in vacuo and the residue is dissolved in 80 ml of anhydrous methanol. 3A molecular sieve is added. Furthermore, 0.61 g of sodium borohydride is added at 0°C. The mixture is left to stand for one hour at 0°C and for one hour at 20-25°C, and then poured into ice water and extracted with dichloromethane. The organic extracts are washed with water and dried over anhydrous sodium sulfate. The solvent is removed in vacuo and the residue is purified by light chromatography on silica gel eluting with a mixture of dichloromethane and methanol 49:1. The obtained base is treated with ethanolic hydrogen chloride. After crystallization from ethanol, the title compound is obtained. Yield: 40%, m.p. 200-202°C.

Example 45

8-{2-hydroxy-3-[4-(2-methoxyphenyl)-1-piperazinyl]-propoxy}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride

A solution of 3.7 g of Intermediate XL and 4.64 g of 1-(2-methoxyphenyl)-piperazine in 40 ml of dimethylformamide was stirred at 80°C for 3 hours. After cooling to 20-25°C, the reaction mixture is poured into 400 ml of water and extracted with dichloromethane. The aqueous phase is made alkaline with 1N sodium hydroxide solution and extracted with ethyl acetate. The combined organic fractions are washed in turn and dried over anhydrous sodium sulfate. Solvents are evaporated under vacuum. The residue is purified by light chromatography on silica gel eluting with ethyl acetate. Fractions containing the title compound in base form were combined and dried in vacuo. The residue is dissolved in dichloromethane and 1 equivalent of ethanolic hydrogen chloride is added. The solvents are removed in vacuo and the residue crystallized from ethanol. 5 g of the title compound containing one molar equivalent of ethanol is obtained in this way. T.t. (122) 126-128°C with decomposition.

Example 46

8-(3-(4-(2.methoxyphenyl)-1-piperazinyl)-propylthio}-methyl-4-oxo-2-phenyl-4H-1-benzopyran

A mixture of 4.4 g of Intermediate XXXIV, 2.5 g of l-(2-methoxyphenyl)-piperazine, 1 g of potassium iodide and 1.8 g of anhydrous potassium carbonate in 40 ml of dimethylformamide at 100°C was stirred for 3 hours. After cooling to 20-25°C, the reaction mixture is poured into 350 ml of water and extracted with dichloromethanone. The organic extracts are washed with water and dried over anhydrous sodium sulfate, and the solvent is then evaporated in a vacuum. The residue is purified by chromatography on a silica gel column eluting with a mixture of ethyl acetate and petroleum ether 3:2, and crystallization from ethanol yields 3.9 g of the title compound, m.p. (70) 96-99°C.

Example 47

8-{3-[4-(2-methoxyphenyl)-1-piperaziny]-propylsulphonyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride

A solution of 3.8 g of Intermediate XXXV and 4 g of 1-(2-methoxyphenyl)-piperazine in 40 ml of dimethylformamide is heated at 50°C for 7 hours. After cooling to 20-25°C, the reaction mixture is poured into 500 ml of water and extracted with dichloromethane. The organic extracts are washed with water and dried over anhydrous sodium sulfate, and then the solvent is removed in vacuo.

The residue is purified by light chromatography on silica gel with elution with a mixture of ethyl acetate: petroleum ether 1:1. The base of the title compound is obtained. The residue was taken up in ethanol and one equivalent of ethanolic hydrogen chloride was added to give 4.5 g of the title compound, mp (215) 226-228°C.

Example 48

8-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethylsulphamoyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride

A solution of 4.5 g of Intermediate XLII and 5.8 g of 1-(2-methoxyphenyl)-piperazine in 40 ml of dimethylformamide is heated at 70°C for 7 hours. After cooling to 20-25°C, the reaction mixture is poured into 150 ml of water and extracted with dichloromethane. The organic solution is washed with water and dried over anhydrous sodium sulfate, and then the solvent is evaporated under vacuum. The residue is purified by light chromatography on silica gel eluting with a mixture of ethyl acetate:petroleum ether 3:7, and the title compound is obtained by salification with ethanolic hydrogen chloride. Yield: 2.9 g, m.p. 236-238°C.

Example 49

8-{N-methyl-2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethylsulphamoyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride

The title compound is obtained by the procedure described in Example 48, but using Intermediate XLI instead of Intermediate XLII. T.t. 194-198°C (ethanol).

Example 50

8-{N-carbamoyl-3-(4-(2-methoxyphenyl)-1-piperazinyl]-propylamino}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methanesulphonate hemihydrate

A mixture of 4.06 g of the compound from Example 33 and 1.5 g of potassium cyanate in 42 ml of glacial acetic acid was stirred at 50°C for 4 hours. The reaction mixture is poured into ice water and made alkaline. The precipitate is collected by suction filtration, dried and purified by light chromatography using a silica column and eluting with a mixture of ethyl acetate and methanol 98:2. Fractions containing the title compound as a base were evaporated to dryness in vacuo and one equivalent of methanesulphonic acid was added to the residue after dissolution in 30 ml of dichloromethane. The solvent was evaporated in vacuo and the residue crystallized from ethanol to give 3.1 g of the title compound (m.p. 157-160 °C, with decomposition).This compound contains one molar equivalent of ethanol.

Example 51

8-{4-[4-(2-methoxyphenyl)-1-piperazinyl]-1-oxobutyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methanesulphonate

A solution of 1.33 ml of anhydrous dimethylsulphoxide in 9 ml of dichloromethane is added at -70°C to a solution of 0.74 ml of oxalyl chloride in 6 ml of dichloromethane. After stirring at -70°C for 15 minutes, a solution of 2.8 g of the compound from Example 21 (as a base) in 14 ml of dichloromethane was added. After 15 minutes at the same temperature, 4.7 ml of anhydrous triethylamine is added and the temperature rises to -30°C for 30 minutes. Stirring was continued at -30°C for a further 30 minutes. After allowing the temperature to rise to 0°C, the mixture was diluted with 120 ml of water and extracted with dichloromethane. The organic phase is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness under vacuum. The residue is purified by light chromatography on a silica column eluting with a mixture of ethyl acetate and chloromethane 9:1. Fractions containing the title product as a base are evaporated to dryness in vacuo and one equivalent of methanesulphonic acid is added to the residue which is dissolved in 30 ml of dichloroethane. The solvent was evaporated in vacuo and the residue crystallized from ethanol to give 2.9 g of the title compound, m.p. 194-195°C.

Example 52

8-{3-(2-(1,4-benzodioxanyl)methylamino]propylcarbamoyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methanesulphonate

A mixture of 5.56 g of Intermediate XLIII, as a base, 4.53 g of 2-(p-toluenesulphonyloxymethyl)-1,4-benzodioxane and 1.9 g of anhydrous potassium carbonate in 80 ml of anhydrous dimethylformamide was stirred at 110°C for 5 hours.

The reaction mixture was cooled to room temperature, poured into water and extracted with dichloromethane. The organic phase is washed with water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness under vacuum. The residue is purified by light chromatography on a silica gel column with elution with a mixture of ethyl acetate and methanol 95:5. Fractions containing the title compound as base are evaporated to dryness in vacuo. The residue is dissolved in ethanol and one equivalent of methanesulphonic acid dissolved in ethyl acetate is added. The crystallized product is filtered and recrystallization from ethanol yields 2.4 g of the title compound, m.p. 172-174°C.

Example 53

8-(4-(4-(2-methoxyphenyl)-1-piperazinyl)-butyl]-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methanesulphonate

A solution of 2.8 g of Intermediate XLVI and 0.13 g of p-toluenesulphonic acid in 150 ml of methanol is refluxed for 5 hours. After cooling to 20-25°C, add 0.8 g of anhydrous potassium carbonate and continue mixing for 3 hours. After filtration, the reaction mixture was evaporated to dryness in vacuo to give 2.5 g of 8-(4-,4-dimethoxybutyl)-3-ethyl-4-oxo-2-phenyl-4H-1-benzopyran. NMR (CDCl3, δ)

1.6-1.9 (4H, m, CHCH2CH2CH)

2.2 (3H, s, flavone CH3)

2.9 (2H, t, F1'-CH2)

3.3 (6H, s, 2 x OCH3)

4.4 (1H, t, CH(OCH3)2)

7.3 (1H, dd, flavone CH in 6)

7.5-7.8 (6H, m, flavonic CH in 7, and 5 x phenolic CH)

8.1 (1H, dd, flavone CH in 5)

A solution of 2.5 g of the thus prepared compound in 10 ml of water and 30 ml of acetic acid is heated to 50°C for two and a half hours. The reaction mixture is cooled to room temperature, diluted with ice water, made alkaline with an aqueous sodium carbonate solution and extracted with chloroform. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to dryness in a vacuum, the residue is purified by light chromatography on silica gel eluting with a mixture of petroleum ether:ethyl acetate 3:1. 2.1 g of 8-(4-ozobutyl)-3-methyl-4-6xo-2-phenyl-4H-1-benzopyran are obtained (75% yield) and used in the next step without further purification.

NMR (CDCl3, δ)

1.9-2.1 (2H, dd, CH9CH2CH2CHO)

2.2 (3H, s, flavone CH3)

2.5 (2H, t, CH2CHO)

2.9 (2H, t, F1'-CH2)

7.3 (1H, dd, flavone CH u6)

7.5-7.7 (5H, m, flavone CH in 7, and 5 x phenyl CH)

8.1 (1H, dd, flavone CH in 5)

9.7 (1H, s, CHO)

To a solution of 8 g of 1-(2-methoxyphenyl)-piperazine in 30 ml of methanol, 2.3 ml of 6N hydrochloric acid in ethanol, a solution of 2.1 g of the thus prepared compound in 40 ml of methanol and 0.4-5 g of sodium cyanoborohydride are successively added. After stirring the reaction mixture at room temperature for 24 hours, it is poured into 500 ml of ice water and extracted with dichloromethane. The organic phase is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness under vacuum. The residue is purified by light chromatography on a silica column eluting with a mixture of ethyl acetate:petroleum ether 9:1. Fractions containing the title compound as base are evaporated to dryness in vacuo. The residue is dissolved in 30 ml of dichloroethane and one equivalent of methanesulphonic acid is added. The solvent was evaporated in vacuo and the residue crystallized from acetone to give 2.35 g of the title compound (m.p. 141-143°C).

Example 54

8-[3-(4-phenyl-1-piperidinyl)-propylcarbamoyl]-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methanesulphonate

This compound was prepared by the procedure described in Example 11, but using 4-phenylpiperidine instead of 1-(2-methoxyphenyl)-piperazine and conducting the reaction for one hour instead of 5 hours. Purification is carried out by light chromatography using a silica column with elution with a mixture of dichloromethane and methanol 100:5. T.t. 157-159°C (ethyl acetate). The corresponding base melts at (127) 147-149°C (ethanol).

Example 55

8-[3-(4,4-diphenyl-1-piperidinyl)-propylcarbamoyl]-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methanesulphonate

This compound was prepared by the procedure described in Example 11, but using ,4,4-diphenylpiperidine instead of 1-(2-methoxyphenyl)-piperazine and conducting the reaction for 2 hours instead of 5 hours. T.t. 221-223°C (ethyl acetate).

Example 56

8-(3-[4-(4-fluorobenzoyl)-1-piperidinyl]-propyl-carbamoyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran

This compound was prepared by the procedure described in Example 11, but using 4-(4-fluorobenzoyl)-piperidine instead of 1-(2-methoxyphenyl)-piperazine and conducting the reaction for 30 minutes instead of 5 hours.

Purification is carried out by light chromatography using a silica column with elution with a mixture of dichloromethane:5N methanolic ammonia with a gradation from 100:1 to 100:20. T.t. 181-183°C (ethanol).

Example 57

8-{3-[4-(2-oxo-1-benzimidazolinyl)-1-piperidinyl]-propyl-carbamoyl}-3-methyl-oxo-2-phenyl-4H-1-benzopyran

This compound was prepared by the procedure described in Example 11, but using 4-(2-oxo-1-benzimidazolinyl)-piperidine instead of 1-(2-methoxyphenyl)-piperazine. Purification is carried out by light chromatography using a silica column, eluting with chloroform: 5N methanolic ammonia 100:3. T.t. 238-241°C (ethanol).

Example 58

8-{3-[4-(2-pyrimidinyl)-1-piperazinyl]-propylcarbamoyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methanesulphonate

The title compound was prepared using the procedure described in Example 11, but using 1-(2-pyrinidinyl)-piperazine instead of 1-(2-methoxyphenyl)-piperazine and reacting for 2 hours. The product is purified by light chromatography using a silica column eluting with chloroform:methanol 100:3. The desired fractions are dissolved in dichloromethane and one equivalent of methanesulphonic acid is added to the solution. After evaporation of the solvent in vacuo, the residue is boiled for one hour with ethyl acetate and then collected by filtration. T.t. 200-210°C. The product contains 0.2 equivalents of ethyl acetate and 0.1 equivalents of water. The corresponding base melts at 178-180 C (ethanol).

Example 59

8-{3-[4-(2-hydroxyphenyl)-1-piperazinyl]-propylcarbamoyl)-5-ethyl-4-oxo-2-phenyl-4H-1-benzopyran

Proceeding as described in Example 11, but using 1-(2-hydroxyphenyl)-piperazine instead of 1-(2-methoxy phenyl)-piperazine, and heating for one and a half hours instead of five hours, and using a mixture of dichloromethane:methanol 100 :3 to 100:10 as eluent for column chromatography, the title compound is obtained. T.t. 118-12C°C (ethanol 95%).

Example 60

8-(4-[4-(2-methoxyphenyl)-1-piperazinyl]-butylcarbamoyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methane

sulphonate

This compound was prepared according to the procedure described in Example 12, but using 4-[4-(2-methoxyphenyl)-1-piperazinyl]-butylamine instead of 3-(4-(2-methoxyphenyl)-piperazinyl]-propylanine. stirred at room temperature for 22 hours, diluted with water and filtered with suction, washed with water - (insoluble solids). The crude residue was dried and purified by chromatography on a silica column eluting with a mixture of ethyl acetate:methanol 9:1. Fractions containing pure product as a base, are washed and evaporated to dryness under vacuum, and dissolved in dichloromethane. Methanesulphonic acid is added to the solution and the salt is precipitated by the addition of 2 volumes of ethyl acetate, filtered and recrystallized from ethanol to give the title compound, mp 230-232 ° C. This compound contains 0.3 molar equivalents of ethanol.

Example 61

8-(3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylsulphamoyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methane

sulphonate

This compound was prepared by proceeding as described in Example 12, but using Intermediate VIII instead of 8-chlorocarbonyl-5-methyl-4-oxo-2-phenyl-4H-1-benzopyran and stirring for 24 hours instead of 2.5 hours. The crude product is purified by chromatography on a silica column eluting with a mixture of ethyl acetate and methanol 98.5:1.5. The collected fractions containing the pure product as a base are evaporated to dryness under vacuum and dissolved in dichloromethane. Methanesulfonic acid was added to the solution and the solvent was removed by evaporation in vacuo. The crude salt crystallizes from ethanol to give the title compound, m.p. (196) 198-200°C.

Example 62

8-(3-[N-methyl-2-(2-methoxyphenoxy)-ethylamino]-propylcarbamoyl]-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran

A solution of 10.5 ml of 40% formaldehyde in water is added to a suspension of 6.66 g of the compound prepared in Example 14 in 55 ml of acetonitrile and 20 ml of water. After stirring for 15 minutes at room temperature, 2.70 g of sodium cyanoborohydride 95% is added to the red solution, and after a further 15 minutes under the same conditions, 1.38 ml of acetic acid is added.

After stirring for 3 hours, the solvents were removed in vacuo and the residue was taken up with 250 ml of water and 250 ml of chloroform. After addition of 3N sodium hydroxide, the organic phase is separated and the aqueous phase is extracted with ss. with chloroform twice. The solvent was removed from the collected organic phases by vacuum evaporation and the residue was purified by light chromatography on silica gel eluting with a mixture of: chloroform:5.2N methanolic ammonia 100:0.5 to 100:2.

The collected fractions containing the pure title compound as base were evaporated to dryness in vacuo and the residue was dissolved in hot ethanol. The solution is acidified with ethanolic hydrogen chloride and after evaporation of the solvent in vacuo, the residue is taken up in diethyl ether and stirred at room temperature. The crude product was collected by filtration and crystallized from acetonitrile to give 3.1 g of the title compound. T.t. 146-148°C.

Example 63

8-(N-methyl-3-[4-(2-methoxyphenyl)-1-piperazinyl]-prepionamido}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methane sulphonate

Proceeding as described in Example 37 but using Intermediate L instead of Intermediate X and stirring for 4 hours at 90°C instead of 6 hours at 60°C afforded the title compound as a crude base. After purification on a silica column, eluting with a mixture of ethyl acetate:methanol 95:5, crude methanesulphonate is obtained as described in Example 61, and crystallization from acetone gives the title compound, m.p. 200-202°C.

Example 64

8-(3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylcarbamoyl}-3-phenyl-4-oxo-4H-1-benzopyran dimethanesulphonate

The title compound is prepared by proceeding as described in Example 12, but using Intermediate LVI instead of 8-chloro-carbonyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran and stirring for 24 hours instead of 2.5 hours . The crude product is purified by column chromatography, eluting with ethyl acetatemethanol 92:8, and the pure base, obtained by vacuum evaporation of the collected fractions, is dissolved in dichloromethane. Two equivalents of methanesulphonic acid are added. Crude dimethanesulphonate, obtained after evaporation of the solvent, is recrystallized from acetone, m.p. 153-156 (200)°C.

Example 65

8-(3-[(3,4-dihydro-1-oxo-2H-naphthyl)-methylamino}-propylcarbamoyl]-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methane sulphonate

A mixture of 6 g of Intermediate XLIII, 2.4 g of 2-methylene-α-tetralone (prepared as described in Org. 3ynth., 60, 88, 1981) and 3.14 ml of triethylamine in 48 ml of anhydrous dimethylformamide was stirred at room temperature for 6 hours and then at 50°C for one hour. The reaction mixture is diluted with water and extracted with dichloromethane. The organic layers are washed with water, dried over anhydrous sodium sulfate and evaporated to dryness under vacuum. The crude residue was purified twice by column chromatography, eluting first with a mixture of dichloromethane-methanol 95:5 and then with a mixture of dichloromethane:methanol:5.8N methanolic ammonia 98:2:0.2, thus obtaining 1.74 g of the title compound as a base. The base is converted to methanesulphonate by the procedure described in Example 61. The salt is recrystallized first from acetone and then from acetonitrile to give the title compound, m.p. (69) 157-159°C.

Example 66

8-(2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethoxycarbonylmethyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran dihydrochloride

The title compound was prepared by the procedure described in Example 5, but using Intermediate XLVII in place of 8-carboxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran and 1-(2-choroethyl)-4-(2 -methoxy-phenyl)-piperazine instead of 1-(3-chloro propyl)-(2-methoxyphenyl)-piperazine. T.t. 193-196°C from ethanol:diethyl ether.

Example 67

8-{4-[4-(2-methoxyphenyl)-1-piperazinyl]-butylsulphamoyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran dimethane

sulphonate

The title compound was prepared as described in Example 61, but using 4-[4-(2-methoxy phenyl)-1-piperazinyl]-butylamine instead of 3-(4-(2-methoxyphenyl)-1-piperazinyl)-propylamine. , Crude dimethanesulphonate

crystallizes first from acetonitrile and then from ethanol. T.t. 172-174°C.

Example 68

8-(N-(2-tetrahydropyranyoxy)-3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylcarbamoyl}-3-methyl-4-oxo-2-phenyl-1H-1-benzopyran methanesulphonate hemihydrate

A solution of 3.5 g of 1-(3-chloropropyl)-4-(2-methoxyphenyl)-piperazine in 30 ml of anhydrous dimethylformamide is added dropwise, with stirring at 0°C, to a mixture of 3.92 g of O-(2-tetrahydropyranyl)-hydroxyl- amine (prepared as described by R.N. Watrener et al., Angewandte Chem. Int. Ed., 5, 511, 1966).

Stirring was continued for 2 hours at 0°C and then for 12 hours at 110°C. The reaction mixture was then cooled to room temperature and the dimethylformamide was removed by vacuum distillation. The residue is taken up in water and extracted with ethyl acetate.

The combined organic layers are washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo to give 4.39 g of 1-(3-(3-tetrahydropyranyloxyamino)-propyl)-4-(2-methoxyphenyl)-piperazine.

1H-NMR (CDCl3, δ)

6.50-6.75 (m, 4H, aromatic protons)

5.20 (bs, 1H, KH)

4.60 (m, 1H, O-CH-O)

3-30-4.00 (m, 5H, OCH3 and tetrahydropyran CH2C)

2.8U-3.20 (m, 6H, piperazine 2 x CH2, alkyl chain CH2N)

2.20-2.80 (m, 6H, piperazine 2 x CH2, alkyl chain CH2N)

1.30-2.00 (m, 8H, tetrahydropyran 3 x CH2, alkyl chain C-CH2-C)

A solution of 2.79 g of 8-chlorocarbonyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran in 47 ml of chloroform was added dropwise at room temperature to a mixture of 3.26 g of the compound, prepared as described, and 1.42 g of potassium carbonate in 47 ml of chloroform. The reaction mixture is stirred for 3 hours and then diluted with 75 ml of chloroform and washed three times with 1 M sodium hydroxide. The gypsy layer is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness under vacuum. The crude residue is purified by chromatography on a silica column eluting with a mixture of ethyl acetate and methanol 98:2. The collected fractions were evaporated to dryness in vacuo to give 2.99 g of pure title compound as base. The base is dissolved in dichloromethane and methanesulphonic acid is added to the solution. The solvent is removed by evaporation in vacuo and the crude salt is crystallized from ethyl acetate to give the title compound, m.p. 159-160°C.

Example 69

8-(4-[4-(2-methoxyphenyl)-1-piperazinyl]-butyramido}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methane sulphonate hemihydrate

The title compound was prepared by the procedure described in Example 38, but using Intermediate XLVIII instead of Intermediate XLIV and stirring for 1 hour at 70°C and 2 hours at 130°C instead of 7 hours at 100°C. After. according to the usual procedure, the crude residue is purified by chromatography on a silica column eluting with ethyl acetatemethanol 95:5. Fractions containing pure title compound as base are pooled and evaporated to dryness in vacuo. The residue is dissolved in dichloromethane and one equivalent of methane sulphonic acid is added to the solution. After evaporation of the solvent to dryness in vacuo, the crude salt crystallizes from acetone, m.p. 175-176°C.

Example 70

E-8-(2-[4-(2-mthoxyphenyl)-1-piperazinyl]-ethoxyimino-methyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran

A solution of 5.4 g of 3-formyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran and 5.13 g of Intermediate LII in 10 ml of chloroform, containing a 3A molecular sieve, was stirred at reflux for 6 hours. . The molecular sieve is removed by filtration and the solution is evaporated to dryness in vacuo. The crude product is purified by chromatography on a silica column eluting with a mixture of ethyl acetate and petroleum ether 7:3. The two groups of fractions are collected and evaporated to dryness under vacuum. The first eluted group of fractions (less polar) contains almost pure title compound, the second group (more polar) is a 1:1 mixture of E and Z diastereoisomers as determined by NMR.

1H-NMR (CDCl31, δ)

8.75 (dd, 0.5H, benzopyran CH in 7, Z)

8.65 (s, 0.5H, imine CH, E)

8.30 (dd, 1H, benzopyranic CH in 5, E+Z)

8.15 (dd, 0.5H, benzopyran CH in 7, E)

8.00 (s, 0.5H, imine CH, Z)

7.60-7.75 (m, 2E, phenyl CH in 2' and 6', E+Z)

7.50-7.60 (m, 3H, phenyl CH in 3', 4' and 5', S+Z)

7.45 (dd, 0.5H, benzopyran CH in 6, 3)

7.4-1 (dd, 0.5H, benzopyran CH in 6, E)

6.70-7.10 (m, 4E, phenyl protons, E+Z)

4.41 (t, 2H, CH2O, E+Z)

3.86 (s, 3E, CH2O, E+Z)

3.05-3.20 (m, 4H, piperazine 2 x CH2, E+Z)

2.70-2.90 (m, 6H, piperazine 2 x CH2i CH2, E+Z)

2.20 (s, 1.5H, benzopyranic CH3, in 3, E)

2.18 (s, 1.5E, benzopyranic CH3 in 3, Z)

The E diastereoisomer crystallizes from a mixture of ethanol:water 2:1 to give 2.5 g of pure title compound, m.p. 107-109°C.

Example 71

8-(N-hydroxy-3-[5-(2-methoxyphenyl)-1-piperaziny]-propylcarbamoyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methane sulphonate 0.25 H2O

A solution of 2.04 g of the compound from Example 63 as a base in 104 ml of 1.6 N ethanolic hydrogen chloride was stirred for 12 hours at room temperature. Ethanol was removed by evaporation in vacuo and the residue was taken up in 1N sodium hydroxide and dichloromethane. The organic layer is collected, washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. One molar equivalent of methanesulphonic acid is added to a solution of the residue in dichloromethane. The solvent was removed and the crude methanesulphonate was crystallized from acetone to give 1.02 g of the title compound, m.p. 211-213°C. The product contains 0.25 moles of water.

Example 72

E-8-<2-(2-(4-(2-methoxyphenyl)-l-piperazinyl]-ethylcarbamoyl}-ethyl>-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methane sulphonate 1.2 H2O

The title compound was obtained by the procedure described in Example 61, but using Intermediate IV instead of Intermediate VIII and 2-[4-(2-nethoxyphenyl)-1-piperazinyl]-ethylamine instead of the corresponding propylamine, in 1,1,2,2-tetrachloroethylene as solvent . Finally, the reaction mixture is diluted with water and chloroform and washed with 1N aqueous sodium hydroxide solution, and then with water. The organic layer, after drying over anhydrous sodium sulfate, is added to methanesulphonic acid and the solvents are evaporated in a vacuum. The crude product crystallized twice from isopropanol to give the title compound containing 1.2 molar equivalents of water, m.p. 124-127°C.

Example 73

8-[4-[4-(2-methoxyphenyl)-1-piperazinyl]-butylsulphinyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methanesulphonate

The title compound was prepared according to Example 58, but using Intermediate LIV instead of Intermediate XLIV, stirring at 70°C for 3 hours and again at 90°C for 3 hours after addition of a catalytic amount (0.01 equivalent) of potassium iodide. Purification by chromatography on a silica column eluting with a mixture of ethyl acetate:methanol 9:1 gives the title compound as a base. The crude base, dissolved in dichloromethane, is added to one molar equivalent of methane sulphonic acid. After removal of the solvent by evaporation in vacuo, the resulting salt crystallized from acetone to give the title compound, m.p. 183-184°C.

Example 74

8-{3-[3-(2-methoxyphenoxy)-propylamino]-propylcarbamoyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methane

sulphonate hemihydrate

The title compound was prepared according to the procedure described in Example 76, but using 3-(2-methoxyphenoxy)-propyl chloride (prepared as described by B. Willham, Tetrahedron, 20, 1185, 1964) in place of 2-(2,6- dimethoxy phenoxy)-ethyl bromide. The residue after extraction with dichloromethane is purified by chromatography on a silica column eluting with a mixture of dichloromethane: methanol: 5:7 methanolic ammonia 9:1:0:3 the pure base is converted into methanesulphonate which is crystallized twice from a mixture of ethyl acetate:acetonitrile 9:1 giving the title compound melting at (60) 87-90°C.

Example 75

8-(3-[2-(2-methylthiophenoxy)-ethylamino]-propylcarbamoyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methane

sulphonate

1.85 g of 95% sodium borohydride is added to a solution of 7 g of Inter-mediator LIX in 70 ml of methanol stirred at 0°C. After stirring for one hour at the same temperature, the solvent was removed by evaporation in vacuo. The residue is diluted with water and 2N hydrochloridnon acid and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo to give 5.5 g of pure 2-(2-methylthio-phenoxy)-ethanol as an oil. 8.57 g of p-toluenesulphonyl chloride was added in portions to a solution of the thus prepared compound in 35 ml of pyridine stirred at 0°C. After standing for 14 hours at room temperature, the reaction mixture is poured into cold 2N hydrochloric acid and extracted with dichloromethane. The organic layer is washed twice with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo to give 7.8 g of a 3:1 mixture of 2-(2-methylthiophenoxy)ethyl p-toluenesulphonate and 2-(2-methyl-thiopienoxy)-ethyl chloride (determined by NMR) as a low melting point solid which is used without further purification. A homogeneous mixture of 3.3 g of the previous mixture and 8 g of Intermediate XLIII is kept in an oil bath at 140°C for 20 minutes. After this period, the melted mass cools down to room temperature and solidifies. The solid residue is taken up in dichloromethane and 4 N sodium hydroxide. The organic layer is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo.

The crude product was purified by chromatography on a silica column eluting with a mixture of dichlororethanmethanol 9:1 to give 2.07 s of the title compound as a base. It is converted by the usual procedure into crude methanesulphonate which crystallizes from acetone and then from acetonitrile. 14-3-146°C.

Example 76

8-(3-[2-(2,6-dimethoxyphenoxy)-ethylamino]-propylcarbamoy)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride

A homogeneous mixture of 3.3 6 2-(2,6-dimethox7phenoxy)-ethyl bromide (prepared as described in J. Augstein et al., J. Med. Chem., 8, 356, 1965) and 8.4 g of Intermediate XLIII is heated- in an oil bath at 150°C for 10 minutes. The melted mass is cooled to room temperature and solidified. The solid residue is taken up in ethyl acetate and 2 N sodium hydroxide. The organic layer is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The oily residue is purified twice by chromatography on a silica column, eluting first with a mixture of ethyl acetate: ethanol: 5N methanolic ammonia 97:3:0.3 and then with a mixture of dichloromethanermethanol: triethylarin 90:10:0.3. This gives 3.3 g of pure title compound as a base. The crude hydrochloride, obtained by the usual procedure, crystallizes from acetone and then from acetonitrile. T.t. 179-181°C.

Example 77

8-{3-[4-(5-chloro-2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-(methyl-4-oxo-2-phenyl)-4H-1-benzopyran

This compound was prepared by the procedure described in Example 11, but using 1-(5-chloro-2-methoxyphenyl)piperazine instead of 1-(2-methoxyphenyl)piperazine and conducting the reaction for 6 hours instead of 5 hours. Purification was carried out by light chromatography on silica gel with elution with a mixture of chloroform: 5N ammonia in methanol (100:1). The title product obtained by crystallization from 95% ethanol melts at 163-166 C.

Example 78

(E)-8-(4-[4-(2-methoxyphenyl)-1-piperazinyl]-1-butenyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran

33.3 ml of a one-molar solution of lithium ris(trimethylsilyl)amide in anhydrous tetrahydrofuran was added dropwise over 15 minutes to a suspension of 6.4 g of 3-hydroxypropyltriphenylphosphonium bromide in 60 ml of anhydrous tetrahydrofuran cooled to -15°C. Then a solution of 4 g of 8-fr:yl-3-methyl-4-oxo-2-phenyl-4E-1-benzopyran in 40 ml of tetrahydrofuran was added dropwise. The reaction mixture is stirred at 0°C for 30 minutes, then at room temperature for one and a half hours.

The reaction is quenched with methanol, and then evaporated to dryness in a vacuum, giving a residue that is purified by chromatography on a silica column eluting with a mixture of ethyl acetate and petroleum ether 6:4. The collected fractions were evaporated in vacuo to give 4.17 g of 8-(4-hydroxy-1-butenyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran as a mixture of E-Z diastereoisomers in the ratio 3.5:1 as determined by NMR -om.

1H-NMR, 200 MHz (CDCl3, δ)

8.10-8.20 (d, 1H, benzopyranic CH in 5, Z+Z)

7.30-7.80 (m, 7H, other aromatic, E+Z)

6.80-7.00 (2d, 1H, aryl-CH=, E+Z)

6.41 (dt, 0.78H, CH-CH2, E)

5.90 (dt, 0.22H, CH-CH2, Z)

3.60-3.80 Cm, 2H, CH2O, E+Z)

2.45-2.60 (m, 2H, CH-CH2, E+Z)

2.18 (s, 3H, benzopyranic CH3, in 3, E+Z)

1.60-1.90 (with, , E+Z)

1.65 g of p-toluenesulphonyl chloride was added to a solution of 2.2 g of the previous mixture in 24 ml of anhydrous pyridine and stirred at 0°C. The mixing is continued for 48 hours at the same temperature, and then the reaction mixture is poured into cold 1N hydrochloric acid and suction filtered. The gummy solid is washed with water and taken up in dichloromethane. The solution is dried over anhydrous sodium sulfate and evaporated to dryness in vacuo to give 2.30 g of (E,Z)-4-{8-[3-methyl-4-oxo-2-phenyl-4H-1-benzopyranyl]-3-butenyl p-toluenesulphonate which has the same diastereoisomeric composition as the previous Intermediate.

A solution of 2.85 g of the previous p-toluenesulphonic acid ester and 2.98 g of 1-(2-methox:yphenyl)-piperazine in anhydrous dimethylformamide was stirred at room temperature for 48 hours. After this time, the mixture is poured into 250 ml of water and extracted with ethyl acetate. The organic layer is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in a vacuum, giving a residue that is purified by chromatography on a silica column eluting with a mixture of ethyl acetate and petroleum ether 6:4. The collected fractions were evaporated to dryness in vacuo and the crude product crystallized from 70% ethanol to give 1.48 g of the title compound melting at 119-121°C.

1H-NMR, 200 MHZ (CDCl3, δ)

8.14 (dd, 1H, benzopyran CH in 5)

7.85 (dd, 1H, benzopyran CH in 7)

7.41-7.70 (m, 5H, phenyl CHs)

7.34 (dd, 1H, benzopyran CH in 6)

6.70-7.10 (m, 5H, aryl-CH+ and methoxyphenyl CHs)

6.30-6.50 (dt, 1H, Jtrans=16.5 Hz, CH-CH2)

3.86 (s, 3H, CH3O)

3.00-3.15 (m, 4H, 2 piperazine CH2)

2.50-2.80 (m, 8H, 2 piperazine CH2, CHCH2CH2N)

2.18 (s, 3H, benzopyranic CH3 in 3)

Example 79

(E)-8-<2-{2-[(2-methoxyphenyl)-1-piperazinyl]–ethoxycarbonyl]-ethyl>-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methane sulphonate

The title compound was prepared according to the procedure of Example 6, but using Intermediate III instead of 8-carboxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran. After the usual procedure, the residue is crystallized twice from ethanol, the obtained solid is purified by chromatography on a silica column eluting with a mixture of chlcroform ethyl acetate 8:2, giving a pure base that dissolves in a mixture of chloroformrethanol 1:1. Metha-nesulphonic acid was added to the solution and the solvents were removed by evaporation in vacuo. The crude salt crystallizes from isopropanol to give the pure title compound melting at 193-195°C. This compound contains 0.33 equivalents of isopropanol and 0.25 equivalents of water.

Example 80

8-(2-[4-(2-ethoxyphenyl)-1-piperazinyl]-ethylcarbamoylmethyl)-4-oxo-2-phenyl-1H-1-benzopyran methane sulphonate

hydrate

A mixture of 2.8 g of Intermediate XLVII and 1.28 g of 1-hydroxybenzotria-zol in 20 ml of anhydrous dimethylformamide was stirred at 0-5°C for 15 minutes. A solution of 1.96 g of dicyclohexylcarbodiimide in 20 ml of anhydrous dimethylformamide was added dropwise to the mixture over a period of about 40 minutes. After stirring for 8 hours at room temperature, a solution of 2.24 g of 1-(2-aminoethyl)-4-(2-methoxyphenyl)-piperazine in 15 ml of anhydrous dimethylformamide was added. After stirring for 5 hours and standing overnight at the same temperature, the insoluble substances are filtered and the filtrate is poured into about 300 ml of water and alkalized by adding 1N sodium hydroxide. The mixture is extracted with dichloromethane and the organic layer is separated, dried over anhydrous sodium sulfate and evaporated in vacuo. The crude product is purified by light chromatography on silica gel eluting with a mixture of chloroform methanol 95:5. One molar equivalent of methanesulphonic acid is added to a solution of the crude base in ethanol. Diethyl ether is added until the salt crystallizes. The salt is then filtered and recrystallized from ethanol:diethyl ether 1:2 to give 1.15 g of the title compound, m.p. 160-162°C.

Example 81

8-(N-acetyl-3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylcarbamoyl)-3-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran

A solution of 2.85 g of intermediate XLII, 5.04 g of 1-(3-chloropropyl}-4-(2-methoxyphenyl)-piperazine and 2.58 g of anhydrous potassium carbonate in 50 ml of dimethylfonnamide was stirred at 90°C for 7 hours. After cooling to room temperature , the reaction mixture is poured into 500 ml of water and extracted with dichloromethane. The organic layer is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in a vacuum. The residue is purified by chromatography on a silica column eluting with a mixture of ethyl acetate: petroleum ether 7: 3 to give 1.89 g of the title compound melting at (55) 62-63°C.

Example 82

8-(2-(4-(2-methoxyphenyl)-1-piperazinyl]-ethylsulphonylamino}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methane)

sulphonate

1.05 ml of 2-chloroethanesulphonyl chloride is added dropwise to a solution of 5 g of 3-amino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran and 1.4 ml of triethylamine mixed at 0°C. The reaction mixture was stirred at room temperature for two days.

After filtering off the precipitated solids, the solution was evaporated to dryness in vacuo to give a crude residue containing 8-(ethenylsulphonylamino)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran which was used in beige purification. A mixture of 7.54 g of this residue and 5.8 g of 1-(2-methoxy-phenyl)-piperazine and 4.15 g of potassium carbonate in 100 ml of dimethyl-formamide was stirred at room temperature for 4 hours, poured into 600 ml of water and extracted with ethyl acetate. The organic layer is evaporated to dryness in a vacuum and the residue is purified by chromatography on a silica column eluting with a mixture of petroleum ether:acetone 8:2. The collected fractions were evaporated to dryness in vacuo and crystallization from 70% ethanol afforded 0.75 g of the title compound as base. The solid is dissolved in dichloromethane and one equivalent of methanesulphonic acid is added to the solution. Crude methanesulphonate, obtained by evaporation in vacuo, crystallized from acetone to give 0.6 g of the title compound melting at 202-203°C.

Example 83

8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylthiocarbamoyl}-3-methyl-4-oxo-2-phenyl-4H--benzopyran methane

sulphonate

A mixed mixture of 0.8 g of 8-formyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 0.75 g of 1-(3-aminopropyl)-4-(2-methoxy phenyl)-piperazine and 0.14 g of sulfur in 5 ml of pyridine is refluxed for 6 hours. After evaporation of the solvent in a vacuum, the residue is purified by light chromatography on silica gel eluting with chloroform. The obtained title compound (as a base) is dissolved in dichloromethane and one equivalent of methanesulphonic acid is added. The title compound is obtained by evaporation in vacuo and crystallization of the residue from acetonitrile. Yield: 0.7 g, m.p. 189-190°C.

Example 84

8-{4-[4-(2-methoxyphenyl)-1-piperazinyl]-butylsulphonyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methane

sulphonate 1/4H2O

The title compound was prepared according to Example 73, but using Intermediate LX instead of Intermediate LIV. It was purified by chromatography on a silica column with elution with a mixture of ethyl acetate and petroleum ether 7:3. One equivalent of methanesulphonic acid is added to a solution of the crude base in dichloromethane. After removal of the solvent by evaporation, the resulting salt crystallizes from acetone to give the title compound, m.p. 212-214°C.

Example 85

8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylcarbamoyl]-3-hydroxymethyl-4-oxo-2-phenyl4H-1-benzopyran 0.4

ethanol

A mixture of 3.6 g of Intermediate XCV and 1.65 g of 1-hydroxybenzotriazole in 35 ml of anhydrous dimethylformamide was stirred at 0-5°C for 15 minutes. A solution of 2.5 g of dicyclohexylcarbodiimide in 35 ml of anhydrous dimethyl formamide was added dropwise. After stirring for one hour at the same temperature, a solution of 1-(3-aminopropyl)-4-(2-methoxyphenyl)-piperazine was added. After stirring for two hours at the same temperature and standing overnight at room temperature, the reaction mixture is evaporated to dryness in a vacuum. The residue is purified by light chromatography eluting with a mixture of dichloromethanemethanol 100:3, followed by crystallization from ethanol. 2.5 g of the title compound, m.p. 152-154°C.

Example 86

8-(3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylcarbamoyl)-4-oxo-2-phenyl-4H-1-benzopyran methane sulphonate 0.25

H2O

3.6 ml of diethyl cyanophosphate was added dropwise at 0-5°C to a stirred solution of 4-g of 8-carboxy-4-oxo-2-phenyl-4H-1-benzopyran (prepared as described in Da Re et al., Ber ., 99 1962, 1966) and 3.75 g of 1-(3-amino propyl-4-(2-methoxyphenyl)-piperazine in 35 ml of anhydrous dimethyl formamide. Immediately after that, 2.5 ml of triethylamine is added dropwise at the same temperature. After stirring. during 30 minutes at 0-5°C and 1 hour at room temperature, the reaction mixture is poured into 350 ml of 2.5% aqueous sodium carbonate solution. The formed precipitate is stirred for one hour at room temperature, collected by suction filtration and crystallized from ethanol. The base of the title compound thus obtained is dissolved in dichloromethane and one equivalent of methanesulphonic acid is added. After evaporation in vacuo, a glassy solid is obtained which is triturated and refluxed for one hour in acetone to give 5 g of the title compound which melts at 191-194°C.

Example 87

3-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylcarbamoyl}-2,3-dihydro-4-oxo-4H-1-benzopyran methane sulphonate

A solution of 0.84 ml of thionyl chloride in 17 ml of anhydrous dichloromethane is added dropwise to a solution of 2.0 g of 8-carboxy-2,3-dibydro-4-oxo-4H-1-benzopyran (prepared according to Lichtenberger et al. Bull.Chem. Soc.Fr ., 275, 1953) and 1.75 ml of triethylamine in 17 ml of dichloromethane mixed at room temperature.

Stirring was continued for 1.5 hours at the same temperature, after which time the reaction mixture was evaporated to dryness in vacuo to give crude 8-chloro carbonyl-2,3-diydro-4-oxo-4H-1-benzopyran.

It is used in the procedure of Example 10 instead of 8-chlorocarbonyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran to prepare the base of the title compound which is purified by light chromatography eluting with a mixture of ethyl acetate and methanol 85 :15. Yield: 1.91 g of pure base. After dissolution in dichloromethane, acidification with methanesulphonic acid and evaporation to dryness in vacuo, the resulting crude salt crystallized from acetonitrile to give 1.57 g of the title compound melting at 175-177°C.

Example 88

S-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylcarbamoyl}-4-oxo-4H-1-benzopyran methane sulphonate 1.25 H2O

The title compound is prepared by the procedure described in Example 87, but using Intermediate LXII instead of 8-carboxy-2,3-dihydro-4-oxo-4H-1-benzopyran. The crude methanesulphonate is taken up in diethyl ether, filtered and crystallized several times from acetonitrile. T.t. 155-157°C.

Example 89

8-[3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylcarbamoyl]-6-bromo-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran

This compound is prepared according to Example 85, but using 8-carboxy-6-bromo-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (prepared as described in EP 107804) instead of 8-carboxy- As a base, 4-oxo-2-phenyl-4H-1-benzopyran is purified by light chromatography on silica gel eluting with a mixture of dichloro-ethanemethanol 100:3, and crystallized from 95% ethanol. T.t. (150) 154-159°C.

Example 90

8-{3-[4-(2-methoxyphenyl)-1-piperazonyl]-propylcarbamoyl}-6-methoxy-4-oxo-2-phenyl-4H-1-benzopyran

1.01 ml of diethyl cyanophosphate and 0.85 ml of triethylamine were added to a solution of 1.7 g of 8-carboxy-6-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (prepared as described in JP 61-15880 ) and 1.51 g of 1-(2-methoxy phenyl)-4-(3-aminopropyl)-piperazine in 20 ml of anhydrous dimethylformamide stirred at 0°C. After stirring for one hour at 0°C to room temperature. The reaction mixture is poured into a mixture of 100 ml of water and 10 ml of 1 N sodium hydroxide. The base of the title compound is precipitated, filtered and washed with water. After desiccation, it is converted in the usual way into methane sulphonate, which crystallizes from acetonitrile. Yield 1.7 g, m.t. 185-186°C.

Example 91

8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylcarbamoyl]-6-hydroxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methane sulphonate

0.8 g of the compound prepared in Example 114 and 5.8 ml of 1 N sodium hydroxide in 10 ml of methanol were mixed at room temperature for 4 hours. After standing overnight, 15 ml of 1N sodium hydroxide and 15 ml of methanol are added at room temperature for one hour. Methanol is evaporated in vacuo and water is added to the residue. The suspension was suction filtered to give 0.48 g of the base of the title compound. It is converted by the usual procedure into methane sulphonate salt, recrystallized from acetonitrile. T.t. 200-202°C.

Example 92

8-(3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylcarbamoyl]-3,6-dimethyl-4-oxo-2-phenyl-4H-1-benzopyran methane

sulphonate

The title compound was prepared according to Example 90, but using 8-carboxy-3,6-dimethyl-4-oxo-2-phenyl-4H-1-benzopyran (prepared as described in Da Re et al., Arch. Pharm. , 296,714, 1963) instead of 8-carboxy-6-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran. Crude methanesulphonate crystallizes from acetonitrile and melts at 196-197°C.

Example 93

8-[3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylcarbamoyl]-3-methyl-6-nitro-4-oxo-2-phenyl-4H-1-benzopyran

This product is obtained by the procedure described in Example 12, but using Intermediate LXVIII instead of 8-chlorocarbonyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran and 1,1,2-trichloroethane instead of chloroform.

After the usual procedure, the crude product is purified by column chromatography eluting with a mixture of dichloromethane methanol 93:2. Evaporation of the collected fractions in vacuo to dryness and then crystallization from ethanol gave the title compound, m.p. 159.5-161°C.

Example 94

8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylcarbamoyl}-6-amino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran

A mixture of 33 S of the compound prepared in Example 93, 109 ml of 1N hydrochloric acid, 105 ml of water and 8.78 g of Raney-Nickel in 950 ml of ethanol is hydrogenated in a Parr apparatus, with a hydrogen pressure of 2 atmospheres and stirring at 4-0 °C during 12 hours. After this time, the catalyst is removed by filtration and washed with 80% ethanol. The base liquid is evaporated in a vacuum to a volume of 80 ml and filtered. The raw product is washed with water and suspended in water, 37% hydrochloric acid is added to pH 1. Insoluble substances are filtered by suction and the filtrate is alkalized by adding 35% sodium hydroxide. The title product precipitates. It is obtained by filtration and washed with water. Desiccation gives 26 g of the compound which melts at (108) 215-217.5°C and is used in Example 95 without further purification. For characterization, 4.7 g of the product was crystallized from ethanol and then from 85% ethanol to give 3 g of the title compound, m.p. 218-219°C.

Example 95

8-{3-(4-(2-methoxyphenyl)-1-piperazinyl]-propylcarbamoyl]-6-acetamido-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran

The title compound is obtained according to the procedure described in Example 36, but using the compound prepared in Example 94 instead of the one prepared in Example 33. The reaction mixture is diluted with water and suction filtered, washed with water (solid). After desiccation at 80°C, this solid is purified by chromatography on a silica column eluting with a mixture of chloroform methanol 95:5. Vacuum evaporation of the collected fractions and crystallization from 95% ethanol gives the title compound, m.p. (150) 218-220°C.

Example 96

8-[3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylcarbamoyl]-6-ethylamino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran

A mixture of 8.42 g of the compound from Example 94-, 0.45 ml of acetaldehyde, 0.59 g of 85% sodium cyanoborohydride and 3.3 ml of 4.85N ethanolic hydrogen chloride in 73 ml of methanol was stirred at room temperature for 5 days. After this time, the reaction mixture is poured into a cold 1.5N sodium hydroxide solution, the suspension is diluted with water and filtered with suction. After desiccation, the residue: is purified by column chromatography eluting with a mixture of chloroform methanol 100:3. By vacuum evaporation of the collected fractions, 6 g of the compound from Example 94 and 2.67 g of the title compound are obtained, melting at 198-201°C after recrystallization from ethanol.

Example 97

8-(3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylcarbamoyl]-6-dimethylamino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran

The title compound was prepared according to Example 35 but using the compound prepared in Example 94 instead of that prepared in Example 33, reacting with 10 molar equivalents of 40% formaldehyde instead of 7 molar equivalents and with 3 moles of sodium cyanoborohydride instead of 2 moles and stirring at room temperature. temperature for 18 hours instead of 4.5 hours. After the usual procedure and purification on a silica gel column with elution with a mixture of chloroform methanol 97:3, vacuum evaporation of the collected fractions and crystallization of the residue from ethanol, the title compound is obtained which melts at 183-186 °C.

Example 98

8-(3-(4-(2-methoxyphenyl)-1-piperazinyl)-propylcarbamoyl)-7-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran

The title compound was prepared according to the procedure described in Example 87, but using intermediate LXIX instead of 8-carboxy-2,3-dihydro-4-oxo-4H-1-benzopyran. After the usual procedure, the solid residue was purified by column chromatography on silica gel with elution with a mixture of ethyl acetate methanol 8:2. The collected fractions were evaporated to dryness in vacuo and the residue was crystallized from acetonitrile to give the title compound melting at 151-152°C.

Example 99

8-(3-(4-(2-methoxyphenyl)-1-piperazinyl]-propylcarbamoyl]-3-methyl-4-oxo-2-(4-trifluoromethylphenyl)-4H-1-benzopyran methane sulphonate hydrate

The title compound was prepared according to the procedure described in Example 90, but starting from Intermediate LZKII instead of 8-carboxy-6-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran. Methane sulphonate melts at (85) 90-120°C (dec.) after crystallization from acetonitrile.

Example 100

8-[3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylcarbamoyl}-2-(4-benzophenyl-3-methyl-4-oxo-4H-1-benzopyran methane sulphonate hemihydrate

The title compound was prepared according to the procedure described in Example 90, but starting from Intermediate LXXIV instead of 8-carboxy-6-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran. The crude methanesulphonate crystallizes from acetonitrile. T.t. 205-210°C.

Example 101

8-(3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylcarbamoyl)-3-methyl-4-oxo-2-(4-phenoxyphenyl)-4H-1-benzopyran merhan sulphonate 0.25 H2O

The title compound was prepared according to the procedure described in Example 90, but starting from Intermediate LXXVII instead of 5-carboxy-5-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran. The crude methanesulphonate crystallizes from acetonitrile. T.t. 200-202°C.

Example 102

8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylcarbamoyl}-2,3-dimethyl-4-oxo-4H-1-benzopyran

This compound was prepared according to Example 86, but using 8-carboxy-2,3-dimethyl-4-oxo-4H-1-benzopyran (prepared according to Da Re, Parmaco Ed. Sci., 11, 678, 1956) instead of 8- carboxy-4-oxo-2-phenyl-4H-1-benzopyran and conducting the reaction at room temperature for 5 hours. It is purified by light chromatography on silica gel with elution with chloroformmethanol 98:2, and by crystallization from acetone. T.t. 155-158.5°C.

Example 103

8-(3-(4-(2-methoxyphenyl)-1-piperazinyl]-propylcarbamoyl]-2-(t-butyl)-3-methyl-4-oxo-4H-1-benzopyran dihydro

chloride dihydrate

This compound was prepared according to Example 86, but using Intermediate LXXVIII instead of 8-carboxy-4-oxo-2-phenyl-4H-1-cenzopyran. The base is purified by light chromatography on silica gel eluting with a mixture of chloroform methanol 4-9:1, and converted into the dihydrochloride in a mixture of methanol:diethyl ether. It melts at 226-229.5°C after recrystallization from a mixture of methanol:diethyl ether 1:1.

Example 104

8-{3-(2-methoxyphenyl)-1-piperazinyl]-propylcarbamoyl]-2-cyclohexyl-3-methyl-4-oxo-4H-1-benzopyran

This compound was prepared according to Example 86, but using Intermediate LXXIX instead of 8-carboxy-4-oxo-2-phenyl-4H-1-benzopyran and conducting the reaction for 5 hours at room temperature. It is purified by light chromatography with elution with a mixture of chloroform:methanol 4-9:1 and crystallization from acetonitrile (m.p. 155-157°C.

Example 105

8-(3-(4-(2-methoxyphenyl)-1-piperazinyl]-propylcarbamoyl)--2-(2-furyl)-3-methyl-4-oxo-4H-1-benzopyran

This compound was prepared according to Example 86, but using Intermediate LXZXI instead of 8-carboxy-4-oxo-2-phenyl-4H-1-benzopyran, and completing the reaction at room temperature for 5 hours. After completion of the reaction, the title compound is isolated by extraction with chloroform and purified by light chromatography on silica gel with elution with a mixture of chloroform:methanol 49:1, and then by crystallization from acetonitrile. T.t. 151-153°C.

Example 106

8-[3-(4-(2-methoxyphenyl)-1-piperazinyl]-propylcarbamoyl)-3-methyl-4-oxo-2-thienyl-4H-1-benzopyran

This compound is obtained according to Example 86, but using Intermediate LXXXIII instead of 8-carboxy-4-oxo-2-phenyl-4H-1-benzopyran. It is purified by mixing with water (to completely remove dimethylformamide), and then by chromatography on a silica gel column with elution with a mixture of chloroform methanol 49:1, and crystallization from acetonitrile. T.p. 174-175°C.

Example 107

8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylcarbamoyl]-4-oxo-2-phenyl-4H-1-benzothiopyran

A mixture of 2.8 g of Intermediate LXXXIV and 3.4 g of 1,1'-carbonyldiimidazole in 60 ml of anhydrous dimethylformamide was stirred under a stream of nitrogen at room temperature for one and a half hours. 2.7 g of 1-(3-amino propyl)-4-(2-methoxy phenyl)-piperazine is added; After a further two hours of stirring at room temperature, the reaction mixture is poured into 300 ml of water and extracted with chloroform. The organic layer is dried over anhydrous sodium sulfate and evaporated in vacuo.

The residue is purified by light chromatography on silica gel eluting with a mixture of chloroform-methanol 49:1, washed with water and crystallized from acetonitrile to give 2 g of the title compound melting at 144-146°C.

Example 108

(E)-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylcarbamoyl}-3-methyl-4-oxo-2-(2-styryl)-4H-1-benzopyran

This compound was prepared according to Example 86, but using Intermediate LXXXVI instead of 3-carboxy-4-oxo-2-phenyl-4H-1-benzopyran. It is purified by crystallization from acetonitrile. T.t. 191-194°C.

Example 109

S-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylcarbamoyl]-3-methyl-2-(4-methylphenyl)-4-oxo-4H-1-benzopyran

This compound was prepared according to Example 86, but using Intermediate LXXXVTI instead of 8-carboxy-4-oxo-2-phenyl-4H-1-benzopyran and completing the reaction at room temperature for 4 hours. After quenching the reaction, the title compound is isolated by extraction with ethyl acetate, dried over anhydrous sodium sulfate and evaporated in vacuo, and then taken up in diethyl ether and crystallized from acetonitrile. T.p. 161-163°C.

Example 110

S-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylcarbamoyl]-2-(4-methoxyphenyl)-3-methyl-4-oxo-4H-1-benzopyran

This compound was prepared according to Example 86, but using 8-carboxy-2-(4-methoxyphenyl)-3-methyl-4-oxo-4H-1-benzopyran (prepared as described in EP 108986) instead of 8-carboxy- 4-oxo-2-phenyl-4H-1-benzopyran, and completing the reaction at room temperature for three and a half hours. It is purified by light chromatography on silica gel with elution with a mixture of chloroform:methanol 4-9:1, and then crystallization: from acetonitrile. T.t. 158-161°C.

Example 111

8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylcarbamoyl}-2-(4-fluorophenyl)-3-methyl-4-oxo-4H-1-benzopyran.

This compound was prepared according to Example 86, but using Intermediate LXXXIX instead of 8-carboxy-4-oxo-2-phenyl-4H-1-benzopyran. It is purified by light chromatography on silica gel with elution with a mixture of chloroform methanol 100:2 to 100:6 and crystallization from 95% ethanol. T.t. 166-153°C.

Example 112

8-{3-H-(2-methoxyphenyl)-1-piperazinyl]-propylcarbamoyl}-6-methane sulphonylamino-3-methyl-4-oxo-2-phenyl-1-

benzopyran hydrochloride

0.032 ml of methanesulphonyl chloride in 1 ml of dimethylformamide was added dropwise over 10 minutes to a solution of 0.21 g of the compound from Example 94 and 0.062 ml of triethylamine in 4 ml of dimethylformamide, stirred at -20°C. Mixing is continued at the same temperature for 3.5 hours. After this time, the reaction mixture was poured into water and the suspension filtered with suction to give 0.1 g of the title compound which crystallized from 80% ethanol. T.t. 272-275°C.

Example 113

8-[3-(4-(2-methoxyphenyl)-1-piperazinyl]-propylcarbamoyl)-3-methyl-2-(4-nitrophenyl)-4-oxo-4H-1-benzopyran

The title compound was prepared according to the procedure described in Example 90, but starting from Intermediate XCVIII instead of 8-carboxy-6-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran. After stirring for one hour at room temperature, the reaction mixture was poured into cold 2% sodium carbonate solution and the precipitated solid was collected by suction filtration. After desiccation and crystallization from ethanol, the title compound melts at (60) 185-187°C

Example 114

8-(3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylcarbamoyl]-6-diethoxyphosphonyloxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran

The title compound was prepared according to the procedure described in Example 90, but starting from Intermediate LXIII instead of 8-carboxy-6-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran and using 2 equivalents of diethyl cyanophosphate instead 1.1 equivalents. Filtration from water gives the title compound which melts at 48-80°C (decomposition). The title compound can be considered a pro-substance of 8-3-4-(2-methoxyphenyl)-1-piperazinyl-propyl-carbamoyl-6-hydroxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran.

Example 115

8-(3-[4(2-methoxyphenyl)-1-piperazinyl]-propylcarbamoyl)-3-methyl-4-oxo-2-trifluoromethyl-4H-1-benzopyran methane sulphonate 2/3 H2O

Proceeding as described in Example 90, but starting from Intermediate C instead of 8-carboxy-6-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, the crude base of the title compound is obtained. After the usual extraction procedure with ethyl acetate, the residue is purified by chromatography on a silica gel column eluting with ethyl acetate and methanol 9:1. It is converted into rethanesulphonate by the usual procedure and crystallized from ethyl acetate. T.t. 145-148°C.

Example 116

8-{N-methyl-3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylcarbamoyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride

This compound was prepared according to Example 12, but using Intermediate CI instead of 3-4-(2-methoxyphenyl)-1-piperazinyl-propylamino. The crude base is purified by light chromatography on silica gel eluting with a mixture of chloroform: 5N methanolic ammonia 100:1, and transformed into the hydrochloride in the usual way. T.t. 195-198°C, after crystallization from acetone.

Example 117

7-{3-(4-(2-methoxyphenyl)-1-piperazinyl]-propylcarbamoyl)-2-benzoyl-3-ethyl-benzo[b]furan

This compound was prepared according to Example 86, but using Intermediate CIII instead of 8-carboxy-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic acid, and completing the reaction at room temperature for 4 hours. It is purified by crystallization from ethanol. T.t. 165-166°C.

Example 118

2-(4-biphenylyl)-8-(3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl-carbamoyl)-3-methyl-4-oxo-4H-1-benzopyran

The title compound is obtained according to Example 86, but using Intermediate CVI instead of 4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic acid. The reaction lasts 20 hours at room temperature. The base is purified by crystallization from ethanol (m.p. 164-166°C).

Example 119

8-(3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl)-3-methyl-4-oxo-2-(3-pyridyl)-4H-1-benzopyran

A mixture of 6.2 g of methyl 3-propionylsalicylate and 5.8 g of nicotinoyl chloride hydrochloride in 18 ml of anhydride pyridine is mixed and heated to 100°C for two hours under nitrogen. After that, 15 ml of triethylamine is added and heating is continued for one hour at the same temperature. The reaction mixture is cooled to room temperature, poured into 600 ml of water and the precipitate is collected by suction filtration and washed with water to give 5.4 g of methyl hydroxy-3-(2-nicotinoyl)propion-benzoate, which is used without further purification in the next step . 3.4 g of this Intermediate is heated to 100°C for 1.5 hours after dissolving in a mixture consisting of 15 ml of acetic acid and 1 ml of 37% hydrochloric acid. After cooling to room temperature, the mixture is poured into 150 ml of water and extracted with ethyl acetate. The organic phase is washed with 5% aqueous sodium hydrogen carbonate and then with water, dried over anhydrous sodium sulfate and evaporated in vacuo to give 1.3 g of crude methyl 3-methyl-4-oxo-2-(3-pyridyl) -4H-benzopyran-8-carboxylate.

1 g of the previous ester is dissolved in 9 ml of methanol and 15 dl of 1,4-dioxane and 1.7 ml of 10 N sodium hydroxide is added slowly, keeping the temperature between 20 and 25°C. After one hour at 50°C, the reaction mixture is poured into 150 ml of water and extracted with ethyl acetate. The aqueous layer is acidified with 1N hydrochloric acid.

The precipitate is collected by suction filtration giving 0.6 g of 3-methyl-4-oxo-2-(3-pyridyl)-4H-1-cenzopyran-8-carboxylic acid, which is used without purification in the next step. The title compound was prepared according to Example 86, but using the above Intermediate in place of 4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic acid and conducting the reaction for 2 hours at room temperature. The base is purified by light chromatography on silica gel with elution with a mixture of chloroform methanol 93:2, and then by crystallization from acetone, yielding 0.15 g (m.p. 134.5-137°C).

Example 120

8-{3-[4-(2-acetoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl-1-4-oxo-2-phenyl-4H-1-benzopyran

1 g of the compound from Example 59 and 0.32 g of 4-dimethylaminopyridine are dissolved in 10 ml of dichloromethane and 0.15 ml of acetyl chloride is slowly added thereto, keeping the temperature between 8 and 10°C.

After standing for two hours at room temperature, the reaction mixture is poured into 70 ml of water and extracted with dichloromethane. The organic layer is washed with a 5% aqueous sodium hydrogen carbonate solution and then with water, dried over anhydrous sodium sulfate and evaporated to dryness under vacuum. The crude base was purified by light chromatography on silica gel eluting with a mixture of ethyl acetate and methanol 9:1, and then by crystallization from ethanol, yielding 0.74 g of the title compound (m.p. 120-123°C).

Example 121

3-methyl-8-{3-(4-(2-methylamiocarbonyloxyphenyl)-1-piperazinyl)-propylcarbamoyl}-4-oxo-2-phenyl-4H-1-benzopyran

3 g of the compound from Example 59 and 1-8 ml of methylisocyanate are dissolved in 30 ml of dry N,N-dimethylformamide and stirred at room temperature for 24 hours. The mixture is diluted with water, stirred for two hours and then suction filtered. The crude base is purified by light chromatography on silica gel eluting with chloroform: 5N ammonia in methanol (100:3). The title compound melts at 132-135°C after crystallization from ethanol.

Example 122

6-acetoxy-8-(3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl]-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran

0.17 ml of acetyl chloride is added dropwise over 5 minutes, with stirring at 0°C, to a solution of 1 g of the compound from Example 91 and 0.32 ml of triethylamine in 36 ml of chloroform. After two hours of stirring at the same temperature, the reaction mixture is diluted with dichloromethane. and water, the organic layer is separated, washed with water, dried over sodium sulfate and evaporated to dryness under vacuum. Crystallization of the residue from acetonitrile gave 0.8 g of the title compound melting at 148-149°C.

Example 123

(R,S)-2,3-dihydro-4-hydroxy-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl]-4H-1-benzopyran methane

sulphonates

The title compound was prepared by the same procedure described in Example 17, but starting from the compound from Example 87, instead of the compound from Example 1. The reaction mixture was diluted with water and stirred for 15 minutes, then extracted with ethyl acetate. The usual procedure gives a crude product which is purified by light chromatography on silica gel eluting with dichloromethane:methanol 95:5. Vacuum evaporation of the collected fractions gives the pure base, which is converted into methanesulphonate and crystallized from acetonitrile (m.p. 172-175°C).

Example 124

2-(4-aminophenyl}-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-ethyl-4-oxo-4H-1-benzopyran

2.22 g of the compound from Example 113 and 0.56 g of Raney-nickel in 96 ml of ethanol and 4-,8-1 acetic acid are hydrogenated in a Parr apparatus (pH2=1 atm) at room temperature. After 6 hours of shaking, the catalyst is removed by filtration and the filtrate is alkalized with 3N sodium hydroxide and diluted with water. After resting for two days, the precipitate of the title compound was collected by suction filtration, washed with water, dried and recrystallized from ethyl acetate and then from ethanol to give 1.5 g (m.p. 192-194°C).

Example 125

2-(4-acetylaminophenyl)-8-[3-(4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl)-3-methyl-4H-1-benzopyran

The title compound was prepared in the same manner as described for the compound of Example 36, but using the compound prepared in Example 124 instead of the compound of Example 53. It was purified by crystallization from 95% ethanol (m.p. 207-209°C).

Example 126

2-(4-hydroxyphenyl)-8-[3-[4-(2-methoxyphenyl)-1-piperarinyl]propylcarbamoyl]-3-methyl-4H-1-benzopyran dihydro

chloride nonohydrate

The title compound was prepared by the procedure described in Example 55, but using Intermediate CVII instead of 4-oxo-2-phenyl-1-4H-1-benzopyran-8-carboxylic acid and carrying out the reaction for 14 hours at room temperature also in the presence of hexamethyl-phosphoramide as a cosolvent. The isolated diethylphosphonyl ester of the compound is hydrolyzed by treatment with alkali and then neutralization with dilute hydrochloric acid. The crude base product is extracted with chloroform and the organic layer is washed with water and evaporated in vacuo. The salt is prepared by adding ethanolic hydrogen chloride to a solution of the base in acetone, evaporating and taking up in acetone (m.p. 193-205°C).

Example 127

8-(3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl)-2-phenyl-4,N1,N4-trioxo-4H-1-benzopyran monohydrate

0.8 g of the compound from Example 107 and 15 ml of acetic acid are supplemented with 0.32 ml of 30% hydrogen peroxide and stirred at 50°C for 3 hours. Then 0.48 ml of 30% hydrogen peroxide is added to the mixture (3 x 0.16 ml every two hours with heating). After cooling, the mixture is poured into 240 ml of water, neutralized to pH 7 using a 5% aqueous sodium hydrogen carbonate solution and extracted with chloroform.

The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated in vacuo to give 0.18 g of the title compound melting at 172-175°C after crystallization from acetonitrile.

Example 128

7-(3-(4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl)-2-phenylbenzo [b]furan

The title compound was prepared by the procedure described in Example 86, but using 2-phenylbenzo[b]furan-7-carboxylic acid (prepared as described in EP 306,226 (1989)) instead of 4-oxo-2-phenyl-4H-1- of benzopyran-8-carboxylic acid, and conducting the reaction for 1.5 hours at room temperature. It is purified by crystallization from carbon tetrachloride (m.p. 132-136°C).

Example 129

8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl-N-methylsulfamoyl]-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methane sulphonate

2.29 g of Intermediate VIII was added in portions with stirring at 0°C to a solution of 1.5 g of Intermediate CI and 0.95 triethylamine in 30 ml of chloroform. After an additional two hours standing at room temperature, the reaction mixture is diluted with dichloromethane, water and 0.5 N sodium hydroxide. The organic layer is washed with water, dried over sodium sulfate and evaporated to dryness under vacuum. The residue is purified by light chromatography on silica gel eluting with a mixture of ethyl acetate:methanol 96:4. Evaporation in vacuo of the collected fractions afforded the pure title compound as a base. It is converted by the usual procedures into the methanesulphonate salt which crystallizes from ethyl acetate to give 2.75g, m.p. 135-141°C (disp.)

Example 130

8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]butyl-N-methylsulphamoyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methane sulphonate

The title compound is obtained in the same manner as described in Example 129, but using Intermediate CVIII instead of Intermediate CI. The title compound crystallizes from acetonitrile (m.p. 173-175°C).

Pharmacological data

Methodology

Male Sprague Dawley rats (Crl: CD'BR) weighing 200 to 300 g, female Albino Swiss mice (Crl: CD-1 (ICR) BR) weighing 20 to 30 g, and male Beagle dogs (10-12 kg ie . m.) were obtained from Charles River, Italy and Nossan (Correzzana, Milano, Italy). The animals were housed so that they could take food and water freely and an artificial light-dark cycle was maintained at 22°C until the day of the experiment.

Acute toxicity

The acute toxicity of the synthesized compounds was evaluated in female albino Swiss mice after intraperitoneal and oral administration. Four logarithmically distributed doses of the compounds were dissolved or suspended in 0.5% Metocel and administered in a volume of 10 ml/kg to groups of 4 mice/dose. Mortality was recorded 7 days after administration. Analysis data: LD50 values and their reliable limit values were calculated according to Weil's method (Biometrics, 8, 249, 1952).

Receptor binding study:

-[3H]prazosin binding (α1 receptors)

Rat cerebral cortexes are homogenized in 50 volumes of the original wet weight of ice-cold 50 mM Tris-HCl buffer pH 7. The homogenates are centrifuged at 48,000 x g for 10 minutes, and the pellets are resuspended in the same volume of ice-cold buffer, centrifuged and resuspended for two more times. The final obtained pellets are resuspended in the same volume of buffer and incubated according to the conditions shown in the table below.

These receptor binding studies, as well as the experimental data for dogs presented below, indicate that the compounds of this invention are α1,-blockers, i.e. they are within the group of compounds used as antihypertensive and anti-BPH agents. See, eg, Frishman, W/.H. et al., Medical Clinics of N. America, 72, 427, 1983 and references therein.

-[3H]8-OH-DPAT binding (5HT-1A receptors)

Rat hippocampus are homogenized in 50 ml of the original wet weight of ice-cold 50 mM Tris-HCl buffer pH 7. The homogenates are centrifuged at 48,000 x g for 10 minutes, and the pellets are resuspended in the same volume of ice-cold buffer, incubated for 10 minutes at 37°C, centrifuged and resuspended two more times. The final obtained pellets are resuspended in the same volume of buffer and incubated according to the conditions shown in the table below.

This receptor binding study serves to demonstrate that the compounds of the present invention are ligands for the 5HT1A receptor. As previously stated, compounds that are 5HT1A. ligands, show anxiolytic and antidepressant effects on animals and humans (Hamon, M. et al., Ann. IT. I. Acad. Sci. 600, 114, 1990, Traber J. et al., T.I.P.3.,8, 437, 1987 ).

[image]

[image]

Incubations are terminated after the appropriate time (see table) by rapid filtration through Whatman GF/B filters, using a Brandel cell harvester. The filters are washed twice with 15 ml of ice-cold buffer (see table). The radioactivity retained on the filters is determined with a liquid scintillation counter. Non-specific binding (typically 10-30%) is assessed by adding high concentrations of specific scavengers (see table). All compounds were initially tested at a concentration of 1x10-6, and in the presence of significant removal activity, and a complete test curve was obtained (down to a concentration of 10-11M). All samples were in triplicate. Test curves were always analyzed (to estimate the IC50 value) using a non-linear curve using the logistic equation according to the method reported by De Lean et al. (Am. J. Physiol., 235, E97, 1978), using the ALLFIT program (available from the National Institutes of Health (N.I.H.) Bethesda, Maryland, USA) written for the IBM PC.

K+-induced bladder band contractions in rats:

The entire bladder of the rat was removed and immediately placed in Krebs solution heated to 37°C. Parts of the detrusor muscle (20-30 mm long, 1-2 mm wide) are cut from the bladder vault. Each strip is placed in 10 ml of physiological bath and connected, with a constant load of 1 g, to an isometric tension gauge (DY-1 Basile, Comerio, Varese, Italy). Contractions were recorded using a Basile 7070 polygraph. After a 60-minute equilibration period, strips are exposed to 80 mM KCl. This causes a rapid phasic contraction and the tope is followed by a slow moving and sustained tonic component. When the tonic contractions are stable, the strips are washed out and 30 minutes later, a new contraction is induced. After two or more reproducible responses are obtained, one concentration of the test drug is added to the bath and a new contraction is induced 30 minutes later. Experimental groups consist of at least two preparations taken from different animals for each concentration of the tested drug. IC50 values of inhibition of agonist-induced contractions were estimated using linear regression analysis.

Effects on urethral contractions and blood pressure in dogs

The experiments were carried out according to the procedure of Imagava et al. (J. Pharmacol. Methods, 22, 103-111, 1989) with modifications such as the sequence: Adult Beagle male dogs, weighing 8-10 kg are anesthetized with pentobarbital sodium (30 mg/kg i.v. and 2 mg/kg/h i.v. ), intubate and spontaneously ventilate. To monitor systemic blood pressure (BP), a PE catheter is introduced into the aortic arch through the right carotid artery.

The collateral from the left femoral vein is cannulated for anesthetic infusion, and the right femoral vein is cannulated for drug administration. For intra-arterial (i.a.) injection of noradrenaline (NA), a PE catheter is introduced into the lower part of the abdominal aorta through the right external iliac artery. By such a process, NA is selectively distributed to the lower urinary tract. Through laparotomy, the urinary bladder and proximal urethra were exposed. To prevent bladder filling, the two ureters are coiled and the urine is drained. To record prostatic urethral pressure, a Micro-tip catheter (6F) was introduced into the bladder via the external urethral meatus and advanced until it was positioned in the prostatic urethra. A ligature was secured between the bladder neck and the urethra to isolate the response of the latter and to avoid interaction with the bladder. Another ligature is placed around the Micro-tip catheter at the external urethral meatus to secure the catheter. The stabilization period was followed by surgery (30 minutes), where the arterial and urethral pressures were continuously monitored as a basal value, i.e., NA was administered at 10-minute intervals. The dose of KA was chosen to cause at least a 100% increase in urethral pressure. Test compounds were administered i.v. in a causative manner with intervals of 15-20 minutes between applications. I.a. injection of NA was repeated approximately every 5 minutes after each test compound dosing. Dose-response curves were constructed by entering the percent inhibition of the increase in urethral pressure (I7A induced), and the percent decrease in blood pressure produced by the test compound. ED25 for diastolic blood pressure (dose inducing 25% reduction) and ID50 (dose inducing 50% inhibition of NA-induced increase in urethral pressure) were determined by linear regression analysis.

the results

Compounds prepared according to the Examples were tested according to the procedures described above, and the results obtained are shown in the Tables below, along with comparative results for the references used. Compounds having a receptor affinity lower than about 500 nM. are generally considered to be of good affinity. Compounds with IC 50 values of less than 100 nM are generally preferred.

[image]

[image]

[image]

Urethra: active dose in inhibition of 50% of urethral contraction indicated by noradrenaline

DBP: active dose in reducing diagnostic blood pressure by 25%

DBP/Urethra: relationship between "active doses (selectivity index) non-selective: basic effect both ns urethra and on DBP

Effective amounts:

The following is a presentation of effective oral, perenteral or intravenous doses presented in mg/kg of body weight per day for the following use:

a) Obstructive diseases of the lower urinary tract:

Generally 0.001-20

Preferably 0.05-1

Most preferred ** 0.3.

b) As antihypertensives:

Generally 0.01-20

Preferably 0.1-5

Most preferred ** 1

c) As anxiolytics-antidepressants:

Generally 0.01-20

Preferably 0.05-5

Most preferred 0.5

d) As bladder spasmolytics:

Generally 0.01-20

Preferably 0.02-10

Most preferred ** 2

**Most preferred values refer to oral dosing. Intravenous doses should be 10 to 100 times lower. Patients to be treated with the disclosed compounds and preparations also include those who have one or more symptoms of depression (as defined, e.g., in Harrison's Principles of Internal Medicine, XII Ed., McGraw-Hill, Inc., p. 2124) or those showing symptoms of anxiety (Harrison, supra, pp. 2131 -2134).

Selective doses for use, i.e. doses that are active in the lower urinary tract without significant effect on blood pressure, depend on the individual compound used within the group, but generally more than 4 times the ED50 of selective compounds can be used without significant effect on blood pressure. Further discoveries and optimization of dosages can be carried out by conventional experiments.

The active compounds of the invention may be administered orally, for example, with an inert diluent or with a suitable carrier or may be incorporated into gelatin capsules or may be compressed into tablets. For reasons of oral therapeutic use, the active compounds of this invention can be incorporated with excipients and used in the form of tablets, dragees, capsules, elixir suspensions, syrups, wafers, chewing gums and the like. Preparations should contain at least 0.5% of the active substance, but the content of the active ingredient can vary depending on the individual form and is usually between 5% and 70% of the weight of the unit.

The amount of the active compound in such preparations is such that a suitable dose can be achieved by using several dosage forms. Preferred compositions and preparations of the present invention are prepared so that the unit dosage form contains between 1.0-300 milligrams of the active compound. Tablets, pills, capsules, dragees and the like may also contain cytocrystalline cellulose, tragacart or gelatin, excipients such as starch or lactose, disintegrants such as alginic acid, Primogel, and the like, lubricants such as cagnesium stearate or Sterotex, glosses such as colloidal silicon dioxide, and sweeteners such as sucrose or saccharin, and flavor corrigents such as peppermint, methyl salicylate or orange corrigents can also be added.

When the dosage form is a capsule, it may contain, in addition to the preceding materials, a liquid base such as a fatty oil. Other dosage forms of the legs contain various other materials that modify the physical form of the dosage form, for example, coatings. Thus, tablets and pills can be coated with sugar, shellac, or some other means. Syrup may contain, in addition to the previous compounds, sugar or another sweetener and certain preservatives, colors and flavoring agents. The materials used in the various preparations must be pharmaceutically pure and non-toxic in the amounts used. For the purpose of parenteral administration, the active compounds according to the present invention can be incorporated into solutions or suspensions. These preparations should contain at least 0.1% of the active compound, but this can vary from 0.5 to 30% of the weight of the preparation. The amount of the active ingredient in such preparations is such that a suitable dose is achieved. Preferred preparations according to the present invention are those prepared so that the parenteral dosage units are between 0.2 and 100 milligrams of the active compound. Solutions and suspensions may also include the following components: a sterile solvent such as water for injections, saline solutions, oils. polyethylene glycol, glycerin, propylene glycol or some other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl paraben, antioxidants such as ascorbic acid or sodium bisulpite; ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates; agents for achieving increased osmotic pressure such as sodium chloride or dextrose. Vials for parenteral agents for multiple doses can be made of glass or plastic materials.

Claims (9)

1. A compound having the general formula I [image] indicated by that ------ represents a single or double bond; X represents an oxygen or sulfur atom or an imino, alkyl-imino, sulphinyl or sulphonyl group; W represents a valence bond or a carbonyl, thiocarbonyl, methylene or hydroxylmethylene group; R 2 represents a hydrogen atom or an alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, carbocyclyl, substituted carbocyclyl, hetero-cyclyl, substituted heterooxyclyl or aroyl group; the substituents for the aforementioned substituted groups are one or more halogen atoms and/or one or more alkyl, cyano, hydroxy, alkyl, phenyl, phenoxy, trifluoromethyl, nitro, amino, alkylanino, dialkylamino, acylamino, alkylsulphonylamino or benzoyl groups; R 3 represents a hydrogen atom or an alkyl, hydroxylalkyl, alkoxy-alkyl, aralkyl, phenyl, hydroxy, alkoxy or aralkyl group; R6 represents a hydrogen or halogen atom or a nitro, amino, alkylamino, dialkylamino, acylamino, alkylsulphonylamino, cyano, hydroxy, alkoxy or alkyl group; R7; represents a hydrogen atom or an alkoxy group; Y represents one or more of the following groups, each of which is shown so that the left side is attached to the hetero-bicyclic ring and the right side is attached to the group Z: (Y1) -, (Y2) -COO-, (Y3) -CONH-, (Y4)-CON(CH7), (Y5) -CON(OH)-, (Y6) -CH(OH)-, (Y7) -CH(OAlkyl)-, (Y8) -CH=CH-, (Y9) -OH-OH-COO-, (Y10) -CH=CH-CONH- (Y11) -CH=NO-, (Y12) -CH2-, (Y13) -CH2COO-, (Y14) -CH2CONH-, (Y15) -CH2NH-, (Y16) -CH2N(CH3)-, (Y17) -CH2N(CCOH3)-, (Y18) -CH2N(CONH2)-, (Y19) -CH2NHOO-, (Y20)-CH2N(CH3), (Y21) -CH2NH-CONH-, (Y22) -GH2NHSO2-, (Y23) -CH2O-, (Y24) -CH2S-, (Y25) -CH2SO-, (Y26) -CH2SO2-, (Y27) -CH2SO2NH-, (Y28) -CH2SO2N(CH5)-, (Y29) -, (Y30) -N(CH3)-, (Y31) –N(COCH3)-, (Y32) -N(CONH2)-, (Y33) -NHCO-, (Y34)-N(CH3), (Y35) -NO-CONH-, (Y36) -NHSO2-, (Y37) -O-, (Y38) -S-, (Y39) -SO-, (Y40) -SO2-, (Y41) -SO2NH-, (Y42) -SO2N(CH3)-, (Y43) -CONHO-, (Y44) -CON(COCH3)-, (Y45) -CSNH-, (Y46) -CSN(CH3)-, [image] (Y48) -NHCOO-, and (Y49) -; Z represents a linear or branched chain alkylene group that has from 1 to 6 carbon atoms and can have one hydroxy substance; and B represents one or more of the following groups: (B1) [image] where Q represents a methylene or ethylene group and A represents one of the following groups: (A1) phenyl group substituted with one or more halogen atoms and/or one or more alkyl, alkoxy or hydroxy groups, (A2) 2-pyrimidinyl group, and (A3) group of the general formula [image] where ---- is the same as previously defined and E represents an oxygen atom or a valence bond, (B2) [image] where each of L1, and L2 in particular represents a hydrogen atom, phenyl, 4-fluorobenzoyl or 2-oxo-1-benzimidazolinyl group or a group of the general formula (CH2)n-O-A where n is 0, 1 or 2, and A is defined in this claim , with the condition that L1 and L2 are not both hydrogen atoms, (B3) [image] where each of R10 and R11 separately represents a hydrogen atom or an alkoxy or an alkylthio group, R12 represents a hydrogen atom or an alkyl group, and n is 2 or 3, (B4) [image] where R12 is already defined in this claim and R13 represents a hydrogen atom or an alkoxy group, and (B5) [image] wherein R 12 is as defined in this claim, or a prodrug, enantiomer, diastereoisomer, N-oxide or pharmaceutically acceptable salt of such a compound. 2. A compound according to claim 1, characterized in that ---- represents a double bond, X represents a hydrogen atom, W represents a carbonyl group, R2 represents a phenyl group, R3 represents a methyl group, R6 represents a hydrogen atom, and R7 represents a hydrogen atom. 3. A compound according to claim 1 or 2, characterized in that Y represents one or more of the groups Y2, Y3, Y37, Y40 or Y41. 4. A compound according to any of the preceding claims, characterized in that Z represents a trimethylene or tetramethylene group. 5. A compound according to any of the preceding claims, characterized in that B represents one of the groups B1 or B3. 6. A compound according to any of the preceding claims, characterized in that B represents a 4-(2-meroxyphenyl)-1-piperazinyl) group. 7. A compound according to any of the preceding claims, characterized in that Y, Z and B together represent a 3-[4-(2-methoxy-phenyl)-1-piperazinyl]-propylcarbamoyl group. 8. Any of the following compounds, characterized by the fact that: 8-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-1-oxoethyl]-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8-{2-[4-(2-methylphenyl)-1-piperaziny]-1-oxoethyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8-{2-[4-82-ethoxyphenyl)-1-piperazinyl]-1-oxoethyl]-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-1-oxopropyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propoxycarbonyl|-3-methyl-4-oxo-2-phenyl-4H--benzopyran, 8-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethoxycarbonyl}-3-methyl-4-xo-2-phenyl-4H--benzopyran, 8-[3-[4-(2-chlorophenyl)-1-piperazinyl]-propoxycarbonyl]-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8-[3-(4-phenyl-1-piperazinyl)-propoxycarbonyl]-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8-[3-[4-(2-methoxyphenyl)-1-piperazinyl]-propoxycarbonyl]-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran 8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-2-methyl-2-propoxycarbonyl}-3-methyl-4-oxo-2-4H-1-benzopyran, 8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylcarbonyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethylcarbamoyl]-3-methyl-4oxo-2-phenyl-4H-1-benzopyran, 8-{3-[2-(2-methoxyphenoxy)-ethylamino]-propylcarbamoyl}-3-methyl-4oxo-2-phenyl-4H-1-benzopyran, 8-[3-[2-(phenyl-1-piperazinyl)-propylcarbamoyl]-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8-{N-methyl-2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethylcaroamoyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran 8-{1-hydroxy-2-[4-(2-methioxyphenyl)-1-piperazinyl]-ethyl}-3-methyl-4oxo-2-phenyl-4H-1-benzopyran, 8-{1-hydroxy-2-[4-(2-methylphenyl)-1-piperazinyl]-ethyl]-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8-{1-hydroxy-2-[4-(2-ethoxyphenyl)-1-piperazinyl]-ethyl[-3--methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8-{1-hydroxy-3-[4-(2-methoxyphenyl)-1-piperazinyl]-propyl[-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8-[1-hydroxy-4-[4-(2-methoxyphenyl)-1-piperazinyl]butyl]-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8-(1-ethoxy-2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl]-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8-{N-methyl-2-[4-(2-methoxyphenyl)-1-piperzinyl]-ethaminomethyl]-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8-[N-acetyl-2-[4-(2-methoxyphenyl)-1-piperazinyl}-ethylaminomethyl]-3-methyl-4-oxo-2-penyl-4H-1-benzopyran 3-[4-(2-methoxyphenyl)-1-piperazinylacetamidomethyl]-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 3-[N-methyl-N-[4-(2-methoxyphenyl)-1-piperazinyl]-acetamidomethyl]-3-methj)-4oxo-2-phenyl-4H-1- benzopyran 3-[2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethoxymethyl]-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 3-[2-[2-(2-ethoxyphenoxy)-ethylamino3-ethoxymethyl]-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 2-[4-(2- methoxyphenyl)-1-piperazinyl]-ethylthiomethyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 3-[2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethylsulphinylmethyl]-3-methyl-4-oxo-2-phenyl-4H-1-benzopyxan, 3-{2-[4-(2-methyloxyphenyl)-1-piperazinyl)-ethylsulphonylmethyl]-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethylamino]-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8-[3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylaminoj-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8-[4-(2-methoxyphenyl)-1-piperazinyl]-butylamino}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8-(N-methyl-methoxyphenyl)-1-piperazinyl)-propylamino)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8-[N-acetyl-3-(2-methoxyphenyl)-1-piperazinyl]-propylamino}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8-[3-[4-(2-methoxyphenyl)-1-piperazinyl]-propionamido}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethylureido]-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethoxyj-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8-[3-[4-(2-methoxyphenyl)-1-piperazinyl]-propoxy}-3-methyl-4oxo-2-phenyl-4H-1-benzopyran, 8-[3-[4-(2-methoxyphenyl)-1-piperazinyl]-butoxy}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8-[5-[4-(2-methoxyphenyl)-1-piperazinyl)-pentyloxy}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8-[3-[4-(2-methoxyphenyl)-1-oxo-1-piperazinyl)-propoxy]-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8-(2-[2-(2,6-dimethoxyphenoxy)-ethylamino]-ethoxy]-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8-[2-hydroxy-3-(2-methoxyphenyl)-1-piperazinyl]-propoxy]-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran 8-{3-[2-(2-methoxyphenyl)-1-piperaziny]-propylthio]-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8-[3-[2-(2-methoxyphenyl)-l-piperazinyl}-propylsulphonyl-3--methyl-4-oxo-2-phenyl-4H-l-benzopyran, 8-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethylsulphamoyl-3--methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8-[1-methyl-2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethylsulphamoyl|-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8-{N-carbamoyl-3-[2-(2-methoxyphenyl)-1-piperazinyl]-propylamino]-3-methyl-4-oxo-2-pheyl-4H-1-benzopyran 8-[4-[4-(2-methoxyphenyl)-1-piperazinyl]-1-oxobutyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8-[3-[2-(1,4-benzodioxanyl)-methylamino]-propylcarbamoyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8-[4-[4-(2-methoxyphenyl)-1-piperazinyl]-butyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8-[3-(4-phenyl-1-piperidinyl)-propylcarbainoyl]-3-methyl-4-oxo-2-phenyl-4H--benzopyran, 8-[3-(4,4-diphenyl-1-piperidinyl)-propylcarbamoyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8-(3-[4-(4-fluorobenzyl)-1-piperidinyl]-propylcarbamoyl]-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8-{3-[4-(2-oxo-1-benzimidazolinyl)-1-piperidinyl]-propyl-carbamoyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8-{3-[4-(2-pyrimidinyl)-1-piperazinyl)-propylcarbamoyl]-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8-{3-14-(2-hydroxyphenyl)-1-piperazinyl]-propylcarbamoyl]-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8-[4-[4-(2-methoxyphenyl)-1-piperazinyl}-butylcarbamyl|-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8-[3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylsulphano-1-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8-(3-[N-methyl-2-(2-methoxyphenxy)-ethylamino]-propylcarbamoyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8-[N-methyl-3-[4-(2-methoxyphenyl)-1-piperazinyl]-propionamido]-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8-(3-4-(2-methoxyphenyl)-1-piperazinyl)-propylcarbamoyl]-3-phenyl-4-oxo-4H-1-benzopyran, 8-[3-[(3[4-dihydro-1-oxo-2-phenyl)-methylamino]-propylcarbamoyl]-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethoxycarbonylmethyl]-3-methyl-4-oxo-2-phenyl-4-H-1-benzopyran, 8-[4-[4-(2-methoxyphenyl)-1-piperazinyl]-butylsulphamoyl]-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8-[N-(2-tetrahydropyranyloxy)-3-[4-(2-methyloxyphenyl)-1-piperazinyl]-propylcarbamoyl]-4-oxo-4H-benzopyran, 8-[N-[4-(2-methoxyphenyl)-1-piperazinyl]-butyamido]-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8-(2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethoxyiminomethyl}-3-methyl-4-oxo-2-phenyl-4H-1-bernzopyran, 8-(2-hyrdoxy-3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylcarbamoyl)-4-oxo-2-phenyl-4H-1-benzopyran, 8-(2-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethylcarbamoyl}-ethenyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran 8-{2-(2-(2-methoxyphenyl)-1-piperazinyl]-butylsulphinyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8-(3-[3-(2-methoxyphenoxy)-propylamino]-propylcarbamoyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8-{3-[2-(2-methylthiophenoxy)-ethylamino]-propylcarbamoyl]-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8-{3-[2-(2,6-dimethoxyphenoxy)-ethylamino]-propylcarbamoyl}-3-ethyl-4oxo-2-phenyl-4H-1-benzopyran, 8-{3-[4-(5-chloro-2-methoxyphenyl)-1-piperazinyl}-proplcarbamoyl]-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran 8-{4-[4-(2-methoxyphenyl)-1-piperazinyl]-1-butenyl]-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8-(2-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethoxycarbonyl}-ethenyl)-3-methyl-4-oxo-4H-1-benzopyran, 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethylcarbamoylmethyl]-4-oxo-2-phenyl-4H--benzopyran, 8-{N-acetyl-3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylcarbamoyl]-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethylsulphonylamino}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8-[3-[4-(2-methoxyphenyl)-1-piperazinyl)-propylthiocarbanoyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8-[4-[4-(2-methoxyphenyl)-1-piperazinyl)-butylsulphonyl]-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 3-[3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylcarbamoyl]-3-hydroxymethyl-4-oxo-2-phenyl-4H-1-benzopyran 3-(3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylcarbamoyl)-4-oxo-2-phenyl-4H-1-benzopyran 3-(3-[4-(2-methoxyphenyl)-1-piperazinyl)-propylcarbamoyl]-2,3-dihydro-4-oxo-4H-1-benzopyran, 3-(3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylcarbamoyl)-4-oxo-4H-1-benzopyran, 3-(3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylcarbamoyl]-6-bromo-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran 8-(3-[4-(2-methoxyphenyl)-1-piperazinyl}-propylcarbamoyl]-6-methoxy-3-methyl-4-oxo-2-phyl-4H-1-benzopyran 8-(3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylcarbamoyl]-6-hydroxy-3-methl-4-oxo-2-phenyl-4H-1-benzopran 8-(3-[4(2-methoxyphenyl)-1-piperazinyl]-propylcarbamoyl)-3,6-dimethyl-4-oxo-2-phenyl-4H-1-benzopyran, 8-(3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylcarbamoyl)-3-methyl-6-nitro-4-oxo-2-phenyl-4H-1-benzopyran, 8-[3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylcarbamoyl]-6-amino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylcarbamoyl}-6-acetamido-3-methyl-4-oxo-4H-1-benzopyran, 8-(3-[4-(2-methoxyphenyl)-1-piperazinyl)-propylcarbamoyl}-6-ethylamino-3-methyl-4-oxo-2-4H-1-benzopyran, 8-(3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylcarbamoyl]-6-dimethylamino-3-methyl-4-oxo-74H-1-benzopyran 8-[3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylcarbamoyl]-7-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran 8-{3-[4-(2-methoxyphenyl)-1-piperazinyl)-propylcarbamoyl]-3-methyl-4-oxo-2-(4-trifluoroylphenyl)-4H-1-benzopyran a pharmaceutically acceptable salt of such a compound. 9. Pharmaceutical preparation, characterized in that it contains a compound according to any of the preceding claims or a "prodrug", enantioner, diastereoisomer, N-oxide or a pharmaceutically acceptable salt of such a compound in admixture with a pharmaceutically acceptable diluent or carrier.