BG98990A - Heterobicyclic compounds - Google Patents

Abstract

The compounds act as spasmolytics of the lower urinary tract and are used in the treatment of urinary incontinence, imperative urge syndrome and other similar disorders. Most of them have low toxicity and have the general formulations according to the invention, pharmaceutical compositions containing these compounds or prodrug enantiomers, diastereoisomers, n-oxides or pharmaceutically acceptable salts of the compounds in admixture with a pharmaceutically acceptable diluent or carrier can be prepared. </ P>

Description

The invention relates to heterobicyclic compounds and pharmaceutical compositions containing them.

flavoksad, which is 8- (2-piperidinoethoxycarbonyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran of formula

/ '/

COOH ₂ CH ₂ --N \

It is used as a pharmaceutical substance in disorders of the urinary tract because it affects the smooth muscle relaxation due to its action as a calcium antagonist. This activity occurs on the smooth muscles of the bladder vault, or it can bind to the central nervous system's center of thought.

The compounds of the invention described below contain substantially more complex amino radicals instead of piperidine groups. In addition, the amendments include alternatives to ethoxycarbonyl groups that separate the amine moiety from the benzopyran ring, alternative 2-, 3-,

6- and 7-substituted patterns in the benzopyran ring, substitution of the ring hetero atom with a sulfur atom or with a sulfinyl, sulfonyl or imino group, and / or 2,3-dihydrogenation of the benzopyran ring. These structural changes allow the new compounds to interact with different biological systems, as confirmed by the affinity of the new compounds to the α-adrenergic and 5HT _1A- serotonergic receptors. Flavoxad has virtually no affinity for these receptors.

Compounds according to the invention

The compounds of the invention are of general formula I

Y-Z-B 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 aroyl group; the substituents of the above substituted groups are one or more halogen atoms and / or one or more alkyl, cyano, hydroxy, alkoxy, phenyl, phenoxy, trifluoromethyl, nitro, amino, alkylamino, di alkylamino, acylamino- , alkylsulfonylamino or benzoyl groups;

R ₃ represents a hydrogen atom or an alkyl, hydroxyalkyl, alkoxyalkyl, aralkoxyalkyl, phenyl, hydroxy, alkoxy or aralkoxy group;

R ₆ represents a hydrogen atom or a nitro, amino, alkylamino, di alkylamino, acylamino, alkylsulfonylamino, cyano, hydroxy, alkoxy or alkyl group;

R 4 represents a hydrogen atom or an alkoxy group;

Y represents one of the following groups, each of which is connected at its left end with the heterobicyclic ring and at its right end with the Z group:

(Y1) -CO-, (Y2) -COO-, (Y3) -CONH-, (Y4) -CON (CH ₃ ) - (Y5) -CON (OH) - (Y6) -CH (OH) -, (Y7) -CH (Oalkyl) -, (Y8) -CH = CH-, (Y9) -CH = CH-COO-, (Y10) -CH-CH-CONH-,

(Yll) -CH = NO-, (Y12) (Y13) -CH ₂ COO-, (Y14) -ch ₂ conh-> (Y15) -ch ₂ nh-> (Y16) -CH ₂ N (CH ₃ ) -> (Y17) -CH ₂ N (COCH ₃ ) -> (Y18) -CH ₂ N (CONH ₂ ) -> (Y19) -ch ₂ nhco- (Y20) -CH ₂ N (CH ₃ ) CO-, (Y21) -CH ₂ NH-CONH-> (Y22) -CH ₂ NHSO ₂ -, (Y23) -ch ₂ o- (Y24) -CH ₂ S-> (Y25) -CH ₂ SO-> (Y26) -CH ₂ SO ₂ -, (Y27) -ch _{2 are 2} nh-, (Y28) -CH ₂ SO ₂ N (CH ₃ ) - _: (Y29) -NH-, (Y30) -N (CH ₃ ) -, (Y31) -N (COCH ₃ ) -, (Y32) -N (CONH ₂ ) -, (Y33) -NHCO-, (Y34) -N (CH ₃ ) CO-, (Y35) -NH-CONH- (Y36) -NHSO ₂ -, (Y37) -0-, (Y38) -S-, (Y39) -SO-, (Y40) -S0 ₂ -, (Y41) -SOoNH-,

(¥ 42) -SO ₂ N (CH ₃ ) -, (Υ43) -CONHO-, (Υ44) -CON (COCH ₃ ) -, (Υ45) -CSNH-, (Υ46) -CSN (CH ₃ ) -, (Υ47) -CON (O-f

(Y48) (Y49) -NHCOO-, and -COS-;

Z represents a linear or branched alkylene chain group of 1 to 6 carbon atoms and optionally one hydroxyl substituent; and

B represents one of the following groups;

(Bi) / \ —N N — A w

in which Q represents a methylene or ethylene group and

A represents one of the following groups:

(Aj) a phenyl group substituted by one or more halogen atoms and / or one or more alkyl, alkoxy or hydroxy groups, (A _? ) One 2-pyrimidinyl group, and (A ₃ ) a group of the general formula wherein --- --- has the meaning given above and E represents an oxygen atom or a valence bond, (B ₂ )

in which each L and L ₂ independently represents a hydrogen atom, a phenyl, 4-fluorobenzoyl or 2-oxo-1-benzimidazolinyl group or a group of the general formula (CH ₂ ) _n -O-A in which n is 0, 1 or 2 , and A has the meaning given above provided that C and L ₂ do not represent a hydrogen atom,

in which each and Rp independently represents a hydrogen atom or an alkoxy or alkylthio group, Rp represents a hydrogen atom or an alkyl group and n is 2 or 3, (B ₄ )

in which R ₁₂ has the meaning given above and Rp represents a hydrogen atom or an alkoxy group, and (B ₅ ) o

in which Rp has the meaning given above.

When ..... represents a double bond, W represents a carbonyl group and X represents an amino group, the ring may undergo tautomerization to give a 4-hydroxyquinoline structure; such tautomeric compounds are included in the invention.

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

The term prodrug is used herein to denote the derivative of a compound of general formula I in which the reaction groups such as amino, imino, or hydroxy groups (especially as or in the W, R 3, R 4, Z, B 1 and B2 portions ) or acidic amino groups (e.g., those in Y3, ΥΙΟ, Y19, Y27, Y36 and Y41) are masked; the derivative releases the compound itself in the living organism and thus has the same pharmacological effect in the body as the compound itself. The prodrugs may be formulated to alter the pharmacokinetic properties of the compound, e.g. so as to prepare a sustained release or sustained release formulation of the compound, or, alternatively, to alter the metabolism, absorption, distribution or plasma half-life of the compound. The compounds prepared below in Examples 114 and 120 to 122 are examples of prodrugs.

D hole

hereinafter referred to as F1.

The preferred substituents in the F1 group are the following:

-—: double bond, X: oxygen atom,

W: carbonyl group, R ₂ : phenyl group, R ₃ : methyl group, R ₆ : hydrogen atom, and R _? : hydrogen atom.

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

The preferred groups that Z may represent are trimethylene and tetramethylene. Y is preferably one of the groups Y2, Y3, Y37, Y40, Y41 or Y42. B is preferably one of the B1 or B3 groups, especially the 1- (2-methoxyphenyl) piperazinyl group.

Conventional abbreviations used herein include Me for methyl, Et for ethyl, Ac for acetyl, A1k for alkyl, THF for tetrahydrofuran, DMF for dimethylformamide and DMSO for dimethyl sulfoxide.

The antagonistic adrenergic activity of the compounds of the invention defines them as useful substances acting on tissues especially rich in adrenergic receptors (such as blood vessels, prostate and urethra). Accordingly, the antiadrenergic compounds established in the invention based on their receptor binding profile may be useful therapeutic agents, e.g. in hypertension and urinary disorders associated with obstructive disorders of the lower urinary tract, including, but not limited to, those caused by benign prostatic hypertrophy.

The serotonergic activity of the compounds of the invention defines them as useful active substances

On the tissues, especially in the central nervous system, where 5HT _1A receptors function. The 5HT _1A receptors are thought to regulate the action and release of serotonin as well as the release of other neurotransmitters and are considered pre- and postsynaptic. The compounds of the invention have biological activity in blocking the binding between these receptors and their various specific ligands (eg serotonin). Accordingly, the compounds of the invention that interact with the 5HT _1A receptor (established as such based on their receptor binding profile) may be useful therapeutic agents for the treatment of depression and depression.

Unexpectedly, the compounds of the invention (especially those that have affinity for both α-adrenergic and 5HT _1A- serotonergic receptors) show high selectivity for the mammalian lower urinary tract. they are significantly more active in antagonizing urethral contractions than in lowering blood pressure. On the contrary, known α-antagonists, such as e.g. prazosin, which is 1- (4-amino-6,7-dimethoxy-2quinazolinyl) -4- (2-furoyl) -piperazine (GB 1156973), does not have such selectivity (and in fact causes hypotension as the most common side effect ), whereas flavone derivatives that are structurally similar to flavoxad, such as terflavoxide, which is 8- (1,1-dimethyl-2-piperidinoethoxycarbonyl) -3-methyl-4-oxo-2-phenyl-4H-1 -benzopyranhydrochloride (EP 0072620), does not affect urethral contractions. Of course, those compounds of the invention that are not selective for the lower urinary tract are preferred as antihypertensive agents, but even selective compounds can often be used as antihypertensive because of their low toxicity.

The compounds of the invention exhibit a good antagonistic effect against potassium chloride-induced contractions of the rat bladder band. This effect may be related to the antagonistic activity of calcium, and it defines new compounds as spasmolytics of the lower urinary tract (ie, useful in the treatment of urinary incontinence, imperative urge syndrome, and the like).

Most of the compounds according to the invention have low toxicity. Thus, they can be used in greater amounts, an advantage that more often compensates for the relatively low activity level of some of these compounds. Naturally, compounds having both high activity and low toxicity are preferred.

The invention further provides pharmaceutical compositions comprising a compound of the invention or prodrug enantiomers, diastereoisomers, N-oxides or pharmaceutically acceptable salts of such compound, in admixture with a pharmaceutically acceptable solvent or carrier.

Synthesis of the compounds of the invention

The compounds of the invention are generally prepared (except when the R ₆ groups and the substituents at R ₂ are OH, NH ₉ or aminoalkyl, and Y = Y ₁₅ or Y 29) as follows: a:

By condensation of compounds F1-Y-Z-L, where L represents a halogen atom or a leaving group such as a tosyloxy group, with compound H-B. Preferably, but not necessarily, the condensation is carried out at a temperature between 20 and 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 shown 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. See also Gibson's chapter in Patai, The Chemistry of the Amino Group, p.45 et. seg., Wiley Interscience, New York, 1968.

An alternative method of preparing compounds of the invention is the condensation (under the same conditions described in the preceding paragraph) of compound Fl-Y-H with compound L-Z-B, where L has the meaning defined above. This condensation is illustrated in Examples 5, 6, 66, 79 and 81 below. In this way, compounds with Y = Y15 or Y29 can be obtained (see Gibson's chapter in Patai).

Compounds of formula (I) with the IN ₂ group in R ₆ or as a substituent in R ₂ can be prepared by reduction of the corresponding compound (I) wherein R ₆ or the substituent in R ₂ are NO ₂ -pypynu. Such reduction may be carried out:

with Raney Ni catalyst in a protic solvent selected from methanol, ethanol, isopropanol, water and a mixture thereof; or with SnCL ₂ , H ₂ O, optionally in the presence of hydrochloric acid, or in a protic solvent such as methanol, ethanol, isopropanol, water, acetic acid and a mixture thereof, 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 and a mixture thereof.

The above reaction temperatures are selected in the range of 20 to 100 ° C (J. March, Advanced Organic Chemistry, III Ed., P. 1103, Wiley Interscience, 1985). Examples of this reduction are given in Examples 94 and 124.

Compounds of formula (I) with the NHAalk group as a substituent of R ₆ can be prepared by monoalkylation using the corresponding compounds (I) as starting materials in which R ₆ = NH ₂ . This can be done e.g. by reacting first the amino compound (I) with excess of trifluoroacetic anhydride, then reacting the resulting trifluoroacetyl derivative with an alkyl-L reagent and finally deprotecting the thus obtained alkylated trifluoroacetyl derivative with potassium borohydrate or boronoylate , or dimethyl sulfoxide. These reactions are described in Examples 32 and 33 and are performed in groups Y.

Another possibility for preparing compounds of Formula I with groups NHAlk or N (Alk) ₂ as R ^ substituent or as a substituent on the phenyl group in R ₂ by alkylation of the corresponding starting compounds (I), where R ₆ = NH ₂ with suitable alkanes in the presence of a reducing agent, such as e.g. sodium cyanoborohydride. These reactions are described in Examples 96 and 97 below.

Compounds with an OH group as R ₆ or as a substituent in R ₂ can be prepared from the corresponding starting compounds (I), alkoxy-substituted at the mentioned positions. This can be accomplished by treating the starting compounds e.g. with BBr ₂ in dichloromethane at 0-40 ° C (T. W. Greene, Protective Groups in Organic Synthesis, page 87, Wiley Interscien.ce, 1981) or according to other methods described in the same literature.

Compounds of general formula I in which ----- represents a single bond can be prepared either by selectively hydrogenating the corresponding compounds in which ----- represents a double bond or by converting a suitable starting material in which 2 The 3-bond is pre-saturated. Such starting materials are prepared according to reaction schemes 4, 6 to 9, 11, 12 and 14 below. The latter method is illustrated in Example 87 and is practically preferred when the parent compound contains a nitro group, since by hydrogenation the nitro group could be converted to an amino group. Selective hydrogenation can be carried out using alternatively:

hydrogen in the presence of a metal or metal oxide catalyst (e.g. palladium / carbon or palladium dioxide) in a protic solvent at 20-120 ° C (EN Rodd, Chemistry of Carbon Compounds, Vol. IVB, page 903, Elsevier, 1959); or di (isobutyl) aluminum hydride in an aprotic solvent (e.g. tetrahydrofuran and / or dichloromethane) at -70 to 0 ° C (H. Sarges at al., J. Med. Chem., 33, 1859, 1990).

Compounds in which W represents a hydroxymethylene group and the bond 2,3 is saturated can be prepared by reducing the corresponding compound wherein W represents a carbonyl group and the bond 2,3 is saturated with sodium borohydride, as reported in Example 123 below.

In some cases, the compounds of general formula I may be prepared by conversion of other compounds of the invention. Such conversions include:

b: Fl-CO-ZB - + F1-CH (OH) -ZB by reduction, as shown in Examples 17 to 20 below, with: F1-CH (OH) -ZB -> F1-CH (OAlkyl) -ZB by esterification, as shown in Example 22 below, d: Fl- (CH ₂ ) _n -NH-ZB - + Fl (CH ₂ ) _n -N (CH ₃ ) -ZB where η = 0 or 1 , by N-methylation as shown in Example 35 below.

is: Fl- (CH ₂ ) _n -NH-ZB -> Fl- (CH ₂ ) _n -N (COCH ₃ ) -ZB where n = 0 or 1, by N-methylation, as shown in Example 36 more- down.

f: Fl- (CH ₂ ) _n -NH-ZB -> Fl- (CH ₂ ) _n -N (CONH ₂ ) -ZB where η = 0 or 1, by reaction with potassium isocyanate, as shown in Example 50 -down.

g ^; h:

and:

k:

F1-CH (OH) -ZB -> Fl-CO-ZB by oxidation, as shown in Example 51 below. Fl-YZB - »Fl-YZB (N-okcug) by oxidation, as shown in Examples 43 and 122 below. H ₂ N-F 1 -YZB -> CH 2 CONH-Fl-YZB (where H ₂ N-F 1 represents an Fl-group in which R ₆ is an amino group or R ₂ includes an amino group) using the Nacylation method described in examples 36 and 95 below.

F1 (R ₆ = NH ₂ ) -YZB -> F1 (R ₆ = CH ₃ SO ₂ NH) -YZB by amidification using the method described in Example 112 below.

HYZN (Alk) -CH ₂

Oh

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

Some compounds may be prepared by coupling reactions. For example, compounds in which Z contains a hydroxyl substituent can be prepared by attachment to an epoxy group.

1: FL-Y-CH ₂ -CH-CH ₂ + H-B-> F 1 -Y-CH ₂ -CH (OH) -CH ₂ -B as shown in Example 45 below.

It is also possible to join in a double connection, e.g.

m: F1-Y-CH = CH ₂ + H-B- »F1-CH ₂ -CH ₂ -B as shown in Examples 37, 63 and 82 below.

Other synthesis schemes include the formation of Y, Z or B during the reaction, e.g.

n: F1- (X) - (Q) -C1 + A-NH-ZB -> F1- (X) - (Q) -N (A) -ZB (where X = bond, CH ₂ or CH = CH, Q = CO or SO ₂ , and A =

H, alkyl or OP ₁ , where P ₂ is a protecting group), as shown in Example 12 (particularly preferred) and in Examples 60, V 61, 64, 67, 68, 72, 87, 88, 93, 98, 116 , 129 and 130.

The same compounds may be prepared by other schemes including:

F1- (X) -COOH + A-NH-ZB in the presence of a binding agent (e.g., dicyclohexylcarbodiimide, Ν, Ν'-carbonyldiimidazole or diethylcyanophosphonate) optionally in the presence of an activator (e.g. 4-dimethylaminopyridine or N-hydroxylidene) or N-hydroxylidene or trifluoromethoxybenzoidene; or a chlorinated solvent (e.g. 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. 4 »Org, Chem., 5, 61, 1968; Ishihara, Chem. Pharm.Bull., 39, 3236, 1991); as shown in Examples 80, 86, 89,90, 92,99 go 11, 113 go 115, 117 go 119 and 128.

F1- (X) -COOH + A-NH-ZB without solvent at 150-220 ° C (Mitchell et al., J. Am. Chem. Soc., 53, 1879, 1931) or in high-boiling ether solvents (e.g. diglym);

Fl- (X) -COO-Alk 4- A-NH-ZB optionally in the presence of a binder (eg trimethylaluminum) in an aprotic and / or chlorinated solvent (eg hexane, dichloromethane) at or without -10/80 ° C solvent at 80-180 ° C (S. M. Weinreb et al., Tetrahedron, 4171, 1977); M. F. Lipton et al., Org. Synth., 59, 49, 1979);

F1- (X) -COOH + alkyl chloroformate in the presence of a tertiary amine (e.g. triethylamine), followed by the addition of ANH-Z-B at 0-80 ° C; an activator (e.g., 1-hydroxypiperidine) may be added before the amine is attached (Albertson, Org. React., 12, 157, 1962).

o: F1-COC1 + HS-Z-B -> F1-Y49-Z-B p: F1-COC1 + HO-Z-B -> F1-Y2-Z-B as shown in Example 10 below.

q: FLCHO + H ₂ -NO-ZB - + Fl-Yll-ZB as shown in Example 70 below.

r: Fl-CHO + A-HN-ZB -> F1-CS-N (A) -ZB (where A = H or CH ₃ ) in the presence of sulfur in an aprotic solvent, e.g. 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.

s: F1-NH ₂ + HCO-ZB - + F1-Y29-ZB as shown in Example 34 below.

t: F1-Y-CH ₃ + HO-CH ₂ -B-> F1-Y-CH ₂ -CH ₂ -B as shown in Example 4 below, and: F1-CH = CH-CONH ₂ + HOC ₂ -B - + Fl-Y10-CH ₂ -B.

ν:

I-U-2G ₃ + NSO-SP _G O- / / - HY-GVZ

Rn under reducing conditions as shown in Example 44 below.

w;

R10 l— \

F1-YZ-NH ₂ + MCH ₂ ) _n ~ SI) F1-YZ-B3

Rii ^ as shown in Examples 74, 75 and 76 below.

F1-Y-Z-NH2 +

F1-Y-Z-B4 as shown in Example 52 below.

x:

F1-YZ-NH ₂ +

H-Y-Z-B5 as shown in Example 65 below.

* $! ** · »

y: F1-Y-Z-CHO + HB F1-Y-Z-B as shown in Example 53 below.

Those of skill in the art will know that everyone

Tigers synthesis routes b) to y) can be simplified provided that the reaction intermediates do not have other groups that are sensitive to the same reagents (eg: CO, NH ₂ , NHAlk or OH). Compounds of formula I having such reactive groups can be prepared by methods b) to y) only if the reactive groups in the starting materials are pre-protected and after the reaction the protection is removed, as shown in Example 71, Selected Examples of Protection and deprotection of various reactive groups can be found in T. W. Green, Protective Groups in Organic Synthesis, Wiley Interscience, 1981 (2nd Edition 1991).

Alternatively, non-reactive groups (eg NO ₂ ) can be left unprotected during the first reaction and then reactive (eg NH ₂ ) as a final step in the reaction scheme. See, e.g. a).

Which synthesis technique will be preferred depends on the compound to be synthesized, but method n) is generally preferred for the compounds that can be prepared therefrom. Those skilled in the art will undoubtedly have other synthetic methods in mind.

Starting substances

The starting materials (Fl-YZL and Fl-Y-H) used for the preparation and described above can be obtained from simple compounds such as Fl-CHO, F1-COC1, F1-NH ₂ and Fl-OH by transformations, known to those skilled in the art. A number of such transformations are described in detail below. Many of these simple compounds (Fl-CHO, F1-COC1 , F1-NH ₂ and F1ON) are commercially or in the literature given their synthesis. Those not commercially available can be synthesized according to one or more of the following reaction Schemes 1 to 16.

Reaction scheme 1 results in a compound in which W represents a carbonyl group and X represents an oxygen atom.

Scheme 1

A - CO, C, H ,, CO ₂ C, H _S. NO,, CH = CHCHc = CO ₂ H, NH,

Eman la

Method of operation without isolating the phenyl ester intermediate:

R3CH2COCI or (R ₃ CH ₂ CO) 2O and Lewis acid (eg AlCl ₃ or ZnCl ₂ ), without solvent or in aprotic solvent (eg nitrobenzene or chlorinated solvent) at 20-180 ° C.

Method of isolating the intermediate phenyl ester:

R ₃ CH ₂ COC 1 or (R 4 CO 2 CO 2 O is heated with the starting material or other esterification methods are used, such as the Schotten-Bauman method. The isolated ester is then heated in a nitrobenzene or other unprocessed solvent (eg chlorinated solvent), or without solvent, at 20-180 ° C, in the presence of Lewis acid such as AlCl ₃ or ZnCl ₂ (AM Blatt, Org. React., 1, 342.1 942).

Stage lb

R ₂ COC1 or (B ₂ CO) ₂ O and R ₂ COONa without or in a high boiling non-permeable solvent (such as o-dichlorobenzene) m, g 150-220 ⁰ C; this reaction permits the direct conversion of compounds (2) into compounds (6) when compounds (2) have A = COOH;

R2C (OAlk) ₃ in the presence of HCl 10 at 20-40 ° C or in pyridine in the presence of piperidine at 60-80 ° C;

R ₂ COC1 or (R2CO) 2O in a chlorinated solvent at -10 to 120 ⁰ C in the presence of a base such as 1,8-diazabicycloundecene (DBU). Stage 1s

R ₂ COC1 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 NEt ₃ or 4 dimethylaminopyridine.

Stage Id

K _? CO ₃ in acetone or methyl ethyl ketone at 20-80 ° C]

NaH in DMSO or THF at 0-40 ° C;

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

Stage le

HCl or H ₂ SO ₄ in AcOH reflux or 6 alcohol (MeOH, EtOH, isopropanol) at 20 ° C to boiling point;

CF ^ COOH in dichloromethane at 20-40 ° C;

p-toluenesulfonic acid in benzene or refluxing toluene.

Stage If

R ₂ COC1 and K ₂ CO ₃ or KOH in water and a catalyst for phase V conversion to water or toluene under reflux;

R ₂ COOAlk and lithium bis (trimethylsilyl) amide or lithium diisopropylamide in THF at -78 to 0 ° C.

Stage lg

When A is COOH ₃ or COO ₂ H ₅ group:

NaOH in aqueous EtOH at 0-75 ° C;

LiOH in aqueous DMF, MeOH or THF or a mixture thereof at 10100 ° C;

HCl in an aprotic solvent such as dioxane at 60-120 ° C When A is NO ₂ :

- reduction with a Raney Nickel catalyst in a protic solvent (eg isopropanol) or a mixture of protic solvents at 20-100 ⁰ C;

reduction with hydrogen and a catalyst (e.g. Raney Nickel or Pd / C) in a protic solvent (e.g. MeOH, EtOH, isopropanol or a mixture thereof) at 20-100 ° C;

reduction with SnCl ₂ in the presence of aqueous HCl in a protic solvent (eg AcOH) at 20-100 ° C;

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

When A is a CH = CHCH ₃ group:

oxidation with Na ₂ Cr ₂ O ₇ or other oxidant such as KMpO ₄ in auemoH / H ₂ SO ₄ at 0-100 ° C.

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

Scheme 2

'W *

Eman 2a

R ₂ COOCH (R ₃ ) CN or R ₂ COOCH (R ₃ ) COOAlk in polyphosphoric acid at 50-120 ° C;

R ₂ OC-COOAlk and A1 ₂ O ₃ in an aprotic solvent (eg Et ₂ O) at 0-40 ° C;

R ₂ OC-COOAlk and a base in an aprotic solvent (eg THF or DMF) at 20-140 ° C;

The last two options are treated 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 stoichiometrically 30% H ₂ O ₂ in acetone at 25-60 ° C; m-chloroperbenzoic acid in chloroform at 0-30 ° C.

Step 2d

30% H ₂ O ₂ in acetone at 50-80 ° C.

Reaction Scheme 3 provides compounds (2) in which R _? 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 scheme 1 and 2 using the corresponding phenols or thiophenols (unsubstituted in position 2 or 6 with COOAlk or NO ₂ ).

Scheme 3

Oh Oh

XI 2

Stage 3

HCO and HCl gas in AcOH containing aqueous HCl (a.lA18N m, r 50100 ° C (R. Da Re et al., Ann. Chim., 46, 904, 1956), This method can be used when R ₂ is other than H or CH 2 OH.

The ordinary intermediate 2,3-dihydro (----- = double bond) can be prepared according to reaction scheme 4, provided that if there are other reactive groups (eg NH ₂ OH) they have been previously protected, as described above. The compounds thus obtained (4) can be converted into the corresponding derivatives with A = COOH or NH ₂ in accordance with step Ig.

Scheme 4

What?

e

Step 4a

R ₂ CHO, aqueous NaOH in EtOH or other protic solvent;

R ₂ -CHO, NaH or potassium tert-butoxide in THF (or other bipolar anhydrous solvent) at 0-150 ° C.

Step 4b mineral acid (e.g. HCl or H ₂ SO ₄ ) in water or other protic solvent (e.g. EtOH, AcOH) at 0-100 ° C.

Step 4c

R ₂ -CHO, 0.1N aqueous NaOH or other suitable base in a protic solvent;

R ₂ -CHO, pyrrolidine in a protic (e.g. MeOH) or polar aprotic solvent at 0-100 ° C (HJ Kabbe, Synthesis, 1978, p. 886).

Step 4d lithium diisopropylamide in THF at 0-20 ° C; then trimethylsilyl chloride and organic base (eg NEt ₃ ) (S. E. Kelly et al., Z Org. Chem., 56, 1325, 1991).

Step 4e

R ₂ -CHO in a chlorinated solvent (eg dichloromethane) at -78 ° C, then TiCl ₄ or other Lewis acid (S. E. Kelly et al., J. Org. Chem., 56, 1325, 1991) .

Eman 4f lithium diisopropylamide in THF at -78 ° C, then R ₂ -CHO (A. Banerij et al., Tetrahedron Letter, 1979, 1685).

Eman 4q

R ₂ -CH = CR ₃ COC1, Lewis acid (eg AlCl ₃ ) in a suitable solvent (eg nitrobenzene) or without solvent at 20-180 ^° C.

Eman4h

R ₂ -CH = CR ₃ COOAlk, triethylbenzylammonium hydroxide in aprotic solvent (eg benzene) or 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 = COOCH ₃ or COOC ₂ H ₅ were hydrolyzed to A = COOH compounds).

Step 4i concentrated H ₂ SO ₄ or Ρ ₂ θ5 or Lewis polyphosphoric acid or acid in nitrobenzene or toluene or without solvent at 0-180 ° C. (Hydrolysis of A = COOAlk to A = COOH takes place in the same way).

Ordinary starting materials with R _g = OH or OR _g , where R _g is alkyl or aralkyl, can be prepared by reaction scheme 5 in which 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 with R ₃ = H) can be obtained by reaction scheme 4, starting from the corresponding phenols or thiophenols with R ₃ = H. The 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, 4486, John Wiley and Sons, New York, 1985; L, Renu et al. , Eur. J. Med. Chem. Chim. Ter., 4, 385, 1977 and references cited therein).

Substitute A in compounds (3) and (6) of reaction scheme 5 may be converted to substituent B in the manner of step lg of reaction scheme 1.

'We *'

Scheme 5

A

Step 5a aqueous NaOH in solvent-alcohol (e.g. MeOH or EtOH), followed by 30% H ₂ O ₂ at -10 to -78 ° C. (ND Meyer et al., J. Med. Chem., 34, 736, 1991 and cited literature). (He can when A is CH = CH-CH ₃ ; when A = COOR immediately becomes COOH). Step 5b

When ----- = single connection:

amyl nitrate or other 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 cited); then H ₂ SO ₄ in a protic solvent (e.g. AcOH) at 10-100 ° C (Acheson RM, An Introduction to the Chemistry of Heterocyclic Compounds, 34Ί, John Wiley and Sons, New York, 1976). When ------ double connection:

lithium diisopropylamide in dry THF at -78 ° C; then AcOH and 30% H ₇ O ₂ (W. D. M. Cunningham et al., Anti-Cancer Drug Design, 7, 365, 1992).

Eman 5c

R ₇ -CH = CH-NO ₂ (1 to 1.5 equivalents) in a suitable solvent (eg diisobutyl ether, DMSO or DMF) in the presence of a base (eg KOH or NaOH) in a catalytic or stoichiometric amount at 20-150 ° C (see L. Renu, supra, and T. Sakakibara et al., Bull. Chem. Soc. Jpn., 51, 3095, 1978).

Eman 5d

15% H ₂ O ₂ , NaOH or other base (e.g. NEt ₃ ) in a protic solvent such as MeOH at 20-100 ° C (SR Deshpande et Ά, Synthesis, 835, 1983) or photolysis or alkaline hydrolysis (Rao TS et al ., Heterocycles, 22, 1377, 1984), or KO ₂ in benzene containing 18 crown-6-ether at 20-100 ° C (Rao TS et al., Heterocycles, 26, 2117, 1987). He is possible when A is CH = CH-CH ₃ ; when A = COOR immediately becomes COOH).

Stage 5f.

R _g L, where L represents a leaving group (e.g. alkylsulfate, halogen, tosyl) and a base (e.g. K ₂ CO ₃ , NaH, KOH, NaOH or LiOH) in a suitable solvent (e.g. THF, DMSO, DMF, benzene) ) in the presence or not of a phase conversion catalyst (eg benzyltriethylammonium bromide) at 0-180 ° C.

Step 5f by the methods of step lb.

Reaction Scheme 6, wherein A has the same meaning as Reaction Scheme 1, yields compounds in which W represents a thiocarbonyl group. Compounds (1) and (2) of reaction scheme 6 can be prepared according to reaction scheme 1, 2, 4 and 5. Substitute A in compound (4) of reaction scheme 6 can be converted to substituent B defined in reaction Scheme 1, by the method of step lg

Figure 6

Step 6a

P ₂ S 4 in pyridine npu 50-100 ° C (Stavaux et al., Bull. Soc. Chim. Fr., 2082, 1967).

Eman 6b

P ₂ S ₅ or B ₂ S ₃ or SiS ₂ 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., 21, 643, 1978; Clausen et al., Tetrahedron, 3635 (1991).

Eman 6c

COC1 ₂ without solvent or with an inert solvent (eg benzene) at 40-90 ° C (A. Schonberg et al., Chem. Ber., 101, 701, 1968). Eman 6d thioacetic or thiobenzoic acid or potassium diethylxanthate in a suitable solvent (e.g. benzene) at reflux (A. Schonberg, cited above).

Reaction Scheme 7, in which A has the same meaning as Reaction Scheme 1, yields 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 scheme 1, 2, 5 and 6. Substitute A in compounds (7) of reaction scheme 7 can be transformed by the method of step lg in substituent B defined in reaction scheme 1.

Scheme 7

Step 7a

1,2-echanedithiol or 1,3-propanedithiol in aprotic solvent (eg dichloromethane or benzene or toluene) at 0-110 ° C in the presence of a catalyst (eg p-toluenesulfonic acid or boron trifluoro-ether at).

Step 7b

R2COOCH2R3 in a suitable mixture of solvents (e.g. EtOAC or dichloromethane plus EtOH or MeOH) saturated with gaseous HCl at 0-40 ° C; then aqueous HClO ₄ in AcOH at 20100 ° C (L. Jurd, Tetrahedron, 28, 493, 1972).

Step 7c

L1AIH4 in THF reflux (if A is different from COOR and NO ₂ );

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

Eman 7d

Earlier nickel in solvent-alcohol (eg isopropanol) at room temperature to reflux (Hilton et al., J. Am. Chem. Soc., 90, 6887, 1968).

Eman 7e

NaBH ₄ in a suitable solvent (e.g. MeOH or EtOH or DMSO) at -10 to 50 ° C (L. Jurd, above);

LiAlH ₄ in THF (or other suitable solvent) at 0-50 ° C (when A is different from COOR or NO ₂ ) (Degani et al., Ann. Chim., 61, 793, 1971; Kurosawa, Bull. Chem. Soc. Jpn. 51, 1175, 1978).

Eman 7f trityl perchlorate in acetonitrile at room temperature (Degani et al., Above).

Eman 7g melt with P ₂ O ₅ npu 80-180 ° C (Hortmann et al., Z Am. Chem. Soc., 96, 6118, 1974).

Eman 7am

NaBH ₄ g EtOH or other suitable solvent at 0 ° C to reflux (K. Apowa, Bull. Chem. Soc. Jpn., 40, 1884, 1967).

Hydrogen (1-10 atm) in EtOH (or other suitable solvent) in the presence of a catalyst, e.g. 5% or 10% Pd / C or Raney-nickel or PtO ₂ at room temperature to 80 ° C (K. Napaua, above). It is not possible when A is CH = CH-CH ₃ . When A = NO ₂ , it is immediately reduced to go NH ₂ .

Aluminum triisopropoxide in isopropanol at room temperature.

Reaction Scheme 8 shows the preparation of simple starting materials such as (4), (5), (6) and (9) when A has the same meaning 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. Substitute A in compounds (4), (5), (6) and (9) of reaction scheme 9 can be converted to substituent B defined in reaction scheme 1 by the method of step lg.

Scheme 8

ο

ι = Η, Ac

Step 8a

Pb (OAc) ₄ in a suitable reflux solvent (e.g. benzene, toluene) (GA Russel et al, J. Am. Chem. Soc., 1906, 1975), Eman 8b

NaBH ₄ in alcohols (see reaction scheme 7, step 7a), then alkaline hydrolysis (when A = COOR can be immediately converted to COOH);

aluminum isopropoxide as described in reaction scheme 7, step 7f;

diborane in THF at -10 ° C to room temperature; then aqueous H ₂ O ₂ in the presence of NaOH (not when A represents CH = CH-CH ₃ ; when A = COOR immediately becomes COOH). (Kirkiacharian et al., CR Hebd. Seances Acad. Sci. Ser. C, 289, 227, 1979);

LiAlH ₄ and A1CD in a suitable solvent (e.g. THF) at 0 ° C to reflux (not for A = COOR or NO ₂ ) (Bocadia et al, J. Chem Soc., 4663, 1961) .

Eman 8c

Hydrogen (100 atm), copper chromium in EtOH at 140 ° C, see Μ. A. Vickars, Tetrahedron, 20, 2873, 1964. When A = NO ₂ immediately becomes an NH ₂ group.

Step 8d

KMpO ₄ in tert-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-CH ₃ ), (see also A, H. Haines, Methods for the Oxidation of Organic Compounds, Academic Press Inc, (London), 1985, Chapter 3.2.2),

- Osmium tetroxide (see AN Haines, supra, chapter 3.2..1) in a suitable solvent (eg Et ₂ O) at room temperature (Baranton et al., Bull. Soc. Chim. Fr. , 4203, 1968) (not when A is CH = CH-CH ₃ );

aqueous H ₂ 0 _? in formic acid or acetic acid at -20 to -50 ° C; then NaOH, H ₂ O, 45 ° C (Baranton et al., supra; AN Haines, supra, chapter 3.2.7) (not when A is CH = CH- CH ₃ ; when A = COOR immediately becomes COOH);

silver acetate and iodine in moist AcOH at 0-20 ° C (K. Napaua, supra; AN Haines, supra, chapter 3.2.3, 3.2.4) (Not when A is CH = CH -CH ₃ ).

Stage 8f

30% H ₂ O ₂ in the presence of NaHCO ₃ in benzonitrile at 0C NO ° C, then LiAlH ₄ in THF at 0-40 ° C (not for A = COOR and CH = CH-CH ₃ ) (Clark et d. , Austr. Journ. Of Chem., 27, 865, 1974).

Eman 8f

Hydrogen (1-50 atm) in a suitable solvent (e.g. EtOH) in the presence of a metal catalyst (e.g. PdCl ₂ ) at room temperature to 78 ° C (when A = NO ₂ is converted immediately to NH ₂ ). (Bolger et al ,, Tetrahedron, 23, 341, 1967).

Eman 8g, see eman 8b (Clark et al., Supra).

Eman 8am

- 0.4M cerium trichloride heptahydrate in MeOH in a suitable solvent (eg MeOH); then NaBH ₄ at 0 to 78 ° C (WO 89/06650);

NaBH ₄ in diglyme at 0 ° C to reflux (G, P, Thakar, Indian I. Chem., 3, 74, 1965) (when A = NO ₂ is converted to NH ₂ );

NaBH ₄ and AlCl ₃ in a suitable solvent (eg THF or benzene) at 0 ° C to reflux (not with A = COOR) (G.P. Thakar, supra);

diborane in THF at room temperature (not when A is CH = CH-CH ₃ ) (G. R. Thakar, supra).

Simple starting compounds with W = CH ₂ and a single bond at position 2,3 can be obtained by reaction scheme 9, in which A has the same meaning as in reaction scheme 1. Compounds (1) from reaction scheme 9 can be obtained by reaction scheme

6. Compounds (1) of reaction scheme 9 may alternatively be prepared from compounds (2) by converting the latter into 4-toluenesulfonic acid ester or methanesulfonic acid ester or to halogen derivatives which can be converted to thioether derivatives (1 ) by nucleophilic substitution with thiol. These simple transformations can be accomplished by known methods known to those skilled in the art. Compounds (2) of Reaction Scheme 9 can be prepared by Reaction Scheme 7. Compounds (3) of Reaction Scheme 9, wherein P = OC (S) -apuA or OC (S) -heteroaryl, or OC (8) O- alkyl, or OC (S) O-apuA, or OC (S) Salkyl may be prepared as compounds (2) by reacting with the appropriate chlorothioformate or chlorothiocarbonate, or 1, Gthiocarbonyl diimidazole, as described in J. Org. Chem., 55, 924, 1990 and Synthesis, 362, 1991 and the cited literature. Compounds (4) can be prepared from compounds (1) or (3) by more conventional base elimination reactions. Compounds (5) can be prepared by Scheme 4. Substitute A in compounds (6) from reaction scheme 9 can be converted to substituent B described in reaction scheme 1 by the method of step lg.

Figure 9

R1 = alkyl, aryl, heteroaryl, H or nothing

P = halogen, O-tosyl, D-mesyl, OC (8) -aryl, OC (8) -heteroaryl, 1-imidazolyl, OC (S) O-apuA, OC (S) O-xemepoapuA

Step 9a

Formerly Ni 6 is a suitable solvent (eg isopropanol) at room temperature up to 100 ° C. When A is NO ₂ it immediately becomes NH ₂ ;

triethyl tin hydride in benzene or other aromatic solvent at 30-150 ° C. For other methods, such as nickel chloride and NaBH ₄ in MeOH or boropyridine complex in trifluoroacetic acid or in dichloromethane in the presence of AlCl _3, see J. March, Advanced Organic Chemistry, page 728, J. Wiley and Sons, New York, 1992 and the literature cited there (not when A is CH = CH ₃ ).

Step 9b

Hydrogen with catalyst according to reaction scheme 8, step 8f. When A is NO ₂ it immediately becomes NH ₂ .

Step 9c

When P is an O-C derivative:

tributyltin 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 CF 4 COOH or BF ₃ (F. M. Mauser, J. Org. Chem. 55,555, 1990);

triethylchlorosilane, sodium iodide in acetonitrile; then Zn powder in AcOH and acetonitrile at room temperature to 80 ^° C (T. Morita et al., Synthesis, 32, 1981) When P is halogen or an OS derivative:

a reducer (e.g., sodium cyanoborohydride in hexamethylphosphotriamide or NaBH ₄ in DMSO) selected from those cited in J. March, Advanc. Org. Chem., J. Wiley, New York, 1992, Chapter 0-76, 0-77.

Eman 9 d

Hydrogen (1-5 atm) in a suitable solvent (e.g. EtOH) in the presence of a catalyst (e.g. 10% Pd / C at 50-78 ° C) (Sarcevic, Helv. Chim. Acta, 56, 1457, 1973). (When A = NO ₂ immediately becomes NH ₂ );

Zn and HCl gas in Et ₂ O or Ac ₂ O in toluene at 0-80 ° C. (Todah, Bull. Chem. Soc. Jpn., 45, 264, 1972) (not for A = NO ₂ ).

Step 9e

Zn and aqueous HCl in a suitable solvent (e.g. EtOH) at 0-78 ° C;

according to step 9d above (when A = NO ₂ immediately converts to CN ₂ );

hydrazine, NaOH in ethane-1,2-diol at 200 ° C (Chemical Abstracts, Ί_4, (1971): 22699) (not for A = COOR, NO ₂ ) or other methods cited in J. March, supra (not for A = COOR, NO ₂ );

according to step 7c (not for A = NO ₂ ).

Reaction Scheme 10 shows pathways for the preparation of compounds in which W represents a valence bond and X represents an oxygen atom or a sulfur atom:

Figure 10

A = COOA1k, N0 ₂ , CH ₃ b = cooh, nh ₂

Step 10a according to eman 1a, but using R ₃ COOC1 or (R ₃ CO) ₂ O instead of R ₃ CH ₂ COC1 or (R ₃ CH ₂ CO) ₂ O, with or without isolation of the phenyl ester intermediate;

hexamethylenetetramine in CF ₃ COOH reflux then aqueous HCl was added. If A = COOAlk, it can be hydrolyzed to COOH under conditions of high acidity, then requiring re-esterification with appropriate alcohol (e.g. using thionyl chloride at reflux) before step 10c.

Step 10b

R ₃ COCH (R ₂ ) Hal in acetone or methyl ethyl ketone or dichloromethane or chloroform in the presence of a suitable base such as e.g. K ₂ CO ₃ , NEt ₃ or NaH, at 20-80 ° C.

Step 10c

R ₂ CH (Hal) COOAlk in a suitable solvent, e.g. DMF, in the presence of a base, e.g. K ₂ CO ₃ , at 70-100 ° C, is followed by hydrolysis of the crude intermediate with a strong base (e.g. KOH) in a protic solvent such as e.g. EtOH at reflux and finally subjected to decarboxylation - conditions of dehydration with a non-protic solvent (eg xylene) and an acid catalyst (eg p-toluenesulfonic acid) under reflux or simply heated at 240 ° C in quinoline;

R ₂ CH ₂ Hal and KOH in EtOH at reflux by cyclization of the isolated phenyl (thio) ether intermediate with sodium methoxide in boiling DMF / MeOH. When A is COOAlk. intermediates (4) with A = COOH can be obtained;

using ArCOCH ₂ Br and K ₂ CO ₃ in acetone under reflux. Compounds (4) with R ₂ = ArCO are obtained.

Eman 10d

Intense stirring in preheated polyphosphoric acid at 90-140 ° C;

Lewis acid (eg AlCl ₃ ) in chlorobenzene at 70-90 ° C. Cyclizations carried out on compounds (3) having R ₃ = C1 with Lewis acid (eg AlCl ₃ ) in o-dichlorobenzene at 45 ° C or with BF ₃ in Et ₂ O at 20-25 ° C yielded compounds (4), where R ₃ = OH, as reported by K. Davies, /. Chem. Soc. RT, 1, 2624, 1957, for compounds having X = S and R ₂ = H.

Step 10f is sodium alcoholate (1 equivalent) in the same alcohol at 0-90 ⁰ C; when A = COOAlk would be appropriate to use AlkOH as the solvent for the reaction;

when r _? = COOAlk and X = S, compounds (4) can be hydrolyzed with a mixture of sulfuric and acetic acid to the corresponding R ₂ = COOH (if A = COOAlk is present, A = COOH can be obtained) and can be selectively decarboxylated with copper in anhydrous quinoline at 210-220 ° C to give compounds (4), where R ₂ = H, according to J. Cooper et al., J. Chem. Soc. (C) 1971, 3405.

Eman lOf

R ₉ CH ₂ X and one equivalent of sodium in EtOH at reflux or with NaHCO ₃ in a mixture of EtOH: water at 60-90 ° C.

Stage 10g

When A = COOAlk or NO ₂ , the methods described in step lg can be used. It should be noted that the reduction of NO _? the group to NH _? group by catalytic hydrogenation, can automatically induce hydrogenation of the double bond at position 2-3, as reported by SL Meisel et al., Heterocyclic Compounds, Ed. Interscience Publ. & SCompounds with

Whose # · '

Condensed Thiophene Rings ”, cmp. 34, (1954) υ M. Ahmed, There, Ed. Wiley-Interscience: '' Benzofurans '', cmp. 56, (1974).

When A = NO ₂ u R ₂ = COAr u is reduced with hydrogen in the presence of a Pt / C catalyst, compounds (5) are obtained, where B = NH ₂ u R ₂ = CH ₂ Ar, as reported in WO 86 / 07056;

when A = CH ₃ and R ₂ , R ₃ , R ₆ are not CH ₃ or R ₂ is not a CH ₃ group, the compounds can be converted to the corresponding:

A = CH ₂ Br by reaction with N-bromosuxinimide in CCl ₄ and 2,2'azobisisobutyronitrile or benzoyl peroxide as reflux catalysts;

A = CHO by reaction of the above compounds with hexamethylenetetramine in chloroform under reflux, followed by acid hydrolysis of the salt in boiling AcOH or by reaction of compounds having A = CH ₃ with tetrabutylammonium dichromate in chloroform under reflux, according to Valenti et al ., Arzneim. Forsch., 40, 122 (1990);

A = COOH by oxidation of the above compounds (A = CHO) with silver oxide in a mixture of a protic aqueous solvent (e.g. EtOHDMF at 0-70 ° C, according to H. R. Rodriques et al., Tetrahedron, 24, 6587, 1968 ) or with KMnO ₄ in tert-butanol in the presence of an aqueous solution of NaH ₂ PO ₄ at 70-75 ° C according to S. Maruzama et al., Tetrahedron Letters 27, 4537 (1986).

Compounds (4) of the above reaction scheme 10 having R ₃ = C ₆ H ₃ or tert-butyl, R ₂ = H and X = O, can be converted to the corresponding intermediates having R ₂ ^: = C ₀ H ₅ or tert-butyl and R ₃ = H by reaction with polyphosphoric acid at 132 ° C according to Davies et al., J. Chem. Soc., 1958, 822.

When X represents an imino or alkylimino group and W has the meaning defined above other than a valence bond, the simple starting materials can be obtained according to the following reaction scheme:

Scheme 11

A = COOA1k, NO ₂

R = H, alkyl

Step 11a

EtOC (R ₂ ) = C (COOEt) ₂ npu 80-140 ° C without solvents or in polar solvent (eg isopropanol).

Stage lib

R ₂ COC (R ₃ ) COOAlk and p-toluenesulfonic acid or methanesulfonic acid in a chlorinated solvent (eg chloroform) or aprotic solvent (eg benzene) under reflux under azeotropic conditions.

Stage lie

Heating in Ph ₂ O in the presence of p-toluenesulfonic acid or phosphoric acid or ZnO as a catalyst at 245-255 ° C according to Hung. Teljies 6251 (Chemical Abstracts, 79, 92026v, 1973);

heating in a high boiling solvent (eg Ph ₂ O), followed by hydrolysis of the uninsulated compounds (4) (R ₃ = COOEt) with strong acid (eg HCl) in a protic solvent (eg acetic acid) under reflux. Compounds (4) are obtained where R ₃ = COOH. The acids isolated above can be decarboxylated by heating in a high boiling solvent (e.g., Ph ₂ O) to give compounds (4), where R ₃ = H, according to R. Albrecht et al., Ber. 105, 3118 (1972);

Eman lid

Heating in a high boiling solvent (eg Ph ₂ O) at 255 ° C;

when R = Alk, compounds (4) are obtained directly from compounds (1) without isolating compounds (3) by condensation with R ₉ COOCH (R ₃ ) COOAlk in polyphosphoric acid at 90-150 ° C according to F, Piozzi et al., Gazz. Chim. It., 100, 678, 1970.

Eman lie

Amalgam of Al / Hg in aqueous EtOH at reflux, followed by acidification with strong acid (eg HCl) and treatment with FeCl ₃ foot reflux according to W. A, Denny et al., J. Med. Chem., 52, 396, 1989.

When A = COO Aik, compounds (4) must be hydrolyzed to the corresponding A = COOH before performing step lie.

When A = NO ₂ , intermediates (5) having A = NH _{2 are obtained} ;

Stage Ilf

R ₂ CH = CHCHO and arsenic acid in strongly acidic media (eg concentrated H ₂ SO ₄ ) and water at 105-115 ° C according to EP 0206802.

When A = COOAlk, compounds (1) must be hydrolyzed to the corresponding A = COOH before performing step f. All compounds (1) have R = H and the resulting compounds (5) have R ₃ = H.

Stage llg

R ₂ CH (Hal) -CH (R ₃ ) COOH in a protic solvent (e.g. water) in the presence of a strong base, such as e.g. NaOH at 100-125 ° C, followed by cyclization of the isolated β-anilinopropionic acid compounds with pre-heated polyphosphoric acid at 120125 ° C or with phosphorous petroxide in a high boiling aprotic solvent (eg xylene) at 120-140 ° C. In some cases, it is appropriate to start from compounds (1) where R = mo3UA or other suitable protecting groups; the resulting compounds (6), where R = mo3UA, can easily be converted to compounds (6), where R = H, by hydrolysis with strong acid (e.g. HCG) in a protic solvent (e.g. AcOH) under reflux.

When A = COOAlk, compounds (6) are obtained

A = COOH.

Eman llh

R ₂ CHO and ethylene in AcOH and HCl at 25-30 ° C, according to KD Hesse, Liebig. Arm. Chem., 741, 117 (1970). Where compounds (1) have R = H, starting materials (7) are obtained with R = R ₃ = H.

epichlorohydrin, followed by cyclization of isolated anilinopropanol derivatives βΝ, Ν-diethylaniline under reflux or o-dichlorobenzene in the presence of a proton acceptor (eg NEt ₃ ), according to SD Boyd et al., J. Org. Chem. 30, 2801 (1965), In this case compounds (7) with R = R ₂ = H and R ₃ = OH are obtained;

Step 1H by hydrogenation in the presence of a catalyst (eg platinum oxide) in a protic solvent (e.g. EtOH) at 20-30 ° C and

2-4 atm, according to G. M. Coppola, /. Heter. Chem. 15, 645, 1978.

When A = NO ₂ , compounds (7) with A = NH _{2 are obtained} .

The compounds thus obtained (4), (6) and (7) can be converted to the corresponding derivatives having A = COOH or NH ₂ according to the methods of reaction scheme 1, step lg.

The synthesis of the simple compounds (7) of reaction scheme 11 having R = H and A = COOH can also be carried out using the method shown in reaction scheme 12:

Scheme 12

A \ o o

W = CH ₂ or Connection 2 3

Step 12a

Oxalyl chloride In a polar solvent (e.g. THF) under reflux, internal Friedyl-Crafts acylation of the crude chlorooxalylamide with Lewis acid (e.g. A1Cl ₃ ) in a non-polar solvent (e.g. CS ₂ ) under reflux according to EP 04059 is followed;

Step 12b

30-35% aqueous H ₂ O ₂ and a strong base (e.g. NaOH) in a polar solvent (e.g. water) at 20-30 ° C, followed by the addition of strong acid (eg HCl) as reported in EP 0402859.

By reaction schemes 13 and 14, simple starting materials can be obtained in which X represents an amino group and W represents a valence bond. In these two reaction schemes, A has the same meaning as in reaction scheme 1.

Figure 13

A

1

Step 13a

ClCH ₂ C (Cl) = CH 2 In the presence of K ₂ CO ₃ at 40-80 ° C, according to L. Purdie, /. Chem. Soc. (C) 1970, 1126.

Step 13b

R ₂ COHal in pyridine or in a chlorinated solvent (eg dichloromethane) in the presence of a proton acceptor (eg NEt ^) at 20-100 ° C or in a polar solvent (eg acetone) in the presence of K ₂ CO ₃ at 20 -80 ° C.

Step 13c

BF ₃ in MeOH at 130 to 155 ° C;

heating at 100 to 110 ° C.

The compounds (5) obtained in step 13c always have R 2 = CH ₃ . Step 13d

R2COCH (OAlk) ₂ in a non-polar solvent (eg toluene) in the presence of iodine as a reflux catalyst under azeotropic conditions, results in a reduction of the isolated (or non-isolated) imino compound with NaBH ₄ in a polar solvent (eg MeOH), in the presence of NaOH as a catalyst under reflux. If A = COOAlk is hydrolyzed to COOH.

* 'Stage 13f

WtT! I I .. I · I —————— Sodium amide in a high-boiling solvent (e.g., Ν, diethylaniline) at 220-250 ° C, according to F. Piozzi et al., Gazz. Chim. It., 93, 1382, 1963;

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

Step 13f

BF ₃ in a non-polar solvent (eg benzene) at 5 to 10 ° C. Stage 13%

Zn or Fe powder in acidic medium (eg AcOH) and water at 70100 ° C. If Α = Ν0 ₉ then go NH ₉ will be reduced.

Eman 13h

Thionyl chloride nog reflux condenser. The resulting acyl chlorides are isolated and reacted with sodium azide in acidic medium (eg AcOH) at 10-20 ° C, then heated at 50-70 ° C. Step 13i diazotization with NaNO ₂ in concentrated H ₂ SO ₄ , followed by aq. ZnCl ₂ at 5-10 ° C and reaction of the isolated diazonium salts with CH ₂ = C (R ₂ ) COOH in a polar solvent (eg acetone) in the presence of a copper salt (eg CuCl ₂ ) at 25-30 ° C. Examples of steps 13g, 13h and 13i are given by A. Allais et al., Eur. J. Med. Chem., 10, 187, 1975.

Eman 13j

R ₂ CH ₂ NO ₂ in a polar solvent (e.g. EtOH) in the presence of a base (e.g. n-butylamine) and catalytic amounts of acid (e.g. AcOH) under reflux.

The compounds thus obtained (5) can be converted to the corresponding derivatives having A = COOH or NH ₂ according to the methods of reaction scheme 1, step lg.

With respect to reaction scheme 14, it is to be appreciated that compounds (4) with R ₂ = H correspond to compounds (5) of reaction scheme 13.

Figure 14

R = Alkyl

Step 14a

NaNO ₂ in aqueous acidic medium (eg HCl) at -5 to +5 ° C;

isoamyl nitrite in polar solvent (eg EtOH) at 510 ° C;

Step 14b an aqueous solution of SO ₂ at 0-10 ° C according to Pfannstiel et al., Ber. 75, 1096, 1942;

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

Eman 14c

R ₂ COCH (R ₃ ) Hal in a basic high boiling solvent (eg Ν, Ν-diethylaniline) at 160-180 ° C or at ordinary heating at 180 ° C without solvent;

R ₃ CC) CH (R ₉ ) Hal in a polar solvent (eg acetone) in the presence of a suitable proton acceptor (eg K ₂ CO ₃ ) under reflux, cyclization of isolated β-anilinoketones with freshly ground ZnCl _{2 is} cyclized in a protic solvent (e.g. EtOH) under reflux;

R ₂ CH (Hal) CN in the presence of BCl ₉ and Lewis acid (eg TiCl ₄ ) in a non-polar solvent (eg benzene) under reflux, cyclization of the isolated 2-amino-halogenoacetophenones with a suitable reducing agent (e.g. NaBH ₄ ) in a polar medium (eg dioxane-water) under reflux according to T. Sagusawa et al., J. Org. Chem., 44, 578, 1979. Compounds (4) with R ₃ = H are prepared by the above method;

R ₂ COCH (R ₃ ) Hal (half equivalent) in polar solvent (eg MeOH) under reflux, cyclization of isolated acidic Schiff bases (eg CF ₃ COOH) cyclized at 20-30 ° C;

Eman 14d

R2COCH2R3, by heating at 100 ° C without solvents or under reflux in a polar solvent (eg MeOH), cyclizes the isolated hydrazone compounds with polyphosphoric acid at 100-130 ° C, or by ordinary heating in ethylene glycol or aqueous formic acid or ethanol formic acid.

The cyclization can be carried out by heating in ethanol HCl under reflux, or in a mixture of AcOH / HCl under reflux, or in orthophosphoric acid at 95-105 ° C, or by ordinary heating with anhydrous ZnCl ₂ at 100-220 ° C. . When A = COOAlk, compounds (4) with A = COOH can be obtained. Step 14e boron-pyridine complex at 0-30 ° C, followed by the addition of a protonating agent (e.g., HCl);

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

NaBH ₄ in the presence of Lewis acid (e.g. A1Cl in pyridine at 0-30 ° C or alternatively in the presence of a salt 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 (eg EtOH) at 20-80 ° C.

Other insult methods have been reported by Houlihan in Heterocyclic Compounds, Part One, Ed. Wiley-Interscience: Indoles, 462 (1972). When A = NO ₂ , compounds (4) can be reduced to the corresponding compounds (5) with A = NH ₂ ;

Step 14f

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

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

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

Compounds (4) having other reaction groups, such as e.g. NH ₂ or OH must be protected using appropriate protecting groups that can be selectively eliminated at the end by methods of deprotection;

Stage 14g

RHal in the presence of alkali metal carbonates (e.g., potassium carbonate), as reported by Houlihan in Heterocyclic Compounds, Part 2, Ed. Wiley Interscience '', p. 90 (1972) and the literature cited therein.

Compounds (5) having other reaction groups such as e.g. NH ₂ or OH must be protected as reported above; Step 14h tetrachloro- [1,4] -benzoquinone in a polar solvent (e.g. ethylene glycol monomethyl ether) under reflux;

copper (II) chloride in pyridine under reflux according to Kikugawa et al., J. Heter. Chem., 16, 1325, 1979.

Compounds (6) having R ₂ and R ₃ other than H can be reduced to the corresponding starting compounds (7) using lithium aluminum hydride according to H. C Printy et al., J. Am. Chem. Soc., 71, 3206, 1949.

Compounds (4) of reaction scheme 14 having R2 = H and R ₃ = OH can be obtained from compounds (7) of reaction scheme 11 having R = R ₂ = H and R ₃ = OH by contraction of the ring, using an oxidant (e.g. sodium period at) and a base (e.g. NaOH) in aqueous EtOH at reflux, according to

S. D. Boyd et al., J. Org. Chem., 30, 2801, 1965.

The starting materials (4), (5), (6) and (7) can be converted to the corresponding A-COOH or NH ₉ by the reaction scheme method

1, step lg and of them in the alternative terminal compounds.

When NH is present, and may interact in subsequent reactions, it must be protected, as reported by T. W. Green in Protective Groups in Organic Synthesis, Wiley Interscience, 1981. Alternatively, non-reactive groups (e.g. NO ₂ ) may to become reactive ones (eg NH ₂ ) as the final step of the scheme.

Starting materials in which W represents a valence bond, X represents an amino group and the substituent in the 7-position is a carboxymethyl group can be prepared according to reaction scheme 15,

Scheme 15

Step 15a

Hydrogen in the presence of 10% Pd / C catalyst at 45 lbs in water containing one NaOH equivalent followed by diazotization with sodium nitrite in HCl at 0-5 ° C and tin chloride. The cyclization is carried out during the acidification of the tin salt with H ₂ S and ends at reflux in xylene, cf. N. E. Baumgarten et al., J. Am. Chem. Soc., 82, 3977, 1960.

Eman 15b

R ₃ CH ₂ COR ₂ in the presence of an acid (eg acetic acid) in a polar solvent (e.g. EtOH) under reflux, as reported by WJ Welstead et al., J. Med. Chem., 22, 1074 (1979) for R ₂ = CH ₂ and R ₃ = C ₆ H ₅ , where steps 15c and 15d have been reported;

Step 15c

Lower alcohol (e.g. MeOH, EtOH) under reflux in the presence of hydrogen chloride flow;

Step 15d strong base (e.g. KOH) in polar solvent (e.g. water) under reflux.

The preparation of simple starting materials with R ₃ = hydroxyalkyl and / or the corresponding ethers can be accomplished by reacting one of the compounds (3) of reaction scheme 1, the compounds (2), (4) or (5) of reaction scheme 2 , compounds (4) of reaction scheme 6, 10, 11 and 15, compounds (5) of reaction scheme 13 and compounds (4) and (6) of reaction scheme 14 having R ₃ = H, CH ₃ according to the reaction scheme 16, where A and B have the same meanings as in reaction scheme 1, R ₄ represents an alkyl or aralkyl group and R _s represents H or an alkyl group:

Scheme 16

R ₄ = Aik, Araik

R ₅ = H, Aik

Step 16a

R ₃ = H, W = CO, CS (u do not have activated phenyl rings):

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., Bull Chem. Soc. Jpn., 57, 2323, 1984);

R ₃ = CH ₃ , W = CO, CS, bond without other methyl groups in the molecule:

N-bromosuxinimide in the presence of benzoyl peroxide or 2,2'-azobisisobutyronitrile in CCl ₄ at 50-80 ° C;

Step 16b

R ₃ = H, Y / = bond, X = O, S NH or N-Alk and no electron donor groups are present in the other rings of the molecule:

phosphorous oxychloride and DMF at 50-140 ° C, or other Vilsmeyer-Haack reagents (see Jutz, A < 4 &gt; Org. Chem., 9,225, 1976);

R ₃ = CH ₃ , W = bond, X = O, S, NH or N-Alk and no other CH ₃ groups: irradiation with a high pressure Hg lamp in a protic solvent (eg AcOH) at 20-100 ° C , as reported by Frasca et al., Tetrahedron, T3, 603, 1973.

Eman 16c sodium or potassium acetate in aprotic solvent (eg acetone, DMF) at 40-120 ° C.

Step 16d

R ₅ in compounds (5) = H:

reducing hydride (e.g. NaBH ₄ ) in a polar solvent (e.g.

MeOH or EtOH or dioxane) at 0-80 ° C;

R ₅ in compounds (5) = alkyl:

alkylmagnesium bromide in aprotic solvent in aprotic solvents (eg Et ₂ O, THF) at 0-60 ° C

Stage 16f

NaOH or LiOH in protic solvents (eg alcohols, water) or mixtures thereof at 25-50 ° C. (In this case, when A = COOA1k can be immediately hydrolyzed to COOH);

Step 16f the same methods reported in step lg of reaction scheme 1, but the oxidation of CH = CHCH ₃ to COOH is for compounds (5);

Step 16g strong base (e.g. NAH) and reagent R ₄ -L (where L represents a halogen atom or tosyloxy group) in an anhydrous aprotic solvent (eg DMF or THF) at 20-140 ° C;

Stage 16h

- R ₄ OH and base (eg Na, NaH) in excess of R ₄ OH or in aprotic solvents (eg DMF or THF) at 20-140 ° C.

The thus obtained simple compounds (6) having a hydroxylalkyl group at position 3 can be reacted as such or alternatively substituted on the hydroxymethyl group by known reagents and by known methods, so that this group does not interfere in subsequent reaction steps for the preparation of the compounds of formula (I) having a protected hydroxyalkyl group such as e.g. R ₃ .

The protected terminal compounds are finally converted by deprotection methods to compounds of formula (I) having R ₃ = hydroxyalkyl.

The prodrugs as defined above can be obtained from the corresponding hydroxides according to method 1 below or from the corresponding amide compounds according to method 2 below.

Method 1 by reacting with chloroformate, isocyanate or isothiocyanate, carbonyl chloride or bromide or other activated acid derivative (eg anhydride) in a suitable solvent (eg chlorinated solvent, DMF, THF, dioxane, acetonitrile, pyridine) in the presence of (e.g. NEt ₃ , pyridine 4-dimethylaminopyridine, NaOH, potassium carbonate or 1,10 diazabicycloundecene or other unspecified) at -20/100 ° C;

by reaction with a carboxylic acid in the above solvents, in the presence of a condensing agent, such as e.g. Ν, Ν-carbonyldiimidazole, carbodiimides or others known to those skilled in the art;

by reaction with dialkyl- or diarylchlorophosphates or dialkylcyanophosphates under the same conditions described above (for examples of such a method for preparing derivatives, see example 144 below and S. O. Thorberg et al., J. Med. Chem., 30 , 2008, 1987).

Method 2

The prodrugs c '' acidic NH groups as discussed above can be synthesized from compounds of formula I to give the H-hydroxy (substituted) methyl derivative and reacted in the same manner as described above for obtaining an oxygen derivative.

The N-hydroxy (substituted) methyl derivative can be isolated or reacted directly to give the desired compound. H-hydroxy (substituted) methyl derivatives of the type Ny-CH 1 R ₁₆ OH, where R ₄ = H or CCC can be obtained by reacting suitable compounds of formula I with formaldehyde or CCI ₃ CHO, as described in H.E. Zaugg, Organic Reactions, 14, Chapter 2, 52 J. Wiley and Sons New York. 1965 or in J. P, Chupp, /. Org. Chem., 28. 2592, 1965.

In cases where B ₄ = phenyl, said compounds can be synthesized by reacting with benzaldehyde and cyclic amine (e.g., morpholine) in MeOH or dichloromethane.MeOH 1: 1 at 0 ⁰ C to reflux and hydrolysis. the intermediate with 0.1N HCl at pH 4 (P. Jacobssen, Annalen, 157, 243, 1884; H. Bundgaart et al., Int. J. Pharm., 22, 45, 1984).

All the reaction schemes and steps described above should be considered as examples which do not limit the scope of the invention. Those of skill in the art will recognize that said chemical conversions are effected on polyfunctional substrates and that the reagents used may interfere by reacting with other available groups in the molecules. E.g. optionally by catalytic hydrogenation, the nitro groups r can be converted into amino groups, but isolated double bonds can also be hydrogenated and halogen atoms removed; lithium aluminum hydride can optionally reduce fused ketones to alkanes (e.g., step 7c of reduction scheme 7), but also COOAlk groups to CH ₂ OH or b ₂ groups to -NfeN-, etc. Adverse reactions can be avoided by selecting suitable conditions or by alternative reagents or other synthesis schemes. If this alternative pathway produces negative results, the unwanted intermediates obtained should be converted into useful ones using methods known to those skilled in the art.

SUMMARY OF THE INVENTION

Detailed description of the preparation of intermediates

8- (3-Bromopropoxycarbonyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate I) g 1,3-dibromopropane was added dropwise at room temperature to a suspension of 30 g of sodium 3-methyl -4-Oxo-2phenyl-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. Add 100 ml of water and stir for 15 minutes. The precipitate was filtered off under vacuum, washed with water and purified by flash chromatography on silica gel, eluting with chloroform: ethyl acetate 95: 5. The combined fractions were evaporated to dryness in vacuo and the residue was recrystallized. 27.7 g of the title compound are obtained. Melting point: 114-115 ° C.

The benzopyranecarboxylate salt used in the above synthesis was obtained 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 w of sodium bicarbonate. 850 ml of acetone were added to the precipitate solution of the desired salt, which was removed by vacuum filtration (62 g, mp> 2280 ° C). The corresponding acid was prepared according to Da Re, P et al., /. Med. Pharm. hem., 2, 263, 1960. 8-hydroxymethyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate II)

467 ml of 1.48N sodium borohydride solution in anhydrous dimethylformamide are added over 30 minutes, with stirring and room temperature, to a solution of 100 g of 3methoxy-4-oxo-2-phenyl-4H-1-benzopyran-8-carbonyl chloride. in 1 ^w liter of anhydrous dimethylformamide. The reaction mixture was stirred

2½ hours at room temperature. 88 ml of 2N hydrochloric acid are added while maintaining the temperature at 0-5 ° C. Then, 102 ml of 12.7N sodium hydroxide solution are added. The mixture was poured into 6 liters of water, stirred for 6 hours and filtered through a funnel funnel, the filter cake washed with 4N sodium hydroxide solution and then with water. The resulting white solid was crystallized from methanol. 50 g of the title compound are obtained. Melting point: 145-147 ° C.

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

A solution of 9.2 g of intermediate III and 7.8 g of thionyl chloride in 75 ml of toluene was refluxed for 3 hours. After cooling to 20-25 ° C, the crystals obtained were removed by vacuum filtration, washed with acetone and dried in vacuo. 6.8 g of the title compound are obtained. Melting point: 196-198 ° C after recrystallization from toluene.

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

A solution of 9.2 g of intermediate III and 7.8 g of thionyl chloride in 75 ml of toluene was stirred at reflux for 3 hours. After cooling to 20-25 ° C, the crystals obtained were removed by vacuum filtration, washed with acetone and dried in vacuo. 6.8 g of the title compound was obtained m.p. (190) 196-198 ⁰ C after recrystallization from toluene. 8-acetyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate V)

1.17 g of magnesium chips, 7.4 ml of anhydrous ethanol and 0.2 ml of anhydrous tetrachloromethane were placed in a round-bottom flask under a stream of nitrogen. When the temperature starts to rise, add 7.5 ml of anhydrous chlorobenzene and then slowly (25 minutes) dropwise a solution of 5.28 ml of anhydrous diethylmalonate and 3.5 ml of anhydrous chlorobenzene in 16 ml of anhydrous ethanol. The reaction flask was heated to 75 ° C for 2 hours, cooled to 25 ^° C and a solution of 8.8 g of 3-methyl-4-oxo-2-phenyl-4H-1benzopyran-8-carbonyl chloride in 88 ml of anhydrous chlorobenzene was slowly added. , without exceeding 35 ° C. The reaction mixture was then stirred for another two hours at 35 ° C, then cooled to 0 ° C. 13 ml of water and 1.9 ml of sulfuric acid (d = 1.84) were added. The resulting solution was decanted from insoluble inorganic substances and distilled in vacuo.

The crude acylmalonate obtained was refluxed for 6 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 was poured into ice water and the precipitate was removed by vacuum filtration and washed with aqueous sodium carbonate solution. Crystallization from 90% ethanol yielded 6.5 g of the title compound. Melting point: 159-161 ° C 8-Bromoacetyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate VI)

A solution of 11.2 g of bromine in 250 ml of chloroform was added over two hours at 20-25 ° C to: a solution of 19.5 g of intermediate V in 700 ml of chloroform. After stirring for 1 hour at 20-25 ° C, the solution was washed with 400 ml of 2N aqueous sodium hydroxide solution and then repeatedly with water, dried with anhydrous sodium sulfate and distilled in vacuo. The crude product was suspended in diethyl ether, separated by vacuum filtration and crystallized from acetone. Yield 16 g of the title compound. Melting point: 134-135 ° C.

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

The title compound was prepared in the same manner as intermediate XXXVI but using 2-aminoethanol instead of 3-aminopropanol. Melting point: 206-208 ° C.

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

A solution of 4.55 g of sodium nitrite in 12 ml of water was added dropwise with stirring to a mixture of 15.1 g of 8-amino3-methyl-4oxo-2-phenyl-4H-1-benzopyran [prepared as described in Da Re, P et al., II. Farmaco (Ed. Sci.), 11, 670, 1956] in 150 ml of hydrochloric acid (d = 1.18) at -5 ° C. Stirring is continued for 30 minutes at 0 ° C. The solution is poured over 10 minutes and at -5 go. 0 ° C in 120 ml of a 30% solution of sulfuric guoccug in acetic acid containing 1.53 g of copper II chloride dihydrate and 13 ml of water. After 1 hour at 0 ° C and 1 hour at 20-25 ° C, 300 ml of ice water were added to the mixture. The precipitate formed was removed by vacuum filtration, washed with water and dried in a desiccator over sodium hydroxide solution to constant weight. 18 g of the title compound are obtained as a crude product. Melting point: 165-170 ° C. It is used without further purification.

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

This compound was prepared in the same way as intermediate XI, but using 1-bromo-3-chloropropane instead of 1-bromo-2-chloroethane. Melting point: 98-102 ⁰ With wash with petroleum ether: diethyl ether 7: 3. 8-Acrylamido-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate X)

A solution of 1.75 ml of acryloyl chloride in 15 ml of anhydrous tetrahydrofuran was added dropwise at -10 ° C with stirring to 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 heating for 1 hour at 0 ° C and 1 hour at room temperature, the reaction mixture was poured into water and filtered under vacuum, the filter cake was washed with water. After drying, 5.5 g of the title compound are obtained. Melting point: 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 as described in Da Re, P. et al., Ann. Chim., 1962, cmp. 506 et seq.], 6.22 g of anhydrous potassium carbonate and 25.5 ml of 1-bromo-2-chloroethane in 70 ml of dimethylformamide were stirred at 60 ° C for 25 hours.

The mixture was cooled to 20-25 ° C and poured into 600 ml of water. The organic solution obtained by extraction with dichloromethane was washed with aqueous sodium chloride and dried over anhydrous sodium sulfate, solvents and excess 1-bromo-2- the chloroethane was evaporated in vacuo. 8.8 g of the title compound are obtained. Melting point: 141-142 ° C after crystallization from chloroform: hexane. 8- (2-azidoethoxy) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XII)

A mixture of 15.2 g of intermediate XI and 6.24 g of sodium nitrogen in 150 ml of anhydrous dimethylformamide was stirred for 12 hours at 70-75 ° C. After cooling to 20-25 ° C, the reaction mixture was poured into 1½ liters of water and extracted with dichloromethane. The organic solution was washed with aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvents were evaporated in vacuo. The residue was mixed with water, separated by vacuum filtration and dried. 14 g of the title compound are obtained. Melting point: 119-120 ° C.

8- [X- (2-hydroxyethyl) -X-methylcarbamoyl] -3-methyl-4-oxo-2-phenyl4H-1-benzopyran (Intermediate XIII)

A solution of 1.6 ml of 2-methylaminoethanol in 10 ml of water was 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 2½ hours at 20-25 ° C, the solvent was removed in vacuo and the residue was mixed with 150 ml of acetone. The mixture was boiled for 15 minutes under reflux and then filtered. The solvent was evaporated from the filtrate and the residue was dissolved in 20 ml of dimethylformamide treated with 14 ml of a 1.4% solution of sodium carbonate, stirred for 30 minutes at 20-25 ° C and diluted by the addition of 150 ml of water. The mixture was extracted with chloroform and the organic phase was washed with 0.5N hydrochloric acid and then with water.

The solution was dried over anhydrous sodium sulfate and the chloroform was evaporated. The resulting oil was mixed with 200 ml of diethyl ether and stirred for 2 hours at 20-25 ° C. The solid was filtered off and crystallized from ethyl acetate. 4.97 g of the title compound are obtained. Melting point: 128-130 ° C.

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

The title compound was prepared in the same manner as intermediate XXXVII, but using intermediate VII instead of intermediate XXXVI and the reaction was carried out at room temperature. Melting point: 181-182 ° C (ethyl acetate). 8- (X-methyl-2-chloroethylcarbamoyl) -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 was added to a solution of 3.37 g of intermediate XIII in 20 ml of dichloromethane and the mixture was stirred for 4 hours at room temperature. Removal of the solvent gave an oil which was mixed with diethyl ether. The title compound was precipitated as a white solid, separated by filtration for use without further purification. Melting point: (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-methyl-4-oxo-2-phenyl-4H-1benzopyran, 4.2 g of anhydrous potassium carbonate and 43.6 g of 1,4dibromobutane in 45 ml of dimethylformamide was stirred for 2 hours at 75 ° C. it is cooled to 20-25 ° C, poured into 100 ml of water and extracted with dichloromethane. The organic solution was washed with aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvents and excess 1,4-dibromobutane were evaporated in vacuo. The residue was washed with 55 ml of petroleum ether: diethyl ether 7: 4 and separated by vacuum filtration. 5.6 g of the title compound are obtained. Melting point: 91-92 ° C.

8- (5-Bromopentyloxy) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XVII)

This compound was prepared by the method described for the preparation of intermediate XVI, but using 1,5dibromopentane instead of 1,4-dibromobutane and purification of the crude material by silica gel column chromatography (eluting with dichloromethane: ethyl acetate 99: 1). Melting point: 7576 ° C, after washing with petroleum ether: diethyl ether 304. 8- (2-chloroethoxymethyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XVIII) ml of thionyl chloride in 18 ml of chloroform are added at 0 ° C with stirring to a solution of 23 g of intermediate XXII and 11 ml of triethylamine in 185 nil of chloroform. The reaction mixture was heated to 70 ° C and stirred for 2 hours. After cooling to room temperature, it is poured into water. The organic phase was separated, washed with brine, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. Yield: 24 g of the title compound. A sample crystallized from ethanol has a melting point of 102-103 ° C.

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

53.4 g of intermediate II and 38.8 ml of anhydrous triethylamine were dissolved in 440 ml of chloroform. To this solution, maintained at -10 to -2 ° C, a solution of 19.8 ml of thionyl chloride in 80 ml of anhydrous chloroform was added dropwise. The reaction mixture was stirred for 4 hours at room temperature and then diluted with 400 ml of water. The aqueous phase was extracted with chloroform and the extracts were added to the chloroform phase. The chloroform solution was washed with brine, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. Yield: 56 g of the title compound which, after recrystallization from ethanol, shows a melting point of 112-113 ° C.

8-Methylaminomethyl-3-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 was added dropwise at 0 ° C with stirring to a mixture of 58.8 g of 8-formyl-3-methyl-4-oxo-

2-phenyl-4H-1-benzopyran, 60.7 g of methylamine hydrochloride and 125 ml of triethylamine in 600 ml of anhydrous methanol. After stirring for 5 hours at 20-25 ° C, the solvent was evaporated in vacuo and the residue was taken up in 200 ml of water and separated by vacuum filtration. The crude product was dissolved in aqueous acetic acid, washed 1e with ethyl acetate and precipitated again with the addition of cold 6N sodium hydroxide solution. 49 g of the title compound are obtained. Melting point: 97-99 ° C after crystallization from 75% ethanol.

8- (2-Chloroethylthiomethyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XXI)

A solution of 37 g of intermediate XIX and 10.5 g of thiourea in 370 ml of ethanol was refluxed for 1 hour. The reaction mixture was cooled to room temperature, where 42 g of 8-amidinothiomethyl-3-methyl-4-oxo-2-phenyl4H-1-benzopyran were spontaneously crystallized. A sample recrystallized from ethanol has a melting point of 233-235 ° C.

ml of 35% aqueous sodium hydroxide solution are added to an intensely stirred suspension of 35 g of the compound thus obtained and 1.05 g of benzyltriethylammonium chloride in 440 ml of 1,2dichloroethane. The mixture was stirred for 2½ hours and then poured into 300 ml of water. The aqueous phase was extracted with 1,2-dichloroethane and the extracts were added to the organic phase, which was washed with sodium hydroxide solution, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The residue was crystallized from methanol. 22 g of the title compound are obtained. Melting point: 82-83 ° C.

8- (2-hydroxyethoxymethyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XXII)

A solution of 2.5 g of intermediate XIX in 25 ml of xylene and 3 ml of dioxane is prepared. 0.15 g of sodium was dissolved in 3.10 ml of anhydrous ethylene glycol and this solution was added dropwise at room temperature to the solution of intermediate XIX. After 5 hours of refluxing, 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 vacuo. The solid residue was crystallized from ethanol. 2.1 g of the title compound are obtained. Melting point: 132-133 ° C.

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

A solution of 9.5 ml of trifluoroacetic anhydride in 20 ml of anhydrous dichloromethane was added dropwise at -5 to 0 ° C to a solution of 5 g of 8-amino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran in 50 ml in anhydrous dichloromethane. The reaction mixture was stirred for 2 hours at 20-25 ° C and then poured onto crushed ice. The organic solution obtained by extraction with dichloromethane was washed with cold 5% aqueous sodium bicarbonate solution and water, and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was crystallized from ethanol. 5.2 g of the title compound are obtained. Melting point: 175-176 ° C.

8-Aminomethyl-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 THF was stirred for 8 hours at room temperature. Thin layer chromatography showed the disappearance of intermediate XXIX. Add 3 ml of water and stir for 24 hours. The solvents were removed with a rotary evaporator and the residue was dissolved in water as acetate. The aqueous solution was washed with ethyl acetate, basified with 37% sodium hydroxide solution and filtered with a funnel funnel, the filter cake washed with water and dried in a desiccator. 18 g of the title compound are obtained. Recrystallized from ethanol, the hydrochloride has a melting point of 156-258 ° C.

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

41.6 ml of 30% aqueous hydrogen peroxide solution was 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 was heated to 60 ° C, stirred at this temperature for 4 ^ ¹ h, cooled to room temperature and poured into 60 ml of water. Filtration with a Buchner funnel yields a filter cake, which is washed with water and dried in a desiccator. Yield: 29.4 g of the title compound. A sample crystallized from ethanol has m.p. (89) 159161 ° C.

8- (2-Chloroethylsulfinylmethyl) -3-methyl-4-oxo-2-phenyl-4H-1benzopyran (Intermediate XXVI) ml A 30% aqueous hydrogen peroxide solution was added dropwise at 10 ° C to a solution of 12 g intermediate XXI in 84 ml glacial acetic acid. The reaction mixture was stirred for 4 hours at room temperature and then poured into 220 ml of water.

The title compound was removed by vacuum filtration, washed with water and dried in a desiccator. Yield: 12.4 g, mp: 142-145 ° C (methanol).

8-1X-methyl-X- (2-chloroethyl) -aminomethyl] -3-methyl-4-oxo-2-phenyl4H-1-benzopyran (Intermediate XXVII)

A mixture of 22 g of intermediate XX, 66 ml of 1-bromo-2chloroethane and 11 g of anhydrous potassium carbonate in 88 ml of dimethylformamide was stirred for 12 hours at 20-25 ° C. The reaction mixture was then poured into 600 ml of water and extracted with dichloromethane. The organic phase was washed with water, dried over anhydrous sodium sulfate and acidified with hydrogen chloride-saturated ethanol. The solvent and excess 1-bromo-2-chloroethane were distilled in vacuo at 70-80 ° C. The residue was mixed with cold 1N aqueous sodium hydroxide solution and extracted with dichloromethane. The organic solution was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo at 25-30 ° C. The crude title compound was purified by flash chromatography on silica gel, eluting with ethyl acetate: petroleum ether 7: 3. 18 g of the title compound are obtained, m.p. 118-120 ° C after crystallization from ethanol.

1- (2-hydroxy-2-methylpropyl) -4- (2-methoxyphenyl) -piperazine (Intermediate XXVIII)

A mixture of 7 g of 1- (2-methoxyphenyl) -piperazine, 7.33 g of anhydrous sodium carbonate, 1.75 g of potassium iodide and 5.6 ml of 1-chloro-2-methyl-2-propanol was stirred for 90 minutes at 70 ° C and another 6 hours at 90 ° C. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic phase was washed with aqueous sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The title compound is obtained in the form of an oil and is characterized as dihydrochloride crystallized from ethanol. Melting point: 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 and 6.8 g of sodium azide in 110 ml of dimethylformamide was stirred for 3 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 1 hour, the crystals were isolated by vacuum filtration, washed with water and dried in a desiccator. Yield: 22 g of the title compound. A sample recrystallized from ethanol has m.p. Mp 132-134 ° C. 8- [X- (2-Hydroxyethyl) -aminomethyl] -3-methyl-4-oxo-2-phenyl-4H-1H-benzopyran (Intermediate XXX)

A solution of 2.38 g of anhydrous zinc chloride and 2.30 g of sodium cyanoborohydride in 71 ml in anhydrous methanol was added dropwise to a mixture of 9.24 g of 8-formyl-3-methyl-4-oxo-

2-phenyl-4H-1-benzopyran and 9.12 g ethanolamine in 90 ml anhydrous methanol. Stirring was continued for 5 hours at 20-25 ° C, after which the solvent was removed in vacuo. 250 ml of water are added to the residue and the undissolved portion is removed by vacuum filtration and washed with water. The crude material was dissolved in 1N acetic acid and the solution was washed with ethyl acetate. The aqueous solution was then basified by the addition of 2N sodium hydroxide solution, the precipitate was collected by vacuum filtration and washed with water. 8.5 g of the title compound are obtained. Melting point: 117-121 ° C, after drying at 60 ° C.

8- (X-methyl-X-chloroacetylaminomethyl) -3-methyl-4-oxo-2-phenyl-4H-

1-benzopyran (Intermediate XXXI)

A solution of 6 ml of chloroacetyl chloride in 60 ml of 1,2-dichloroethane was 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 for 2 hours at 20-25 ° C, 150 ml of water were added to the reaction mixture and the phases were separated. The organic phase is washed with water and

Ί9 dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was crystallized from ethanol. They are obtained

22.5 g of the title compound. Melting point: 146-148 ° C. 8-chloroacetamidomethyl-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 was added dropwise, with stirring at-5 ° C, to a mixture of 10 g of intermediate XXIV and 5.5 ml of triethylamine in 80 ml.

1,2-dichloroethane. The reaction mixture was stirred for 1 hour at room temperature, then 150 ml of water were added, the phases were separated; the aqueous phase was extracted with 1,2-dichloroethane and the extracts were added to the organic phase, which was then washed with cold saturated sodium bicarbonate solution, washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The residue was crystallized from ethanol. They are obtained

10.7 g of the title compound. Melting point: 152-155 ° C.

8- [N-acetyl-N- (2-chloroethyl) -aminomethyl] -3-methyl-4-oxo-2-phenyl4H-1-benzopyran (Intermediate XXXIII)

8.65 g of intermediate XXX and 4.15 ml of triethylamine were dissolved in 70 ml of tetrahydrofuran. At -10 ° C, a solution of 2.35 ml of acetyl chloride in 23 ml of tetrahydrofuran was added dropwise over 40 minutes. After 3 hours stirring at 0-10 ° C and 2 hours at 20-25 ° C, the solvent was removed in vacuo. Add 100 ml of water to the residue. It is extracted with dichloromethane, the organic extracts are collected and the solvent is removed in vacuo. The residue was dissolved in 50 ml of methanol. Add 3 g of potassium carbonate and 10 ml of water. After stirring for 20 minutes at 50 ° C to hydrolyze the resulting ,-, а diacetyl derivative, the solvent was removed in vacuo and the residue treated with water and dichloromethane as described above. The dichloromethane solution was evaporated again to dryness,

5.9 g of 8- [N-acetyl-X- (2-hydroxyethyl) -aminomethyl] -3methyl-4-oxo-2-phenyl-4H-1-benzopyran are obtained. 171-172 ° C. To a solution of the compound thus obtained 6.1 g in 70 ml of dichloromethane was added dropwise at 0 ° C 3.6 ml of thionyl chloride in 30 ml of dichloromethane. After stirring at 20-25 ° C for 90 minutes, the mixture was washed with water and dried. The solvent was removed in vacuo. The crude title compound was obtained, which was used without further purification.

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

A solution of 20.1 g of tin dichloride dihydrate in 18 ml of hydrochloric acid (d = 1.18) was added over 5 minutes at 65 ° C to a solution of 6 g of intermediate VIII in 70 ml of acetic acid. After 10 minutes, the reaction mixture was cooled to 30-35 ° C and the solvent removed in vacuo. The residue was dissolved in water and the insoluble portion was removed by vacuum filtration, washed with water and dried. 3.2 g of 8-mercapto-

3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, m.p. 115-118 ° C after crystallization from ethanol.

A mixture of 8 g of the compound thus obtained, 27 ml of 1-bromo-3-chloropropane, 0.2 g of tetrabutylammonium bromide and 6.2 ml of 35% sodium hydroxide solution in 80 ml of benzene, was stirred vigorously for 4 hours at 20-25 ° C. Add 100 ml of water and 40 ml of dichloromethane. The organic phase was separated, washed with water and dried over anhydrous sodium sulfate. Solvents and excess 1-bromo-chloropropane were removed in vacuo. The residue was purified by silica gel column chromatography, eluting with petroleum ether: ethyl acetate 9: 1. 5.7 g of the title compound are obtained. After crystallization from methanol, it has a melting point of 84-86 C.

8- (3-chloropropylsulfonyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XXXV) ml of 30% hydrogen peroxide are added at 20-25 ° C to a solution of 3.45 g of intermediate compound 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 formed which was removed by vacuum filtration, washed with water and dried. 3.4 g of the title compound are obtained. After crystallization from acetone, the compound has m.p. 16-163 ° 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 was 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 ml of acetone. The thick slurry was stirred for 3 hours at 20-25 ° C. The solvents were removed in vacuo and the residue was dissolved in 300 ml of water. After stirring for 1 hour, the precipitate was removed by vacuum filtration and washed with water. The crude compound was purified by crystallization from 95% ethanol. 23.8 g of the title compound are obtained. Melting point: 191-193 ° C. An additional amount of 4.7 g of this compound was obtained from the crystallization filtrate, which was concentrated in vacuo.

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

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 minutes under reflux, the solvent was removed in vacuo and the residue was crystallized from acetonitrile. 3 g of pure title compound are obtained, m.p. (188) 193-194 ° C 8- [1-Hydroxy-4- (4-methylphenylsulfonyloxy) -butyl] -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XXXVIII)

1.12 g of sodium cyanide in 3 ml of water were added at 20-25 ° C and stirred to a mixture of 3.96 g of 8-formyl-3-methyl-4-oxo-2-phenyl4H-1-benzopyran, 2.61 g of morpholine and 4.48 g of p -toluenesulfonic acid in 20 ml of tetrahydrofuran and 30 ml of 1,2-dichloroethane. The reaction mixture was refluxed for 4 hours, then 10 ml of cold water were added. The tetrahydrofuran was distilled off under normal pressure, then 10 ml was added

1,2-dichloromethane and 10 ml of chloroform. The organic phase was separated, washed with aqueous sodium chloride solution, dried over anhydrous sodium sulfate and evaporated in vacuo to dryness. The residue was suspended in diethyl ether, filtered and crystallized from chloroform: ethyl acetate. Yield: 3.55 g 8- (morpholinocyanomethyl) -3methyl-4-oxo-2-phenyl-4H-1-benzopyran, 236-238 ° C.

3.5 ml of a 30% solution of potassium hydroxide in anhydrous methanol are added with stirring and room temperature to a suspension of

22.8 g of the compound thus obtained in 520 ml of anhydrous tetrahydrofuran. 6.3 ml of acrylonitrile in 20 ml of tetrahydrofuran were added dropwise to this suspension and the reaction mixture was stirred for 1 hour at room temperature, the solvents were evaporated in vacuo. Crystallization of the methanol residue is obtained

23.22 g 8- (1,3-dicyano-1-morpholinopropyl) -3-methyl-4-oxo-2-phenyl4H-1-benzopyran.

23.2 g of the compound thus obtained were dissolved in 250 ml of dioxane. 250 ml of 6M hydrochloric acid are added and the mixture is refluxed 2 ^l / h. o'clock. After cooling to room temperature, the mixture was poured into 700 ml of aqueous sodium chloride solution and extracted with ethyl acetate. The extracts were washed with aqueous sodium hydroxide solution and treated with 700 ml of 1M sodium hydroxide solution. The aqueous phase was washed with ethyl acetate and acidified with 37% hydrochloric acid. The precipitate was removed by vacuum filtration and crystallized from ethanol. they do

10.2 g of 8- (3-carboxy-1-oxopropyl) -3-methyl-4-oxo-2-phenyl-4H-1benzopyran, m.p. 191-192 ° C.

Diborane obtained by dripping a solution of 2.1 ml of freshly distilled bortrifluorodiethyl ether in 10 ml of anhydrous diglyme in 19 ml of a 0.66M solution of sodium borohydride in diglyme was bubbled into a suspension of 2.28 g of the compound thus obtained in 23 ml of anhydrous tetrahydro. stirred at 0 ° C under nitrogen. Stirring was continued for 20 minutes at 0 ° C and another 20 minutes at room temperature. Methanol was carefully added to the mixture at 0 ° C to interrupt the reaction. The solvents were removed by evaporation in vacuo. The residue was purified by flash chromatography on silica gel, eluting with petroleum ether: ethyl acetate 3: 7. The combined fractions were evaporated in vacuo. 2 g of 8- (1,4-dihydroxybutyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran are left. 133-134 ° C.

** 2.8 g of p-toluenesulfonyl chloride are added at 0 ° C and stirred to a solution of 3.17 g of the compound thus obtained in 32 ml of anhydrous pyridine. The mixture was stirred at 0 ° C for 6 hours and allowed to stand at -4 ° C overnight without stirring. It is then poured into 200 ml of aqueous sodium chloride solution, acidified with 10 ml of 12N hydrochloric acid and filtered under vacuum, the filter cake is dissolved in chloroform, the solution is washed with aqueous sodium chloride and dried over anhydrous sodium sulfate. . The solvent was distilled off in a rotary evaporator. The residue was purified by flash chromatography on silica gel, eluting with petroleum ether: ethyl acetate 1: 1. The separated fractions were evaporated to dryness in vacuo. 3.04 g of pure title compound are obtained, 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-methoxyphenyl) -piperazine in 60 ml of dimethylformamide was stirred for 4 hours at 80 ° C. After cooling to 20-25 ° C, the reaction mixture was poured into 500 ml of ice-cold 0.5N sodium hydroxide solution and extracted with dichloromethane. The organic phase was washed with water and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue purified by flash chromatography on silica gel, eluting with dichloromethane: ethanol 95: 5, to give 9.8 g

2- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propyl} -dioxolane in the form of an oil.

NMR CDC1 ₃ (δ)

1.5-2.0 (4H, t, CH ₂ CH ₂ CH)

2.2-3.2 (10H, t, 5 xCH ₂ N)

3.7- 4.0 (7H, t, OCH ₃ u2xOCH ₂ )

4.8 (1H, t, OSNO)

6.7- 6.9 (4H, m, aromatic protons)

A solution of 12.8 g of the compound thus obtained in 200 ml of tetrahydrofuran and 420 ml of 1N hydrochloric acid was kept at 20-25 ⁰ C for 24 hours. The solution was then basified with 5N sodium hydroxide solution and immediately extracted with dichloromethane. The organic phase was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo and the residue was purified by flash chromatography on silica gel, eluting with dichloromethane: methanol 97: 3. 6.4 g of the title compound are obtained in the form of an oil.

NMR C1) C1 ₃ (δ)

1.5-2.0 (2H, m, CH ₂ CH ₂ CH ₂ )

2.2-2.8 (8H, m, 3 x CH ₂ N in CH ₂ CHO)

2.9-3.2 (4H, m, 2 x CH ₂ NAr)

3.8 (3H, s, OCH ₃ )

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) ml of 2,3 epoxypropyl chloride are added dropwise at 20-25 ° C and stirred at a mixture 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 6 hours at 20-25 ° C, the reaction mixture was poured into 100 ml of water and the precipitate formed was removed by vacuum filtration. After drying and purification by flash chromatography on silica gel (eluent petroleum ether: ethyl acetate 65:35), 4.45 g of the title compound are obtained, m.p. 128-129 ° C.

8- [X-methyl-2- (4-methylphenylsulfonyloxy) -ethylsulfamoyl] -3methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XLI)

A solution of 5 g of intermediate VIII in 60 ml of dichloromethane and 20 ml of tetrahydrofuran was added dropwise at 0 ° C to a mixture of 2.5 ml of 2-methylaminoethanol and 2.1 ml of triethylamine in 20 ml of dichloromethane. After stirring for 2 hours at 20-25 ° C, 100 ml of water and 100 ml of dichloromethane are added to the reaction mixture. the phases were separated and the organic solution was dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography, eluting with petroleum ether: ethyl acetate 3: 7. This gives 4.5 g of 8- (N-methyl-2-hydroxyethylsulfamoyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, m.p. 146-147 ° C after crystallization from ethanol.

The compound thus obtained is converted to the title compound by p-toluenesulfonylation according to the second step of the process for the preparation of intermediate XLII, described below. The title compound was used without further purification, 8- [2- (4-methylphenylsulfonyloxy) -ethylsulfamoyl] -3-methyl-4-oxo-

2-Phenyl-4H-1-benzopyran (Intermediate XLII)

A solution of 5 g of intermediate VIII in 37 ml of tetrahydrofuran was added dropwise at 0 ° C to a mixture of 25 ml of tetrahydrofuran. After stirring at 20-25 ° C, the reaction mixture was poured into 400 ml of water. A precipitate formed, which was removed by ^w vacuum filtration, washed with water and air-dried. 4.6 g of 8- (2-hydroxyethylsulfamoyl) -3-methyl-4-oxo-2-phenyl4H-1-benzopyran are obtained, mp 186-187 ° C after crystallization from ethyl acetate.

2.1. g of p-toluenesulfonyl chloride was added portionwise at 0 ° C to a solution of 3.6 g of the compound thus obtained in 25 ml of pyridine. After 6 hours at 20-25 ° C, the reaction mixture was slowly poured onto crushed ice containing a small excess of hydrochloric acid. A precipitate formed which was removed by vacuum / filtration and washed with water. 4.9 g of the title compound are obtained, m.p. (163) 166-169 ° C, after crystallization from ethyl acetate,

8- (3-Aminopropylcarbamoyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyranhydrochloride (Intermediate XLIIT)

A solution of 21.6 g of 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8carbonyl chloride in 250 ml of anhydrous tetrahydrofuran was added dropwise with stirring and 0-10 ° C in a solution of 17 g of 3- (2-methyl- 2-propoxycarbamoyl) -propylamine (prepared as described in Saari, WS et al., J. Med. Chem., 33, 97, 1990) r 13 ml of triethylamine. After stirring for 2 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 recrystallized from ethanol. Melting point: 178-180 ° C.

A solution of 4.3 ml of trifluoroacetic acid in 15 ml of anhydrous dichloromethane was added dropwise at -5 ° C and stirred to a solution of 3.3. g of the compound thus obtained in 35 ml of anhydrous dichloromethane. After warming to room temperature, the mixture was stirred for 8 hours. The dichloromethane and excess trifluoroacetic acid are evaporated at 20-25 ° C in a rotary evaporator. The oily residue was dissolved in dichloromethane and a 1N solution of sodium hydroxide was added. The organic phase was washed with water, dried over anhydrous sodium sulfate and filtered. An excess of ethanol, saturated with hydrogen chloride, was added to the filtrate and the solvent removed in vacuo. The residue was crystallized from ethanol. 1.5 g of the title compound are obtained. Melting point: 253-255 ° C.

8- (2-Chloroethylureido) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XLIV) ml of 2-chloroethylisocyanate were added at room temperature and stirred to a solution of 3.9 g of 8-amino- C-methyl-

4-Oxo-2-phenyl-4H-1-benzopyran in 52 ml of anhydrous dimethylformamide. Stirring was continued for 5 hours at 70 ° C. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic phase was evaporated to dryness in vacuo. The residue was suspended in diethyl ether with stirring. The title compound was then filtered and recrystallized from methanol. Yield 3.74 g, m.p. 213-214 ° C. (2, E) -8- {4- [2- (1,3-dioxanyl)] - 1-butenyl} -3-methyl-4-oxo-2-phenyl4H-1-benzopyran 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)] - ethyltriphenyl88 phosphonium bromide in 10 ml of anhydrous tetrahydrofuran. The mixture was 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 was added dropwise to the mixture, which was then heated for 90 minutes. to 0 ° C and then to room temperature for 30 minutes The reaction was quenched by the addition of methanol The solvents were evaporated in vacuo and the residue was purified by flash chromatography on silica gel, eluting with ethyl acetate: petroleum ether 3: 7. The title compound is obtained as a mixture of diastereoisomers E and Z. Melting point: (93) 98-100 ° C. The ratio of the two isomers is determined by NMR spectroscopy and is E : Z = 65:35.

NMR, CDC1 ₃ (δ)

8.1- 8.2 (m, 1Η, CH at the 5-position of the benzopyran ring)

7.2-7.8 (m, 7H, or aromatic CH-groups of benzopyran and phenyl rings)

6.9 (dt, 1H, Fl-CH of E-isomer)

6.8 (dt, 1H, Fl-CH of the Z-isomer)

6.4 (dt, 1H, F1-CH = CH of the E-isomer)

5.9 (dt, 1H, F1-CH = CH on the Z-isomer)

4.6- 4.7 (t, 1H, OSNO)

3.6- 4.2 (t, 4H, OCH ₂ O of dioxane ring)

2.4-2.7 (t, 2H, CHCH ₂ CH)

1.9-2.3 (m, 5H, CH ₃ and CH ₂ at 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 0.2 g of 10% Pd / C catalyst and 1g of intermediate XLV in 24 ml of methanol was hydrogenated in a Parr apparatus at room temperature under 1.5 atmospheres of hydrogen pressure. After the theoretical amount of hydrogen has been absorbed, the catalyst is filtered off and the solvent is evaporated off in vacuo. The residue was crystallized from cyclohexane. the title compound is obtained, m.p. 118-119 ° C.

8-Carboxymethyl-3-methyl-4-oxo-2-phenyl-4H-1-benz opiran (Intermediate XLVII)

4.5 g of potassium permanganate were added in portions for P / 2 hours with stirring and 0-10 ° C to a mixture of 2.76 g of 8-allyl-methyl-4-oxo-2-phenyl-4H-1-benzopyran (P. Da Re, US 3350411), 0.17 g Aliquat 336, 1.12 ml acetic acid, 56 ml dichloromethane, 3.2 ml sulfuric acid (d = 1.84) and 60 ml water, Stirring is continued for 5 hours at room temperature. 3.4 g of sodium metabisulphite were added portionwise at 0-5 ° C for 15 minutes. The organic phase was isolated, washed with water and extracted with 60 ml of 1N aqueous sodium hydroxide solution. the aqueous phase was acidified by the addition of dilute hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous sodium sulfate. After filtration, it is evaporated to dryness in vacuo. The residue was treated with tetrachloromethane and the solid was separated by vacuum filtration. 1 g of the title compound is obtained, m.p. 191-192 ° C (acetonitrile).

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

The title compound was prepared in the same manner as intermediate X, but using 4-chlorobutyryl chloride instead of acryloyl chloride. The resulting solid, separated from the water by filtration and dried, was washed with hot diethyl ether and separated by vacuum filtration. The title compound is obtained. A sample crystallized from 50% aqueous ethanol and washed with diethyl ether, m.p. (153) 162-164% '.

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 was added dropwise, with stirring, at -5 ° C to a suspension of 0.045 g of sodium hydride (80% in mineral oil). After stirring at room temperature for 1 hour, 0.092 ml of methyl iodide in 0.6 ml of anhydrous dimethylformam are added dropwise. The reaction mixture is then stirred for 1 hour at 50 ° C, cooled to 20 ° C, poured into water, filtered under vacuum and dried at 60 ° C for 3 hours. 0.6 g of 8- (X-methyltrifluoroacetamido) -3methyl-4-oxo-2-phenyl-4H-1-benzopyran are obtained.

NMR (CDCl ₃ , δ)

8.15 (dd, 1H, benzopyran CH in 5)

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

3.30 (s, 3H, CH ₃ -N)

2.10 (s, 3H, benzopyran CH ₃ 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 dimethyl sulfoxide was stirred for 1 hour at room temperature and then quenched with excess 4N hydrochloric acid. After evaporation of the ethanol in vacuo, the residue was washed with water, then with 3N sodium hydroxide and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The solid residue was crystallized from ethanol. 0.22 g of the title compound are obtained, m.p. Mp 143-146 ° C. 8- (X-Methylacrylamido) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate L) this compound is prepared in the same way as intermediate X, but using intermediate XLIX instead of 8-amino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran. Instead of diluting with water, THF was removed by vacuum evaporation and the crude 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. A sample purified by silica gel column chromatography (eluent ethyl acetate-tetroleum ether 4: 6) and crystallized from cyclohexane, m.p. Mp 136-137 ° C.

1- [2- (1,3-dihydro-1,3-dioxo-2H-isoindol-2-yloxy) -ethyl] -4- (2methoxyphenyl) -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 dimethyl sulfoxide was stirred for 4 hours at 100 ° C. The mixture was cooled to room temperature, poured into water and extracted with ethyl acetate. The separated organic phase was washed with 1N sodium hydroxide. dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. 7.58 g of the title compound are obtained. A sample crystallized from cyclohexane has m.p. (76) 80-83 ° C

1- (2-aminooxyethyl) -4- (methoxyphenyl) -piperazine hydrochloride (Intermediate LII)

A solution of 6.59 g of intermediate LI and 1.10 ml of 85% hydrazine hydrate in 130 ml of 95% ethanol was refluxed for 4 hours. The ethanol was evaporated in vacuo. The residue was washed with water, then with excess 37% hydrochloric acid and filtered. The acidic aqueous solution was basified with 5% sodium hydroxide and extracted with chloroform. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness in vacuo to give 4.3 g of the title compound as an oil. A sample of this compound is converted to the corresponding hydrochloride using ethanol hydrochloride in dichloromethane. The solvents were removed by evaporation in vacuo and the crude product was crystallized from ethanol. The title compound is obtained, m.p. Mp 208-209 ° C.

8- (4-Chlorobutylthio) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate LIII)

The title compound was prepared in the same way as intermediate XXXIV, but using 1-bromo-4-chlorobutane instead of 1-bromo-3-chloropropane. Melting point: 81-84 ⁰ C (ethanol). 8- (4-Chlorobutylsulfinyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate LIV)

The title compound was prepared in the same way as intermediate XXVI, but using intermediate LIII instead of intermediate XXI, a sample crystallized from cyclohexane: benzene 0.5: 1, m.p. 124-125 ° C, 8-Carboxy-4-oxo-3-phenyl-4H-1-benzopyran (Intermediate LV)

A solution of 38.22 g of silver nitrate in 75 ml of water was added dropwise, with stirring, at 20-25 ° C to a solution of 22.5 g of 8formyl-4-oxo-3-phenyl-4H-1-benzopyran (prepared according to the description of G. Atassi et al., Eur. J. Med. Chem. - Chim. Ter., 20, 393 (1985) in 150 ml of 85% ethanol and 450 ml of dimethylformamide, then dropwise, with stirring and 15- 20 ° C, 85% solution of 32.67 g of potassium hydroxide in 195 ml of water was added, After further stirring at room temperature, the reaction mixture was filtered in vacuo; the mother liquor was acidified with 37% hydrochloric acid and diluted with 1.2 liters of water. After vacuum filtration and washing With neutralization with water, the title compound was obtained as a crude substance, suspended in 150 ml of ethyl acetate and stirred with 444 ml of O. 3M sodium bicarbonate to give clear phases, the aqueous phase was washed with 75 ml of ethyl acetate, after this was acidified with 37% hydrochloric acid, filtered and dried at 60-65 ° C to give 19.12 g of the title compound, m.p. (215) 218 ° C. A sample crystallized from ethanol has the same m.p.

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

A mixture of 15.97 g of intermediate LV and 15.6 ml of thionyl chloride 6 75 ml of anhydrous toluene was stirred for 4 hours at 80-85 ° C. After removal of the solvents in vacuo, the residue was washed twice with 20 ml of toluene and evaporated to dryness in vacuo. 16 g of the title compound are obtained, m.p. (126) 138-140 ⁰ C, which is used without further purification. Melting point: (130) 138-140 ° C (toluene).

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

Mixture of 3.5 g of 8-carbamoyl-3-methyl-4-oxo-2-phenyl-4H-1benzopyran (described in JP 61-238783), 4.8 ml of acetic anhydride and 0.25 ml of sulfuric acid (0 = 1 = 098 ) was stirred for 3 minutes at 140 ° C. The reaction mixture was cooled to room temperature, diluted with water and filtered under vacuum. Washing with water and drying in a desiccator afforded 3.88 g of the title compound.

NMR (CDCl ₃ , δ)

10.50 (bs, 1H, imide NH)

8.35-8.70 (m, 2H, CH at the benzopyran ring positions 5 and 7)

7.45-8.00 (t, 6H, other aromatic CHs)

2.60 (s, 3H, CH ₃ CO)

2.20 (s, 3H, CH ₃ at the 3-position of the benzopyran ring)

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

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

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

A mixture of 10.5 g of intermediate LVIII and 140 ml of 2N hydrochloric acid in 85 ml of anhydrous tetrahydrofuran was stirred for 2 hours at 50 ^° C. The organic solvent was evaporated in vacuo and the aqueous residue was extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. 9.5 g of the title compound are obtained as a solid, which is used without further purification. The sample crystallized from cyclohexane represents the pure title compound, mp, 102-104 ° C 8- (4-chlorobutylsulfonyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate LX)

The title compound was prepared by the same method as intermediate XXV, but using intermediate LIII instead of intermediate XXI, crystallized from diisopropyl ether and mp 112-115 ° C. 8-Ethoxycarbonyl-4-oxo-4H-1-benzopyran (Intermediate LXI)

4.35 g of metallic sodium were added in pieces at room temperature to a solution of 9.85 g of ethyl 3-acetyl-2-hydroxybenzoate (synthesized from 3-acetyl-2-hydroxybenzoic acid, obtained according to the description of R. E. Ford, J. Med Chem., 29, 538, (1986), boiling under reflux for 1.5 hours in 6N ethanol hydrochloric acid, evaporating to dryness in vacuo, and the crude product was purified by column chromatography on silica gel (eluent ethyl acetate: petroleum ether 8 : 2) - mp 47 ° C (hexane)) in 98 ml of ethyl formate.

The reaction mixture began to boil spontaneously under reflux for 20 minutes; it was then stirred for 4 hours at room temperature and then removed by evaporation in vacuo ethyl formate. The crude product obtained is washed with 120 ml of ethanol and 67 ml of 5.67M ethanol. The mixture was stirred for 30 minutes under reflux; it was then cooled to room temperature and evaporated to dryness in vacuo. The residue was purified by silica gel column chromatography with ethyl acetate: petroleum ether 3: 7 to 6: 4 as eluent. 8.31 g of the title compound are obtained. A sample crystallized from cyclohexane has m.p. 88-89 ° C.

8-carboxy-4-oxo-4H-1-benzopyran (Intermediate LXII) ml of 6N hydrochloric acid was added to a solution of 4.0 g of intermediate LXI in 30 ml of dioxane and the resulting mixture was stirred for 5 hours under reflux. The reaction mixture was cooled to room temperature and poured into 200 ml of water. After 12 hours at 0 to 5 ° C, the title compound was filtered under vacuum. After washing with water and diethyl ether, 2.8 g of the title compound are obtained after drying in a desiccator, which is used without further purification. A sample washed with boiling acetonitrile: methanol 25: 1, filtered and crystallized from acetic acid, m.p. 253-254 ° C.

8-carboxy-6-hydroxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate LXIII) ( ¹ mo of 1.5 g of 8-carboxy-6-methoxy-3-methyl-4 -oxo-2phenyl-4H-1-benzopyran (prepared as described in JP 61-15880) and 28 ml of 57% hydrochloric acid in 47 ml of acetic acid are stirred at reflux for 18 hours. The reaction mixture is cooled to room temperature and is poured into water; 1N sodium hydroxide is added to adjust the pH to 4-5, 2 g of sodium thiosulphate is added and stirring is continued for 15 minutes, then the crude title compound is filtered off under vacuum and dissolved in 0.5M. trine hydroxide; the alkaline solution was washed with ethyl acetate and acidified to pH 1 by the addition of 37% hydrochloric acid. The title compound was isolated by vacuum filtration and dried in a desiccator. Yield: 1.12 g of the title compound, which was used without further further purified and mp 279-282 ° C after crystallization from 50% ethanol.

2-hydroxy-5-nitro-3-propionylbenzoic acid (Intermediate LXIV)

97.1 g of 2-hydroxy-3-propionylbenzoic acid, prepared as described in Brit 1, 343, 119 (1974), were added over 5 minutes to 500 ml of sulfuric acid (0 = 1.84), stirred at -25 ° C. A mixture of 40 ml of 65% nitric acid and 100 ml of sulfuric acid (0 = 1.84) was added over 40 minutes while maintaining the temperature of the reaction mixture between -20 and -13 ° C. The mixture was stirred for an additional 30 minutes at -18 ° C. The mixture was then carefully poured onto a mixture of 2.0 kg of crushed ice and 500 ml of water, stirred for 10 minutes and filtered. After washing with water and drying for 6 hours at 50 ° C, the title compound is obtained. Crystallization of the solid from 50% ethanol gave 91.5 g of the title compound, m.p. 186-189 ° C, which was used without further purification. A sample which was recrystallized from 50% ethanol had a m.p. Mp 189-191 ° C.

ethyl-2-hydroxy-5-nitro-3-propionylbenzoate (Intermediate LXV)

A solution of 93.3 g of intermediate LXIV and 25 ml of sulfuric acid (0 = 1.84) in 490 ml of ethanol was refluxed for 17 hours. After cooling to room temperature, 'W97' was added portionwise

47.7 g of sodium carbonate and the ethanol was evaporated in vacuo. The residue was washed with 1.2 liters of water, basified by the addition of 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 (mp 75-77 ° C). A sample which was crystallized twice from ethanol had m.p. 7677 ° C.

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

A mixture of 48.1 g of LXV intermediate, 63 ml of benzoyl chloride and 85.6 g of sodium benzoate was stirred for 8 hours at 180 ° C (bath temperature). The paste mixture was cooled to 60-70 ° C; 700 ml of ethanol were added and the resulting mixture was again stirred for 30 minutes at 50 ° C; at 5 ° C, ensuring that the temperature does not exceed 15 ° C, 60 ml of 35% sodium hydroxide are added. Vacuum filtration followed by washing with 50% ethanol and water yielded a crude substance which was purified by double passage through a chromatographic column on silica gel, initially dichloromethane: petroleum ether in a ratio of 8: 2 to 9: 1, then with dichloromethane and finally with dichloromethane: ethyl acetate 95: 5, Evaporation in vacuo of the combined fractions afforded the title compound, which was washed with 140 ml of ethanol. Yield: 43 g, mp, 132-133 ° C (ethanol).

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

A mixture of 15.9 g of LXVI intermediate and 48 ml of 1N sodium hydroxide in 320 nil ethanol was stirred at reflux for 30 minutes. The organic solvent was evaporated in vacuo and the resulting suspension was diluted with 200 ml of water and acidified with 37% hydrochloric acid. Filtration and washing with diethyl ether are obtained

11.1 g om the title compound, m.p. (258) 286-292 ° C and used without further purification. After crystallization from dimethylformamide: water 6: 4, the title compound has 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 LXVII intermediate, 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 afforded 6.5 g of the title compound, m.p. 161-162 ° C, which was used without further purification. A sample that crystallizes from toluene has the same melting point.

8-Carboxy-7-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate LXIX)

216 ml of O. 3M solution of potassium permanganate in water were added dropwise over 40 minutes to a mixture of 7.94 g of 8-formyl-7-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, (obtained , according to a description of Da Re et al., Z Org. Chem., 25, 1097, 1960) in 54 ml of 5% sodium dihydrogen phosphate in 162 ml of tert-butanol, which was stirred at 75 ° C. After stirring at the same temperature for another hour, the reaction mixture was cooled to room temperature and 81 ml of 1M sodium dithionate was slowly added thereto. The mixture was extracted with ethyl acetate. The organic phase was washed four times with 160 ml of 0.5N sodium hydroxide; the combined aqueous, alkaline phases were washed with diethyl ether and acidified with 37% hydrochloric acid. The title compound precipitates. It is filtered off, washed with water and, after drying in a desiccator, 3.3. Mr Rücker Used in the following reactions without further purification. Melting point: 180-181 ° C after crystallization from 95% ethanol.

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

A solution of 6.7 g of 4-trifluoromethylbenzoyl chloride (obtained from the corresponding benzoic acid and thionyl chloride in benzene under reflux and used without further purification) in 50 ml of chloroform was added dropwise to a solution of 7.13 g of ethyl 2-hydroxy-3-propionyl-benzoate. 4.9 ml of triethylamine in 50 ml of chloroform. The mixture was stirred for 2 hours at room temperature .; the solvent was then evaporated in vacuo and the residue purified by column chromatography over silica gel with eluant petroleum ether: ethyl acetate 85:15. The combined fractions were evaporated to dryness in vacuo to give 7.4 g of the title compound as an oil.

NMR spectrum at 60 MHz (CDCl3, δ)

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

7.5 (t, 1H, phenol ring, CH in 5)

4.2 (q, 2H, COOH ₂ )

2.9 (q, 2H, COCH ₂ )

1-1.3 (2t, 6H, 2xCH ₃ )

8-Ethoxycarbonyl-3-methyl-4-oxo-2- (4-trifluoromethylphenyl) -4H-

1-benzopyran (Intermediate LXXI)

A mixture of 6.96 g of intermediate LXX and 2.58 g of potassium tert-butoxide in 35 ml of pyridine was stirred for 2 hours at 100 ° C. The reaction mixture was then cooled to room temperature and poured into a solution of 50 ml of acetic acid in 600 ml. water and extracted with ethyl acetate. The organic phase was washed with 10% hydrochloric acid and water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. 6.9 g of 1- (2-hydroxy-3-ethoxycarbonyl) -2-methyl-3- (4-trifluoromethylphenyl) -1,3-propanedione are obtained. Solution of the compound thus obtained and 2.2. ml of 37% hydrochloric acid in 35 ml of glacial acetic acid is stirred for 1¾ hours at

100

100 ° C. After cooling to room temperature, the mixture was poured into 630 ml of 1N sodium hydroxide and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo, and the crude compound was purified by column chromatography on silica gel with petroleum ether-ethyl acetate 85:15. Evaporation to dryness in vacuo afforded 2.95 g of the title compound, m.p. 111-113 ° C after crystallization from cyclohexane. 8-carboxy-3-methyl-4-oxo-2- (4-trifluoromethylphenyl) -4H-1-benzopyran (Intermediate LXXII)

A mixture of 2.95 g of intermediate LXXI and 0.43 g of lithium hydroxide monohydrate in 12.5 ml of methanol and 12.5 ml of tetrahydrofuran containing 8 ml of water was stirred for ¹ hour at room temperature. The mixture was poured into a solution of 30 ml of 1N hydrochloric acid in 300 ml of water and filtered under vacuum. 2.47 g of the title compound are obtained which is used without further purification. A sample crystallized from 60% ethanol has m.p. 253-254 ° C.

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

The compound was bubbled following the process for the preparation of intermediate LXX and LXXI in the established order but with starting compound 4-benzoylbenzoyl chloride instead of 4trifluoromethylbenzoyl chloride, the reaction being carried out in 1,2dichloroethane instead of chloroformin and chloroformin and chloroformin . After the usual treatment, the residue was purified by column chromatography on silica gel with eluent dichloromethane: ethyl acetate 9: 1. After evaporation of the combined fractions to dryness in vacuo, the title compound was obtained which was used without further

101 purification. A sample that crystallizes from cyclohexane has m.p. 125-136 ° C (dec).

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

The compound was prepared in the same way as intermediate LXXII, but starting from intermediate LXXIII instead of intermediate LXXI. It was purified by dissolving the crude compound in 0.5M sodium hydroxide, washing the aqueous phase with ethyl acetate, and precipitating the pure title compound by the addition of 37% hydrochloric acid. A sample that crystallizes from acetic acid has m.p. 260-262 ° C.

Ethyl 2- (4-phenoxybenzyloxy) -3-propionylbenzoate (Intermediate LXXV)

The compound was prepared by the method described for intermediate LXX but from 4-phenoxybenzoyl chloride instead of 4trifluoromethylbenzoyl chloride. Evaporation of the solvent gave the pure title compound.

NMR spectrum at 200 MHz (CDC1 ₃ , δ)

8.17 (dd, 3H, phenyl CHs in ortho position to the carboxylate groups)

7.92 (dd, 1H, phenyl CH at the ortho position with respect to the CO group)

7.38-7.48 (t, 3H, phenyl CHs in meta position relative to carboxylate groups)

7.25 (d, 1H, CH in the 4 position relative to the phenoxy ring)

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

4.25 (q, 2H, CH ₂ O)

2.90 ( _q , 2H, CH ₂ )

1.05-1.20 (t, 6H, 2xCH ₃ )

102

8-Ethoxycarbonyl-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 instead of intermediate LXX. Purify by column chromatography on petroleum ether: ethyl acetate 6: 4 as eluent. Evaporation in vacuo afforded the title compound, m.p. 98100 ° C.

8-Carboxy-3-methyl-4-oxo-2- (4-phenoxyphenyl) -4H-1-benzopyran ^W (Intermediate LXXVI I)

This compound is prepared in the same way as intermediate LXXII but starting from intermediate LXXVI instead of intermediate LXXI. Melting point: 216-218 ° C.

8-Carboxy-2- (tert-butyl) -3-methyl-4-oxo-4H-1-benzopyran (Intermediate LXXVIII) ml of pivaloyl chloride were added dropwise while stirring to a solution of 8.9 g of ethyl 2-hydroxy- 3-Propionylbenzoate in 20 ml of anhydrous pyridine. The reaction mixture was stirred at 80 ° C for 6 hours, cooled to room temperature and poured into a mixture of 200 g of crushed ice and 30 ml of 10 N hydrochloric acid. After extraction with diethyl ether, the organic phase is washed with brine, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. 11.4 g of crude ethyl 2-pivaloyloxy-3-propionylbenzoate are obtained.

2.4 g of this compound was dissolved in 4 ml of anhydrous pyridine and to it was added 1 g of anhydrous potassium tert-butoxide. The resulting mixture was heated at 100 ° C for 15 minutes, cooled to room temperature and poured into 50 g of ice water containing 8 ml of 10N hydrochloric acid. After extraction with diethyl ether,

103 The organic phase was washed with brine, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. 2.1 g of crude ethyl-2-hydroxy-3- (2-pivaloylpropionyl) benzoate are obtained, which is used in the next step without further purification. 2 g of the compound thus obtained is heated at 100 ° C for 15 minutes after being dissolved in a mixture containing 15 ml of acetic acid and 1.5 ml of 37% hydrochloric acid. After cooling to room temperature, the mixture was poured into 100 ml of water and extracted with diethyl ether. The organic phase was washed with 5% aqueous sodium bicarbonate solution, then with water, dried over anhydrous sodium sulfate and evaporated in vacuo. 11.6 g of the crude compound 8-ethoxycarbonyl-2- (tert-butyl) -3methyl-4-oxo-4H-1-benzopyran are obtained.

Dissolve 1.5 g of the above ester in 20 ml of methanol. 3 ml of 10 N sodium hydroxide was added slowly while maintaining the temperature between 25 and 35 ° C. After P / ₂ hours at room temperature, the reaction mixture was diluted with 100 ml of water and extracted with ethyl acetate. The aqueous phase was acidified with 3N hydrochloric acid. The precipitate was isolated by vacuum filtration, washed with water and crystallized from ethanol. 0.8 g of the title compound are obtained, m.p. Mp 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 the methods described for intermediate LXXVIII, but starting from cyclohexylcarboxylic acid chloride instead of pivaloyl chloride and with some other minor differences. In particular, ethyl-2-cyclohexylcarbonyloxy-3-propionylbenzoate is obtained by stirring for 8 hours in pyridine, at room temperature and is converted to 2-hydroxy-3- (2-cyclohexyl arbonylpropionyl) benzoate by heating for 2¼ hours is potassium tert-tert-butyl tert -butoxide at 100 ° C.

104

When heated at 100 ° C for P / 2 hours θ, a mixture of acetic acid and hydrochloric acid cyclize to 8 ethoxycarbonyl-2-cyclohexyl-3-methyl-4-oxo-4H-1-benzopyran and hydrolysis to the title compound is carried out for 20 minutes at room temperature. The title compound has m.p. 224 ° C after crystallization from 40% ethanol.

8-Ethoxycarbonyl-2- (2-furyl) -3-methyl-4-oxo-4H-1-benzopyran (Intermediate LXXX)

A mixture of 3.2 g of intermediate XC and 1.3 g of anhydrous potassium tert-butoxide in 8 ml of anhydrous pyridine was stirred for 15 minutes at 60 ^° C, cooled to room temperature and poured into 60 ml of ice water containing 15 ml of 10N hydrochloric acid. After extraction with ethyl acetate, the organic phase was washed with 5% aqueous sodium bicarbonate and water and dried over anhydrous sodium sulfate. Evaporation in vacuo gave the crude compound 3- (2fluoromethylpropionyl) -2-hydroxybenzoate.

2.5 g of the compound thus obtained was stirred with 10 ml of acetic acid and 0.7 ml of 37% hydrochloric acid for 30 minutes at 100 ° C. After cooling to room temperature, the mixture was poured into 180 ml of water. The title compound was precipitated and isolated by vacuum filtration, washed with water and crystallized from isopropanol. Yield: 1.5 g, m.p. Mp 137-139 ° C.

8-Carboxy-2- (2-furyl) -3-methyl-4-oxo-4H-1-benzopyran (Intermediate LXXXI)

A mixture of 3.5 g of LXXX intermediate and 6 ml of 10 N sodium hydroxide in 40 ml of methanol was stirred at room temperature for 1 hour and poured into 500 ml of water. After extraction with ethyl acetate, the aqueous phase was acidified with 3 N hydrochloric acid. The title compound was precipitated and isolated by vacuum filtration, washed with water and crystallized from 7: 3 methanol: chloroform. Yield: 2.55 g, m.p. 272-277 ° C.

105

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

This compound was prepared in two steps according to the methods reported for intermediate LXXX, but using intermediate XCI instead of intermediate XC. After crystallization from isopropanol, the title compound has a melting point of 116-118 ° C.

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

This compound was prepared according to the method described for *** intermediate LXXXI, but using intermediate LXXXII instead of intermediate LXXX. Melting point: 287-294 ° C after crystallization from a mixture of 7: 3 methanol: chloroform.

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

A mixture of 1 g of 8-methoxycarbonyl-4-oxo-2-phenyl-4H-1benzopyran (intermediate HSP), 2.2 ml of 12.5N sodium hydroxide, 15 ml of methanol and 5 ml of dioxane was stirred for 2¼ hours at room temperature. After evaporation in vacuo, water was added to complete dissolution and this solution was extracted with chloroform. The separated aqueous phase was acidified with dilute hydrochloric acid until complete precipitation of the crude compound, which was filtered and purified by crystallization from acetic acid. Yield: 0.62 g, m.p. 302 ° C.

(E) -8-Ethoxycarbonyl-3-methyl-4-oxo-2- (2-styryl) -4H-1-benzopyran (Intermediate LXXXV)

This compound is prepared in three steps according to the methods described for 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 (E) -ethyl106 obtained

2-Hydroxy-3- (2-styrylpropionyl) -benzoate was used for the second step without purification. The title compound has m.p. 129-130 ° C after crystallization from isopropanol.

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

This compound was prepared according to the method described for compound LXXXI, but using intermediate LXXXV instead of intermediate LXXX and the reaction was maintained for 10 hours at room temperature. The title compound has mp 284-286 ° C after crystallization from ethanol. 8-carboxy-3-methyl-2- (4-methylphenyl) -4-oxo-4H-1-benzopyran (Intermediate LXXXVI I)

A mixture of 1.9 g 2-hydroxy-S-propionyl acid (prepared as described in Brit, 1, 343, 119. 1974), 5.2 g of anhydrous sodium 4-methylbenzoate and 3.9 ml 4-methylbenzoyl chloride was stirred for 8 hours at ¹ ^ 185 -195 ° C. After cooling to room temperature, the solidified mass was allowed to stand overnight with 100 ml of chloroform. The mixture was then shaken with 5% aqueous sodium carbonate solution, which was added to pH 8.9. The organic phase was re-extracted with 3% sodium carbonate and the aqueous phases were combined, extracted repeatedly with diethyl ether and acidified with 10 N hydrochloric acid. The precipitate was purified by flash chromatography on silica gel eluting with chloroform: methanol 100: 2 to 100: 20. The title compound obtained by evaporation in vacuo of the combined fractions, m.p. 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 methods described for intermediate XC (first step) and intermediate LXXX (second and third steps). The first stage is

107 used 4-fluorobenzoyl chloride instead of 2-furoyl chloride and the reaction was continued for 20 hours at room temperature. 2- (4-Fluorobenzyloxy) -3-propionylbenzoate is obtained. This compound was used in the second step without purification. The title compound has m.p. 128-130 ° C after washing with 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 was isolated by vacuum filtration, washed with water and dried. 2.3 g of the title compound are obtained, m.p. 249-250 ° C after crystallization from 95% ethanol.

Ethyl-2- (2-furoyloxy) -3-propionylbenzoate (Intermediate XC)

4.35 ml of 2-furoyl chloride are added dropwise, with stirring, and a temperature of 10-15 ° C to a mixture of 8.9 g of ethyl 2-hydroxy-3-propionylbenzoate and 5.4 g of 4-dimethylaminopyridine in 25 ml of dichloromethane. After 2 hours at room temperature, the reaction is interrupted with 200 ml of water. The organic layers were washed with 5% sodium bicarbonate solution, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with petroleum ether: ethyl acetate 4: 1. 9.4 g of the title compound are obtained as a low melting point solid which is used without further purification in the next step.

NMR spectrum at 60 Hz (CDCI ₃ , δ)

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

108

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

7.7.-7.8 (1H, dd, CH 6 5 position of the furan ring)

7.43 (1H, t, CH at the 5 position of the benzene ring)

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

6.6-6.8 (1H, t, CH at the 4 position of the furan ring)

4.3 (2H, q, COOCH ₂ CH ₃ )

2.9 (2H, q, COCH ₂ CH ₃ )

0.95-1.35 (6H, t, 2x CH ₃ )

Ethyl-3-propionyl-2- (2-thienyl arbonyloxy) -benzoate (Intermediate XCI)

This compound was prepared by the method described for intermediate XC, but using 2-thienylcarboxylic acid chloride instead of 2-furoyl chloride.

NMR spectrum at 60 Hz (CDC1 ₃ , δ)

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

4.25 (2H, q, SOOST1 ₂ CH ₃₎

2.9 (2H, q, COCH ₂ CH ₃ )

0.95-1.3 (6H, t, 2xCH ₃ )

8-Methoxycarbonyl-4-oxo-2-phenyl-4H-1-benzothiopyran (CSP intermediate)

A mixture of 16.8 ml methylthiosalicylate, 25.6 ml ethylbenzoyl acetate and 360 g polyphosphoric acid was stirred for 3 hours at 90 ° C. After cooling to room temperature, the mixture was poured into crushed ice and the crude compound was separated by filtration, washed with water and purified by crystallization from ethanol. Melting point: 170-171 ° C.

Elemental analysis for C ₁₇ H ₁₂ O ₃ S:

Calculated (% '): C, 68.90; H, 4.08; 8, 10.82 Found (%): C, 68.59; H, 4.13; 8,10.69

NMR spectrum at 200 Hz (CDC1 ₃ , δ)

8.83-8.95 (dd, 1H, benzothiopyran CH 6 5)

109

8.45-8.53

7.68-7.80

7.55-7.65

7.45- 7.55

7.24

4.00 (dd, 1H, benzothiopyran CH in 7) (m, 2H, 2-phenyl CHs in 2 and 6) (t, 1H, benzothiopyran CH in 6) (m. 3H, 2-phenyl CHs in 3, 4 and 5 ) (s, 1H, benzothiopyran CH in 3) (s, 3H, COOCH ₃ )

8-Ethoxycarbonyl-3-bromomethyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate HCl)

Mixture of 9.2 g of 8-ethoxycarbonyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (prepared as described by Da Re, P. et al., U. Med. Pharm. Chem., 263, 1960 ), 6.4 g of N-bromosuccinimide and 0.04 g of benzoyl peroxide in 80 ml of anhydrous tetrachloromethane were stirred at reflux for 1¾ hours. After cooling to room temperature, the formed succinimide was removed by vacuum filtration and washed with cold tetrachloromethane. The mother liquor was evaporated to dryness in vacuo and the residue was washed with diethyl ether and vacuum filtered. 9.2 g of the title compound are obtained, m.p. 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 30 ml of water was added dropwise at room temperature to a solution of 29 g of HCl intermediate in 300 ml of dimethylformamide. After stirring at 50 ° C for P / ₂ hours, the reaction mixture was poured into 2 liters of water and the precipitated title compound was removed by vacuum filtration. Crystallization from acetone afforded 20 g (two combined yields), m.p. Mp 151-152 ° C.

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

116 ml of 1N sodium hydroxide was added over 10 minutes, with stirring, to a suspension of 14.8 g of intermediate XCIV in

110

300 ml 95% ethanol. The reaction mixture was then heated at 6065 ° C for 15 minutes to give a clear solution which was maintained at room temperature for another 1 hour. After evaporation in vacuo, the residue was dissolved in 200 ml of water and the solution acidified by slow addition of 10 ml of hydrochloric acid (d = 1.18). After stirring for 1 hour at room temperature, the title compound was removed by vacuum filtration, washed with water and crystallized from isopropanol. 9.3 g, m.p. (225) 237-240 ° C.

Ethyl 2- (4-nitrobenzyloxy) -3-propionylbenzoate (Intermediate XCVI)

The compound was prepared according to the scheme described for intermediate XC, using 4nitrobenzoyl chloride instead of 2-furoyl chloride. Obtained as a low melting point solid (mp (40) 78-80 ° C).

NMR spectrum at 60 Hz (CDC1 ₃ , δ)

7.85-8.5 (m, 6H, aromatic CHs)

7.50 (t, 1H, CHs is in the 5 position of the phenol ring) _D 4.25 (q, 2H, CH ₂ O)

3.95 (q, 2H, CH ₂ )

0.95-1.3 (t, 6H, CH ₃ )

8-Ethoxycarbonyl-3-methyl-2- (4-nitrophenyl) -4-oxo-4H-1-benzopyran (Intermediate XCVII)

A mixture of 29.7 g of intermediate HCl1 and 10.18 g6e3 (3ogeH potassium tert-butoxide in 89 ml of anhydrous pyridine was stirred for 13 hours at 100 ° C. The reaction mixture was cooled to room temperature, poured into 400 ml of 4N hydrochloric acid and extracted with dichloromethane The organic phase is repeatedly washed with water, then with 2.5% sodium bicarbonate, dried over anhydrous sodium sulfate and evaporated to dryness under vacuum.

Ill compound was purified by silica gel column chromatography with eluent hexane: ethyl acetate 7: 3. Evaporation of the combined fractions in vacuo afforded 7 g of the title compound, mp (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 intermediateXCVII in 4.75 ml of dioxane and 4.75 ml of methanol was stirred at 50 ° C. 1.29 ml of 1N sodium hydroxide are added and stirring is continued for 3 hours at the same temperature. The reaction mixture was cooled to room temperature and 3N hydrochloric acid was added thereto until pH 1. After vacuum filtration 0.13 g of the title compound was obtained, m.p. 320-321 ° C after crystallization from dioxane.

8-Ethoxycarbonyl-3-methyl-4-oxo-2-trifluoromethyl-4H-1-benzopyran (Intermediate XlX)

3.16 ml of 1,8-diazabicyclo [5.4.0] undec-7-ene are added dropwise with a syringe at 0 ° C and stirred to a mixture of 3 g of ethyl 2-hydroxy-

3-propionylbenzoate and 5.53 ml of trifluoroacetic anhydride. The reaction mixture was stirred for 4 hours at 60 ° C, then cooled to room temperature and diluted with ethyl acetate and water. The organic phase was washed with 1N sodium hydroxide and water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The residue was purified by column chromatography on silica gel with eluant: petroleum ether: ethyl acetate 95: 5. 0.8 g of the title compound are obtained.

NMR spectrum at 200 Hz (CDCl3, δ)

8.41; 8.37 (2dd; 2H, CHs at the 5 and 7 positions of the benzopyran ring) (t, 1H, CH at the 6 positions of the benzopyran ring) -d. 211. With () OS11, ·

7.51

4.46

112

2.22-2.27 (m, 3H, J _HF = 2.16Hz, CH ₃ 6 3 position of the benzopyran ring

1.39 (t, 3H, CH ₂ CH ₃ )

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

The title compound was prepared by the same method as intermediate LXII, but using intermediate XCIX instead of intermediate LXI and after dilution with water was extracted with ethyl acetate instead of filtration. After drying over anhydrous sodium sulfate and evaporation ^w of the organic phase to dryness under vacuum to give the title compound as a solid, m.p. 175-178 ° C.

3- [4- (2-Methoxyphenyl) -1-piperazinyl] -X-methylpropylamine (Intermediate CI) ml A 35% aqueous methylamine solution 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 was heated at 60 ° C in a closed vessel for 5 hours and then cooled to 30 ° C. The solvent was evaporated in vacuo and the residue was stirred with 100 ml of diethyl ether for 30 minutes. Vacuum filtration removes the solid which is dissolved in 200 ml of 100: 3 methanol ammonia ammonium. After stirring at room temperature for 30 minutes, the solution was passed through a chromatography column with chloroform: 5Ν methanol ammonia in a ratio of 100: 5 to 100: 15. the fractions containing the title compound were collected and evaporated in vacuo. 3 g of intermediate CI are obtained as a thick oil.

NMR spectrum at 60 Hz (C1) C1 ₃ , δ)

6.80 (s, 4H, CHs aromatic)

3.75 (s, 3H, OCH ₃ )

3.20-2.75 (t, 4H, piperazine CH _? S in position 3.5)

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2.75-2.10 (m, 8H, piperazine CH ₂ s at position 2.6 and dream ₂ dream ₂ dream ₂ )

2.40 (s, 1H, NH)

2.30 (s, 3H, NCH ₃ )

1.80-1.40 (m, 2H, CH ₂ CH ₂ CH ₂ )

Ethyl-2-benzoyl-3-ethylbenzo [b] furan-7-carboxylate (Intermediate SP)

A mixture of 11.1 g of ethyl 2-hydroxy-3-propionylbenzoate, 9.9 g of phenacyl bromide, 6.9 g of anhydrous potassium carbonate and 200 ml of acetone were stirred at reflux for 7 hours. After cooling to room temperature, the inorganic salts were separated by filtration and the solution was evaporated in vacuo. The residue was purified by flash chromatography on silica gel with eluent - toluene. The title compound was obtained by evaporation of the combined fractions containing it in vacuo and crystallization from 90% ethanol. Yield: 9.8 g, m.p. 64-66 ⁰ p.

7- carboxy-2-benzoyl-3-ethylbenzo [b] furan (Intermediate US)

A mixture of 7 g of intermediate SP, 275 ml of 0.95N sodium hydroxide and 400 ml of dioxane was refluxed for 4 hours. After cooling to room temperature, the dioxane was evaporated in vacuo and replaced with the same amount of water. After filtration through charcoal, the solution is acidified with dilute hydrochloric acid and the precipitate is filtered off and purified by crystallization from acetone. Yield 4.94 g, m.p. Mp 193-195 ° C.

8- methoxycarbonyl-3-methyl-2- (4-methylphenyl) -4-oxo-4H-1-benzopyran (Intermediate C1V)

This compound is prepared in three steps according to the methods described for intermediate XC (first step) and intermediate LXXX (second and third steps). In the first stage it is used

114

4-methylbenzoyl chloride instead of 2-furoyl chloride and methyl-2-hydroxy-

3-propionylbenzoate - instead of ethyl-2-hydroxy-3-propionylbenzoate. The reaction was continued for 4 hours at room temperature. Methyl 2- (4-methylbenzyloxy) -3-propionylbenzoate is obtained. This compound is used without purification in the second step, which is maintained for ¹ hour at 100 ° C. In the third step, 96% sulfuric acid is used instead of 37% hydrochloric acid. The title compound has m.p. 174-175 ° C after crystallization from ethanol.

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

This compound is prepared in three steps according to the methods described for intermediate XC (first stage) and intermediate CIV (second and third steps), in the first step 4phenylbenzoyl chloride is used instead of 2-furoyl chloride and the reaction is continued for 20 hours at room temperature and 13 hours under reflux. Purification was performed by column chromatography on silica gel with eluant petroleum ether: ethyl acetate in a ratio of 100: 5 to 100: 10. 2- (4-Biphenylyl) -3-propionylbenzoate is obtained. The title compound has m.p. 165-167 ° C after washing with 95% ethanol.

8-Carboxy-2- (4-biphenylyl) -3-methyl-4-oxo-4H-1-benzopyran (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 stirred at reflux for 16 hours. After cooling, the mixture was poured into 200 ml of water and extracted with ethyl acetate. The organic phase was separated and extracted with 20% aqueous sodium carbonate solution. The precipitate formed by acidification with dilute hydrochloric acid is vacuum filtered, washed with water and dried. 2.5 g of the title compound are obtained, m.p. 242.5-244 ° C

115

8-Carboxy-2- (4-hydroxyphenyl) -3-methyl-4-oxo-4H-1-benzopyran (Intermediate CVII)

A mixture of 3 g of 8-ethoxycarbonyl-2- (4-methoxyphenyl) -3-methyl-4oxo-4H-1-benzopyran (obtained according to JP 58-225083) and 60 ml of 48% hydrobromic acid in 80 ml of acetic acid was stirred under reflux for 8 hours. After cooling, the mixture was poured into 500 ml of water and the precipitate was isolated by vacuum filtration and washed with water. The crude compound was purified by flash chromatography eluting with chloroform-isopropanol 971 to 7: 1, then eluting with methanol. 1 g of the title compound is obtained, m.p. 300 ° C.

4- [4- (2-Methoxyphenyl) -1-piperazinyl] -1 N-methylbutylamine (Intermediate CVIII)

A solution of 3.8 ml of trifluoroacetic anhydride in 25 ml of anhydrous dichloromethane was added dropwise with stirring at 0 '(' to a solution of 2.53 g of 4- [4- (2-methoxyphenyl) -1-piperazinyl] -butylamine in 25 ml of anhydrous dichloromethane). After stirring at room temperature for 2 hours, the reaction mixture was diluted with dichloromethane and washed with water, the organic phase was dried over anhydrous sodium sulfate and evaporated to dryness in vacuo to give 3.3 g of pure 4- (4- (2methoxyphenyl) -1 -piperazinyl] -Notrifluoroacetylbutylamine. NMR spectrum at 60 Hz (C1) Cl ₃ , δ)

7.70-8.00 (Os, III NH)

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

3.85 (s, 3H, CH ₃ O)

2.90-3.80 (m, 12H, piperazine CH ₂ s, CH ₂ N in CH _? NHCO)

1.50-2.05 (m, 4H, C-CH ₂ CH ₂ -C)

0.88 g of 50% sodium hydride is added in portions with stirring and 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 was added

116

MemuAUogug. The reaction mixture was stirred for another P / ₂ hours at 0 ° C, then poured into water and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo to give 1.13 g of crude 4- [4- (2-methoxyphenyl) -1-piperazinyl] -Nomethylbutylamine 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 was stirred for 1 hour at 60 ° C. After cooling to room temperature, the reaction mixture was poured into water and extracted with dichloromethane. The organic phase was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. 0.82 g of pure title compound is obtained.

NMR spectrum at 60 Hz (CDCl 2, δ)

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

3.85 (s, 3H, CH ₃ O)

2.90-3.20 (t, 4H, piperazine CH ₂ s, positions 3 and 5)

2.30-2.80 (m, 8H, piperazine CH ₉ s, positions 2 and 6; 2 CH ₂ N)

2.50 (s, 3H, CH ₃ N)

1.80 (s, 1H, NH)

1.40-1.80 (m, 4H, C-CH ₂ -CH ₂ -C)

1- (3-amino-2,2-dimethylpropyl) -4- (2-methoxy phenyl) -piperazine

The title compound can be obtained by treating

1- (2-methoxyphenyl) -piperazine with isobutyraldehyde, 37% formaldehyde in water and acetic acid at 90-150 ° C or the same in ethanol, saturated with hydrogen chloride (Mannich reaction) to give 1- (2formyl-2- methylpropyl) -4- (2-methoxyphenyl) -piperazine, which is aminated by treatment with excess ammonia under reducing conditions. The reducing conditions may be hydrogen and a catalyst (e.g. palladium / carbon, Raney nickel or palladium dioxide) in a solvent (e.g. ethanol, methanol, isopropanol, dichloromethane, chloroform or

117 dimethylformamide) at a temperature between room temperature and 80 ° C or a metal hydride (e.g. sodium borohydride, sodium or potassium cyanoborohydride or sodium triacetoxyborohydride) in a solvent (eg methanol, ethanol, chloroform, benzene or 1,2 dichloroethane) (e.g. hydrogen chloride gas or acetic acid).

It can be reacted with 8-chlorocarbonyl-3-methyl-4-oxo-2-phenyl4H-1-benzopyran in the same manner as described in Example 12 below. 8- (2,2-Dimethyl) -3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran is obtained. 8-Trifluoroacetamidomethyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran

This compound can be prepared according to the scheme described for intermediate XXIII, but using intermediate XXIV instead of 8-amino-3-methyl-4-oxo-2-phenyl-4H-1benzopyran. It can be used as starting material instead of intermediate XXIII in the reaction described in Example 32 to give 8- {2- [4- (2-methoxyphenyl) -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 according to the method described for the preparation of intermediate XLIV, but using intermediate XXIV instead of 8-amino-3-methyl-4oxo-2-phenyl-4H-1-benzopyran. It can be reacted with a compound of formula H-B in accordance with (a) to obtain the desired final compounds,

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

This compound can be obtained by reacting intermediate XXIV with 2-chloroethylsulfonyl chloride in

118 halogenated solvent, such as dichloromethane in the presence of triethylamine at 0-40 ° C, according to A.A. Goldberg, J. Chem. Soc., 464, 1945. It can be reacted with the appropriate H-B compounds according to sub-step (m) to obtain the corresponding final compounds.

Proceeding as described above but using as starting compound 8-amino-3-methyl-4-oxo-2-phenyl-4H-

1-benzopyran, FP-Y36 (CH ₂ ) ₂ -B terminal compounds can be obtained. 8-chlorosulfonylmethyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran

This intermediate can be prepared by the addition of 8-amidinothiomethyl-3-methyl-4-oxo-2-phenyl4H-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. Jonson et al., J. Chem. Soc., 61, 2548, 1939. By reacting this intermediate with the appropriate compounds A-NH-Z-B according to sub-step n, the desired terminal compounds can be obtained.

Examples of carrying out the invention

Example 1 8- {2- [4- (2-Methoxyphenyl) -1-pyerazinyl] -1-oxoethyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-hydrochloride

A solution of 11.5 g of 1- (2-methoxyphenyl) -piperazine in 30 ml of methanol was added dropwise at 20-25 ^° C with stirring to a mixture containing 21.4 g of intermediate I1 and 4.1 g of potassium carbonate in 120 ml of methanol. After stirring at room temperature for 4 hours, the reaction mixture was distilled in vacuo. The residue is extracted with chloroform and the organic solution is washed with water, dried over anhydrous sodium sulfate / calcium chloride, filtered and distilled in vacuo, the crude compound obtained is dissolved in acetone and a slight excess of ethanol, saturated with ethanol, is added thereto. hydrogen chloride. After separation by vacuum filtration and

Recrystallization from 95% ethanol afforded 16.3 g of the title compound, m.p. (189) 195-199 ° C.

Example 2 8- {2- [4- (2-Methylphenyl) -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-methylphenyl) -piperazine instead of 1- (2-methoxyphenyl) piperazine and the reaction in dimethylformamide for 1 hour instead of methanol for 4 hours. Melting point: (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-methoxyphenyl) piperazine and the reaction in dimethylformamide for 2 hours instead of methanol for 4 hours. Melting point: 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 ethanol was added dropwise over 3 minutes at 0 in 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 distilled in vacuo and redissolved in 15 ml of methanol. Add 20 ml of 3.6N hydrogen chloride in diethyl ether at 0 ° C. After distillation in vacuo, the residue was suspended in 15 ml of 1,4 dioxane. With stirring at 20-25 ° C, a solution of 8.3 g of intermediate V in 100 ml of 1,4-dioxane was added. After 8 hours stirring under reflux, the reaction mixture was cooled

120 to 30-40 ° C. Add 50 ml of methanol and boil for 2 hours at reflux. After cooling to 20-25 ° C, the resulting solution was diluted with 300 ml of diethyl ether. Stirring was continued for 3 hours at the same temperature. Vacuum filtration removes the title compound and recrystallizes from ethanol. Yield: 4 g, m.p. 209-210 ° C.

Example 5 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propoxycarbonyl} -3methyl-4-oxo-2-phenyl-4H-1-benzopyran-dihydrochloride ** Mixture of 4.24 g 8-carboxy -3-methyl-4-oxo-2-phenyl-4H-1benzopyran and 6.3 g of anhydrous potassium carbonate in 60 ml of dimethylformamide were stirred for 30 minutes at 80 ° C. 5.23 g of 1- (3-chloropropyl) -4- (2-methoxyphenyl) -piperazine are then added and stirring is continued for ₃ h at 80 ° C for ₃ h. The reaction mixture was cooled to room temperature, poured into cold water and extracted with ethyl acetate. The organic extracts were washed with aqueous sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The residue is dissolved. - excess ethanol, saturated with chloro-hydrogen, is added to the ethanol and to the solution. Yield 8.16 g of the title compound, m.p. 198203 ° C.

Example 6 8- {2- [4- (2-Methoxyphenyl) -1-piperazinyl] -ethoxycarbonyl} -3methyl-4-oxo-2-phenyl-4H-1-benzopyran-dihydroorooride

Proceed 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, m.p. 200-203 ° C from ethanol.

121

Example 7

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

A mixture of 2.8 g of 1- (2-chlorophenyl) -piperazine hydrochloride and 4.2 g of anhydrous potassium carbonate in 25 ml of dimethylformamide was stirred for 15 minutes at room temperature. 4.81 g of intermediate I was added and stirring continued for 2 days. The reaction mixture was then poured into 200 ml of cold water and extracted with diethyl ether and ethyl acetate. The organic extracts were washed sequentially with aqueous sodium chloride 0.1N acetic acid, aqueous sodium chloride, 4% aqueous sodium carbonate and water and then dried over anhydrous sodium sulfate. After evaporation to dryness in vacuo, the residue was dissolved in 160 ml of acetonitrile and excess of diethyl ether saturated with hydrogen chloride. The insoluble title compound was crystallized from acetonitrile. Yield: 3.6 g, m.p. Mp 138-143 ° C.

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

The title compound was prepared by the method described in Example 7 but using 1-phenylpiperazine instead of 1- (2-chlorophenyl) piperazine hydrochloride. Recrystallization from methanol gave the compound, mp, 229-231 ° C.

Example 9 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propoxycarbonyl} -3methyl-4-oxo-2-phenyl-4H-1-benzopyran-dihydrochloride

Proceed as described in Example 7 but using

1- (2-methoxyphenyl) -piperazine hydrochloride instead of 1- (2-chlorophenyl) piperazine hydrochloride. the title compound is obtained. This is an alternative way of obtaining the substance of Example 5,

122

Example 10 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -2-methyl-2-propoxycarbonyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-dihydroXoride

5.29 g of intermediate XXVIII in 25 ml of 1,2-dichloroethane was added dropwise at 60 ° C to a solution of 6 g of 8-chlorocarbonyl-methyl-4-oxo-2-phenyl-4H-1-benzopyran in 22 ml of 1. 2-dichloroethane. The reaction mixture was refluxed for 16 hours. It was then cooled to room temperature and poured into cold 0.5N sodium hydroxide solution. Water and dichloromethane are added. The organic phase was separated, washed with aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvents were evaporated and the oily residue was purified by flash chromatography on silica gel and eluent petroleum ether: ethyl acetate 85:15. the combined fractions were evaporated to dryness in vacuo and the residue was dissolved in ethanol. Excess ethanol saturated with hydrogen chloride was added to obtain 6.71 g of the title compound, m.p. 203-204 ° C.

Example 11 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3methyl-4-oxo-2-phenyl-4H-1-benzopyran-dihydrochloride hemihydrate

A mixture of 6.28 g of 1- (2-methoxyphenyl) -piperazine and 5.34 Intermediate XXXVI] was heated at 180 ° C for 5 hours. After cooling, the dark mass was purified by flash chromatography on silica gel eluting with dichloromethane: methanol 100: 3. The resulting fractions containing the title compound were combined, the solvents were removed in vacuo and the residue was dissolved in boiling ethanol. The solution was filtered, acidified with ethanol, hydrogen chloride, and left at 20-25 &lt; 0 &gt; C overnight. The crude compound was separated by filtration and crystallized from ethanol. 5 g of the title compound are obtained; (177) 182-186 p.

123

EXAMPLE 12 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-dihydroorohydride hemihydrate

A solution of 4.48 g of 8-chlorocarbonyl-3-methyl-4-oxo-2-phenyl4H-1-benzopyran in 40 ml of chloroform was added dropwise over 10 minutes at room temperature to a solution of 3.74 g of 3- (4- (2methoxyphenyl) -1-piperazinyl] -propylamine prepared as described in GB 2161807, and 1.97 g of triethylamine in 50 ml of chloroform After stirring for 2 hours, the solution was washed first with 0.5N hydrochloric acid, then with a saturated aqueous solution of sodium bicarbonate and finally with water The chloroform solution was dried over anhydrous sodium sulfate and the solvent was evaporated in vacuo The residue was treated as described Example 11 to obtain 6.67 g of the title compound, mp (117) 182-186 ° C. This represents an alternative route for the preparation of Example 11.

The following salts are also obtained: monohydrochloride hydrate, m.p. 151-154 ° C, monomethanesulfonate, m.p. 162-164 ° C and (±) -polomalate hydrate, m.p. 110-112 ° C.

This example describes the condensation of amine 3- (4- (2methoxyphenyl) -1-piperazinyl] -propylamine with carbonyl chloride, 3methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carbonyl chloride. It should be noted that the amine may condense with the corresponding free acid or the corresponding ethyl ester, equimolar amounts of which are heated with or without solvent, if a solvent is used, a hydrophilic or hydrophobic solvent having a high boiling point is suitable. temperature with an equimolar amount of resp th free acid in the presence of Ν, Ν'-dicyclohexylcarbodiimide and 4124 dimethylaminopyridine in a solvent such as dichloromethane, chloroform, tetrahydrofuran or dimethylformamide.

Example 13 8- {2- [4- (2-Methoxyphenyl) -1-piperazinyl] ethylcarbamoyl} -3methyl-4-oxo-2-phenyl-4H-1-benzopyran-monohydrochloride hemihydrate

The compound was prepared by the method described in Example 16, but using intermediate XIV instead of intermediate XV and heated at 55-60 ° C for 32 hours. The treatment was changed as follows: After removal of the base by filtration, purification was carried out by flash chromatography on silica gel with eluant chloroform: methanol 100: 0.5 and then 100: 1. the fractions containing the title compound were combined and the solvents were removed in vacuo. The residue was crystallized from ethanol. After filtration, the solid is suspended in boiling water and a sufficient amount of dilute hydrochloric acid is added thereto until dissolved. Upon cooling, crystalline salt is separated, which is isolated by filtration. Melting point: 119-123 ° C Example 14

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

Proceed as described in Example 11, but using 2- (2-methoxyphenoxy) -ethylamine (prepared according to Augstein, J et al., ./. Med. Chem., 8, 356, 1965) instead of 1- (2-methoxyphenyl) ) -piperazine, heated for 2 hours instead of 5 hours and using dichloromethane: methanol 100: 5 as eluent. The title compound is obtained. Melting point: 200-202 ° C (ethanol). Example 15

8- [3- (4-Phenyl-1-piperazinyl) -propylcarbamoyl] -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-monohydrochloride hemihydrate

125

It was proceeded as described in Example 11 but using 1-phenylpiperazine instead of 1- (2-methoxyphenyl) -piperazine and heated for 2 hours instead of 5 hours. Dichloromethane: methanol 100: 4 was used as the eluent. the title compound is obtained. Mp (251) 255-258 ^with C with decomposition (87% ethanol).

Example 16 8- {N-methyl-2- [4- (2-methoxyphenyl) -1-piperazinyl] ethylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-monohydroorooride

A mixture of 3.56 g of intermediate XV, 2.35 g of 1- (2methoxyphenyl) -piperazine, 2.76 g of anhydrous potassium carbonate and 1.66 g of potassium iodide in 25 ml of dimethylformamide was stirred for 6 hours at 100 ° C. After cooling, the solvent was removed in vacuo and the residue suspended in 50 ml of water, stirred for another hour at room temperature, removed by filtration, washed with water and crystallized from 95% ethanol in the presence of a small amount of activated carbon ( for discoloration). The base was dissolved in 105 ml of boiling 0.086N hydrochloric acid. After cooling, the crystallized salt was filtered. 4.3 g of the title compound are obtained, m.p. 201-203 ° C.

Example 17 8- {1-hydroxy-2- [4- (2-methoxyphenyl) -1-piperazinyl] -ethyl] -3methyl-4-oxo-2-phenyl-4H-1-benzopyran-hydrochloride

1.36 g of sodium borohydride was added portionwise at 0 to 5 ° C to a solution of 15.5 g of the compound obtained in Example 1 in 1500 ml of methanol. After stirring at 0 to 5 ° C for 90 minutes, 3N hydrochloric acid was added to slightly acidify the reaction mixture, which was then distilled in vacuo. The residue was shaken with 2N aqueous sodium hydroxide solution and extracted with chloroform. The organic phase was dried over anhydrous sodium sulfate / calcium chloride, filtered, acidified with hydrogen chloride-saturated ethanol and distilled in vacuo. After washing with diethyl ether

126 ether gave the crude material which crystallized from ethanol to give 9.5 g of the title compound, m.p. 248249 ° 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 was prepared according to Example 17, but the starting compound used was obtained in Example 2 than Example 1. Melting point: 257-258 ° C (ethanol). Example 19 ^w 8- {1-hydroxy-2- [4- (2-ethoxyphenyl) -1-piperazinyl] -ethyl} -3methyl-4-oxo-2-phenyl-4H-1-benzopyran-hydrochloride

This compound was prepared according to Example 17, but the starting compound was used as obtained in Example 3 than Example 1. Melting point: 241-242 ° C (methanol). Example 20 8- {1-Hydroxy-3- [4- (2-methoxyphenyl) -1-piperazinyl] -propyl} -3methyl-4-oxo-2-phenyl-4H-1-benzopyran-hydrochloride

This compound was prepared according to Example 17, but the starting compound was used as obtained in Example 4 than Example 1. The crude base was purified by flash chromatography on silica gel with ethyl acetate: chloroform 4: 1 eluent. The fractions containing the pure base were combined, acidified with hydrogen chloride saturated ethanol and distilled in vacuo. The residue was crystallized from ethanol. Melting point: (126) 156-160 ° C.

Example 21 8- {1-Hydroxy-4- [4- (2-methyl-oxyphenyl) -1-piperazinyl] -butyl} -3methyl-4-oxo-2-phenyl-4H-1-benzopyran-hydrochloride monohydrate

A solution of 3.04 g of intermediate XXXVIII and 2.45 g of 1- (2methoxyphenyl) -piperazine in 21 ml of anhydrous dimethylformamide

127 was stirred for 5 hours at room temperature. They are additionally added

1.22 g of 1- (2-methoxyphenyl) -piperazine and the mixture was stirred for 4 hours, poured into 300 ml of water and extracted with ethyl acetate. The combined organic extracts were washed with aqueous sodium bicarbonate solution and then with aqueous sodium chloride solution and evaporated to dryness in vacuo. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate: methanol 95: 5. The combined fractions were distilled in a rotary evaporator and the residue was dissolved in 0.81M ethanol hydrochloric acid and re-distilled in vacuo. The solid residue was crystallized from water: ethanol 9: 1. 2.43 g of the title compound are obtained, m.p. 144-146 ° C.

EXAMPLE 22 8 {{1-Ethoxy-2- [4- (2-methoxyphenyl) -1-piperazinyl] -ethyl} -3methyl-4-oxo-2-phenyl-4H-1-benzopyran-hydrochloride Anhydrous dimethyl sulfoxide was added under nitrogen to 6.55 g of sodium hydride (50% in mineral oil, repeatedly washed with hexane). A solution of 3 g of the compound obtained in Example 17 in 50 ml of anhydrous dimethyl sulfoxide was added to the mixture at 20-25 ° C. After stirring at 20 ° C for 1 hour, 0.66 g of ethyl bromide was added. The reaction mixture was stirred for an additional 20 minutes at the same temperature and then poured into ice water. Vacuum filtration gave a crude compound which was purified by flash chromatography (silica gel, eluent chloroform: ethyl acetate 8: 2). The fractions containing the pure title compound were combined, acidified with ethanol, saturated with hydrogen chloride and distilled in vacuo. The residue was crystallized from chloroform: diethyl ether and dried in vacuo at 140 ° C. 1.6 g of the title compound are obtained, m.p. (155) 209 ° C.

128

Example 23 8- {X-Methyl-2- [4- (2-methoxyphenyl) -1-piperazinyl] -ethylaminomethyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-dihydro-AHOH hemihydrate

Mixture of 5.2 g of intermediate XXVII, 3.1 g of 1- (2methoxyphenyl) -piperazine and 2.2. g Anhydrous potassium carbonate in 50 ml of dimethylformamide was stirred for 7 hours at 70 ° C. After cooling to 2025 ° C, the reaction mixture was poured into 500 ml of water and extracted with dichloromethane. The organic phase was washed with water and dried over anhydrous sodium sulfate, the solvent was removed in vacuo. ^w The residue was purified by flash chromatography on silica gel using ethyl acetate: petroleum ether 98: 2 as eluent. The title compound is obtained by forming a salt with ethanol. Melting point: 217-219 ° C.

Example 24 8- {X-acetyl-2- [4- (2-methoxyphenyl) -1-piperazinyl] -ethylaminomethyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-hydrochloride

A mixture of 5 g of intermediate XXXIII and 5.3 g of 1- (2methoxyphenyl) -piperazine in 75 ml of dimethylformamide was stirred for 2 hours at 95 ° C. After cooling to 20-25 ° C, the reaction mixture was poured into 200 ml of water, basified with potassium carbonate and extracted with ethyl acetate. The organic phase was washed with water and dried over anhydrous sodium sulfate. The solvent was removed in vacuo. The residue was purified by flash chromatography on silica gel, eluting with dichloromethane: methanol 100: 0.2. The pure base forms a salt with ethanol hydrogen chloride, which is recrystallized from methanol. Obtain 4.4. g of the title compound, m.p. (200) 227-228 ° C containing one methanol equivalent.

129

Example 25

8- [4- (2-Methoxyphenyl) -1-piperazineAacetamidomethyl] -3-methyl4-oxo-2-phenyl-4H-1-benzopyran-hydrochloride

A mixture of 3.42 g of intermediate XXXII, 2.74 g of 1- (2methoxyphenyl) -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 was poured into water and filtered under vacuum. The resulting solid was purified by flash chromatography on silica gel using ethyl acetate-tetroleum ether 6: 4 as eluent. The combined fractions were evaporated in vacuo and the residue was crystallized from ethyl methyl ketone. The resulting base was treated with an ethanol solution with a molar equivalent of 2.25N hydrochloric acid. Melting point: 168-170 ° C.

Example 26 8- (X-Methyl-N- | 4- (2-methoxyphenyl) -1-piperazinyl] -ethylamidomethyl} -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 methoxyphenyl) -piperazine and 2 g of anhydrous potassium carbonate in 50 ml of dimethylformamide was stirred for 3 hours at 20-25 ° C. The reaction mixture was then poured into 500 ml of water and extracted with dichloromethane. The organic phase was washed with water and dried over anhydrous sodium sulfate. The solvent was removed in vacuo. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate: petroleum ether 6: 4 and crystallized from acetone. 3.6 g of the title compound are obtained, m.p. Mp 144-145 ° C. The base was dissolved in ethanol. 8N hydrochloric acid and water were added. The title compound is obtained, m.p. 218-220 ° C after drying at 100 ° C in vacuo.

130

Example 27

8- {2- [4- (2-Methoxyphenyl) -1-piperazinyl] -ethoxymethyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-dihydroorooride

A mixture of 4 g of intermediate XVIII, 2.4 g of 1- (2methoxyphenyl) -piperazine, 1.96 g of potassium iodide and 1.65 g of anhydrous potassium carbonate in 40 ml of anhydrous dimethylformamide was stirred for 7 hours at 90 ° C. After cooling to room temperature, the mixture was poured into water and extracted with dichloromethane. The combined extracts were washed with aqueous sodium chloride, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The residue was crystallized from ethyl acetate and the isolated crystals were dissolved in ethanol and treated with excess ethanol hydrogen chloride. 5.21 g of the title compound are obtained, mp 199-201 ° C.

Example 28 8- {2- [2- (2-Ethoxyphenoxy) -ethylamino] -ethoxymethyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-hydrochloride

They were proceeded as in Example 27 but using 2- (2-ethoxyphenoxy) -ethylamine instead of 1- (2-methoxyphenyl) -piperazine. Purify by flash chromatography on silica gel using ethyl acetate-methanol 97: 3 as eluent. 4.25 g of the title compound are obtained. Melting point: 191-193 ° C.

Example 29 8- {2- [4- (2-Methoxyphenyl) -1-piperazinyl] ethyl-thiomethyl} -3methyl-4-oxo-2-phenyl-4H-1-benzopyran-hydrochloride

2.5 g of potassium carbonate, 2.13 g of potassium iodide and 3.15 g 1- (2-methoxyphenyl) -piperazine was added to a solution of 5 g of Intermediate XXI in 50 ml of dimethylformamide and the mixture stirred 4 ^1> hours at 90 ° C. After cooling to room temperature, the reaction mixture was poured into 450 ml of water and extracted with ethyl acetate. The organic extracts are washed with water, dried

131 over anhydrous sodium sulfate and evaporated to dryness in vacuo. 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. 6.15 g of the title compound are obtained, m.p. (218) 223-224 ° C.

EXAMPLE 30 8- {2- [4- (2-Methoxyphenyl) -1-piperazinyl] -ethyl-AsuAfin-amphenyl} -3methyl-4-oxo-2-phenyl-4H-1-benzopyran-dihydroorohydride hemihydrate

The title compound was prepared by the method described in Example 29 using Intermediate XXVI instead of Intermediate XXI and preferably stirred for 2V ₂ hours instead of 4 ^ ₂ hours. After the usual treatment, the residue was purified by flash chromatography on silica gel with eluent ethyl acetate: methanol 97: 3. The combined fractions were acidified with excess ethanol, evaporated to dryness in vacuo. The residue was crystallized from ethanol. 5.2 g of the title compound are obtained, m.p. 170-172 ° C. This compound contains 1 equivalent of ethanol.

Example 31 8- {2- [4- (2-Methoxyphenyl) -1-piperazinyl] -ethylsulfonylmethyl} -3methyl-4-oxo-2-phenyl-4H-1-benzopyran-hydrochloride

A mixture of 4,5 g Intermediate XXV, 2.36 g 1- (2-methoxyphenyl) -piperazine and 0.84 g of potassium carbonate in 45 ml of anhydrous dimethylformamide was stirred at room temperature for 2 ¹ / _2h. The reaction mixture was poured into 300 ml of water and filtered under vacuum, washed with water. The solid base was crystallized from ethanol and m.p. Mp 143-146 ° C. The crystals were dissolved in 1,2-dichloroethane and the solution was acidified with ethanol. They are obtained

4.4 g of the title compound, m.p. 229-233 ° C after recrystallization from methanol: water 1: 3.5.

132

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 was 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 cooling bath was removed and a solution of 4.1 g of 1- (2-chloroethyl) -4 (2-methoxyphenyl) -piperazine in 10 ml of dimethylformamide was added at 20-25 ° C after 30 minutes. The mixture was stirred for 5 hours at 90 ° C and then cooled to 20-25 ° C. An additional amount of 0.25 g of sodium hydride (50% in mineral oil) was added, followed by 1.36 g of 1- (2-chloroethyl) -4- (2-methoxyphenyl) -piperazine in 5 ml of dimethylformamide. The mixture was stirred for 8 hours at 90 ° C and again cooled to 20-25 ° C. 200 ml of water were carefully added and the mixture was extracted with ethyl acetate. The organic phase was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo and the residue was purified by flash chromatography on silica gel with eluent 3: 2 hexane ethyl acetate. A mixture of the base of the title compound and the corresponding N-trifluoroacetyl compound is obtained,

3.8 g of this mixture were dissolved in 35 ml of ethanol and 35 ml of dimethyl sulfoxide. To this solution was added 0.55 g of sodium borohydride in portions at 20-25 ° C, the mixture was stirred for 3 hours at this temperature and then poured into 200 ml of water and extracted with ethyl acetate. The organic extracts were washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The residue was dissolved in dichloromethane. Add 2 equivalents of ethanol hydrogen chloride. The title compound was obtained which was recrystallized from ethanol. Yield: 3.8 g, m.p. 231-234 ⁰ p.

133

Example 33 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl]] -propylamino} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride 2.75 hydrate

The compound was prepared using 1- (3-chloropropyl) 4- (2-methoxyphenyl) -piperazine instead of 1- (2-chloroethyl) -4- (2-methoxyphenyl) -piperazine, but as described in Example 32. Melting point: 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 4.5 g of intermediate XXXIX, 3.9 g of 8-amino-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 was stirred for 6 hours at 20-25 ° C. Then 15 ml of 5% aqueous sodium bicarbonate solution are added and the mixture is stirred for 10 minutes. The mixture was then basified by the addition of 0.5N sodium hydroxide solution and extracted with dichloromethane. The organic extracts were washed with water and dried over anhydrous sodium sulfate, the solvent was evaporated in vacuo and the residue was purified by flash chromatography on silica gel eluting with ethyl acetate-petroleum ether 9: 1. The resulting base was dissolved in dichloromethane and 1 equivalent of ethanol hydrogen chloride was added thereto. After removal of the solvent in vacuo, the residue was crystallized from 50% ethanol to give 1.6 g of the title compound. Melting point: (140) 151-153 ° C.

Example 35 8- {X-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 obtained in Example 33 as its base, 4.35 ml of 37% aqueous formaldehyde and

134

1.15 g of sodium cyanoborohydride in 25 ml of acetonitrile was stirred at 20-25 ° C while maintaining the pH in the range 5-6 by adding acetic acid during the reaction. After 4 hours the solvent was evaporated in vacuo. To the residue was added 80 ml of ethyl acetate and 200 ml of ice-cold 1N sodium hydroxide solution. The organic phase was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The residue was purified by flash chromatography on silica gel, eluting with ethyl acetate: petroleum ether 3: 1. The resulting pure base was dissolved in diethyl ether. Add 1 equivalent of ethanol (HCl) and remove the solvent in vacuo. The residue was crystallized from water to give 2 g of the title compound, m.p. Mp 186-187 ° C.

EXAMPLE 36 8-A-Aetiethyl-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 obtained in Example 33 as its base, 2.8 ml of acetic anhydride and 33 ml of pyridine was stirred for 4 hours at 80 ° C. After cooling to 20-25 ° C, the reaction mixture was poured into 200 gAegena water, acidified with 10 N hydrochloric acid and extracted with dichloromethane. The organic extracts were washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The residue was purified by flash chromatography on silica gel, eluting with ethyl acetate: methanol 95: 5. The resulting pure base was dissolved in dichloromethane. Add 1 equivalent of ethanol hydrogen chloride and remove the solvent in vacuo. The residue was crystallized from acetonitrile. 3 g of the title compound are obtained, containing 0.33 equivalents of acetonitrile, m.p. 208.5-210.5 p.

135

Example 37

8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propionamido} -3-methyl4-oxo-2-phenyl-4H-1-benzoyl-hydroxyl

A mixture of 3.97 g of intermediate X and 3.07 g of 1- (2-methoxyphenyl) -piperazine in 40 ml of dimethylformamide was stirred for 6 hours at 60 ° C. The reaction mixture was 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 was removed in vacuo. The crude residue was crystallized from ethanol. The title compound was obtained, which was dissolved in hot ethanol. To the solution was added 1 molar equivalent of 0.81M ethanol. 4 g of the title compound are obtained, m.p. Mp 255-257 ° C.

Example 38 8- {2- [4- (2-Methoxyphenyl) -1-piperazinyl] ethyl-ureido} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-methanesulfonate

A mixture of 3.34 g of intermediate XLIV and 7.22 g of 1- (2methoxyphenyl) -piperazine was stirred for 5 hours at 100 ° C. An additional 1.8 g of 1- (2-methoxyphenyl) piperazine is then added and stirring is continued for 2 hours at 100 ° C. After cooling to room temperature, the reaction mixture was poured into water, extracted with ethyl acetate. The organic phase was washed with aqueous sodium hydroxide solution, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The crude residue was purified by flash chromatography on silica gel eluting with ethyl acetate: methanol 98: 2. The combined fractions were evaporated to dryness in vacuo and crystallized from water: ethanol 4: 6. The crystals were redissolved in dichloromethane and treated with 1 molar equivalent of methanesulfonic acid. Evaporation under vacuum gave crude methanesulfonate,

136 which was crystallized from ethyl acetate: ethanol 1: 1. they do

2.35 g of the title compound, m.p. 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 for 17 hours at 80 ° C. After cooling to 2025 ° C, the reaction mixture was poured into 600 ml of water, basified with 5% aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic extracts were washed with aqueous sodium chloride, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The residue was purified by flash chromatography on silica gel eluting with dichloromethane: methanol 99: 1, then 98: 2. the fractions containing the base of the title compound were combined and the solvent removed in vacuo. The residue was dissolved in ethanol and ethanol was added to it. The title compound was crystallized and separated by vacuum filtration. Recrystallized from 95% ethanol. Yield: 6.5 g, m.p. 224-225 ° C.

Elemental analysis:

H measured %: 0 = 66.38, H = 6.34, N = 5.35, 01 = 6.76, H ₂ O = 3.35 Calculated %: ('= 66.34, 11 = 6.14. N = 5.33, 01 = 6.75, 11.0 = 3.43 NMR spectrum at 60 Hz (CI) CI ₃ -CD ₃ OD) 7.8-7.1 (m, 8H, aromatic protons of the benzopyran ring) 7.1-6.6 (m, 4H, aromatic protons of 2-methoxyphenyl group) 4.8-4.4 (t, 2H, OCH ₂ ) 4.4-4.1 (t, 3H, 11.0 and N ⁺ H) 3.0-3. ιϊ (t, 10H, 5 x CH-, N)

137

3.8 (s, 3H, BCH ₃ )

2.1 (s, 3H, CH ₃ )

EXAMPLE 40 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propoxy} -3-methyl-4oxo-2-phenyl-4H-1-benzopyran-dihydro-AOrid

This compound was prepared by the method described in Example 39, but using intermediate IX instead of intermediate XI. Purification by flash chromatography is omitted as unnecessary in this case. Melting point: 226-227 ° C.

Example 41 8- {4- [4- (2-Methoxyphenyl) -1-piperazinyl] -butoxy} -3-methyl-4oxo-2-phenyl-4H-1-benzopyran-dihydrochloride

Mixture of 7.75 g of intermediate XVI, 4.7 g of 1- (2methoxyphenyl) -piperazine, 3.3. g of potassium iodide and 2.8 g of anhydrous potassium carbonate in 78 ml of dimethylformamide are stirred for 2 hours at 75 ° C. After cooling to 20-25 ° C, the reaction mixture was poured into 600 ml of water and extracted with dichloromethane. The organic extracts were washed with water, dried over anhydrous sodium sulfate and the solvent was evaporated in vacuo. The residue was purified by column chromatography on silica gel with eluting ethyl acetate. The pure title compound thus obtained is converted to the dihydrochloride by treatment with ethanol. Crystallization from ethanol gave 6.5 g of the title compound, m.p. 217-219 ° C

Example 42 8- {5- [4- (2-Methoxyphenyl) -1-piperazinyl] -pentylAxy} -3-methyl-4oxo-2-phenyl-4H-1-benzopyran-hydrochloride

This compound was prepared by the method described in Example 41, but using intermediate XVII instead of intermediate XVI. Melting point: 173 ° C (ethanol). The corresponding base is m.p. 117-118 ° C (ethanol).

138

Example 43

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

2.93 g of magnesium monoperoxyphthalate in 10 ml of water were added dropwise at -15 ° C to a solution of 4.34 g of the compound obtained in Example 40 and 0.1 g of benzyl (triethyl) ammonium chloride in 20 ml of dichloromethane and 20 ml of methanol . The mixture was stirred at 0 ° C for 2 hours and then warmed to room temperature. It is poured into water and basified by the addition of aqueous sodium hydroxide solution. Extraction with dichloromethane, after the usual treatment, yielded a solid which was purified by flash chromatography with dichloromethane: methanol 9: 1 eluent. The combined fractions containing the pure compound were evaporated to dryness in vacuo and the residue was crystallized from acetonitrile. 0.5 g of the title compound are obtained, m.p. 89-92 ° C.

Example 44

8- {2- (2- (2,6-dimethoxyphenoxy) -ethylamino] -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-dimethoxyphenoxyacetaldehyde (prepared according to Nelson, WL et al., 7 Med. Chem., 22 .. 1125, 1979) in 45 ml of benzene was stirred 18 hours at 20-25 ° C and refluxed for 5 hours. The solvent was evaporated in vacuo and the residue was dissolved in 80 ml of anhydrous methanol. A molecular sieve of 3 E. is added. 0.61 g of sodium borohydride at 0 ° C is then added. The mixture was left at 0 ° C for 1 hour and at 20-25 ° C for 1 hour, then poured into ice water and extracted with dichloromethane. The organic extracts were washed with water and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel eluting with dichloromethane: methanol

139

49: 1. The resulting base was treated with ethanol. Crystallization from ethanol gave the title compound. Yield: 40%; 200-202 ° C.

Example 45 8- {2-Hydroxy-3- [4- (2-methoxyphenyl) -1-piperazinyl] -propoxy} -3methyl-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 for 3 hours at 80 ° C. After cooling to 20-25 ° C, the reaction mixture was poured into 400 ml of water and extracted with dichloromethane. The aqueous phase was basified with 1N sodium hydroxide solution and extracted with ethyl acetate. The combined organic extracts were washed with water and dried over anhydrous sodium sulfate. The solvents were evaporated in vacuo. The residue was purified by flash chromatography on silica gel and ethyl acetate eluent, and the fractions containing the title compound as a base were combined and distilled in vacuo. The residue was dissolved in dichloromethane and 1 equivalent of ethanol was added to it. The solvents were removed in vacuo and the residue was crystallized from ethanol. 5 g of the title compound are obtained containing 1 molar equivalent of ethanol. Melting point: (122) 126-128 ° C on decomposition.

Example 46 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylthio} -3-lessA-4oxo-2-phenyl-4H-1-benzopyran

A solution of 4.4 g of intermediate XXXIV and 2.5 g of 1- (2-methoxyphenyl) -piperazine, 1g of potassium iodide and 1.8 g of anhydrous potassium carbonate in 40 ml of dimethylformamide was stirred for 3 hours at 1U0 ° C. After cooling to 20-25 ° C, the reaction mixture was poured into 350 ml of water and extracted with dichloromethane. The organic extracts are washed with water and dried over anhydrous sodium sulfate and after

140 the solvent was evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with ethyl acetate: petroleum ether 3: 2 and crystallization from ethanol. 3.9 g of the title compound are obtained, m.p. (70) 96-99 ° C.

Example 47 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylsulfonyl} -3methyl-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 dimethylformylamide was stirred for 7 hours at 60 ° C. After cooling to 20-25 ° C, the reaction mixture was poured into 500 ml of water and extracted with dichloromethane. The organic extracts were washed with water and dried over anhydrous sodium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate: petroleum ether 1: 1. The base of the title compound is obtained. It is dissolved in ethanol and 1 equivalent of ethanol is added to it. They are obtained

4.5 g of the title compound, m.p. (215) 226-228 ° C.

Example 48 8- {2- [4- (2-Methoxyphenyl) -1-piperazinyl] -ethylsulfamoyl} -3methyl-4-oxo-2-phenyl-4H-1-benzopyran-hydrochloride

A solution of 4.5 g of intermediate XLII and 3.8 g of 1- (2-methoxyphenyl) -piperazine in 40 ml of dimethylformamide was stirred for 7 hours at 70 ° C. After cooling to 20-25 ° C, the reaction mixture was poured into 150 ml of water and extracted with dichloromethane. The organic solution was washed with water and dried over anhydrous sodium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by flash chromatography on silica gel using ethyl acetate: petroleum ether 3: 7 as eluent and the title compound was obtained by forming a salt with ethanol hydrogen chloride. Yield 2.9 s, m.p. 236-238 (

141

EXAMPLE 49 8- {N-MemuA-2- [4- (2-Memokec (1) eHUA) -1-Nunephenyl] -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran- hydrochloride

The title compound was prepared by the method described in Example 48 using intermediate XLI instead of intermediate XLII. Melting point: 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 methanesulfonate hemihydrate

A mixture of 4.06 g of compound of Example 33 and 1.5 g of potassium cyanate in 42 ml of glacial acetic acid was stirred for 4 hours at 50 ° C. The reaction mixture was poured into ice water and basified. The precipitate was removed by vacuum filtration, dried, and purified by flash chromatography on silica gel using eluent ethyl acetate: methanol 98: 2, the fractions containing the title compound as a base were evaporated to dryness in vacuo and after dissolving in 30 ml of dichloromethane was added 1 equivalent of methanesulfonic acid, the solvent was evaporated in vacuo and _y residue was crystallized from ethanol. 3.1 g of the title compound are obtained, m.p. 157-160 ° C when decomposed, this compound contains 1 molar equivalents of ethanol.

Example 51 8- {4- [4- (2-Methoxyphenyl) -1-piperazinyl] -1-oxobupyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-methanesulfonate

A solution of 1.33 ml of anhydrous dimethyl sulfoxide in 9 ml of dichloromethane was added at -70 ° C to a solution of 0.74 ml of oxalyl chloride in 6 ml of dichloromethane. ('ice stirring for 15 minutes at -70 ° C was added a solution of 2.8 g of the compound of Example 21 (as a base) in 14 ml of dichloromethane. After 15 minutes, 4.7 ml of anhydrous was added at the same temperature.

142 triethylamine and the temperature rises to -30 ° C for 30 minutes. Stirring was continued at -30 ° C for another 30 minutes. After the temperature had risen to 0 ° C, the mixture was diluted with 120 ml of water and extracted with dichloromethane. The organic phase was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The residue was purified by flash column chromatography over silica gel and eluent ethyl acetate: dichloromethane 9: 1. The fractions containing the title compound as a base were evaporated to dryness in vacuo, the residue was dissolved in 30 ml of dichloromethane and 1 equivalent of methanesulfonic acid was added. The solvent was evaporated in vacuo and the residue was crystallized from ethanol. 2.9 g of the title compound are obtained, m.p. 194-195 ° C, Example 52

8- {3- (2- (1,4-Benzodioxanyl) -methylamino] -propylcarbamoyl 1-3methyl-4-oxo-2-phenyl-4H-1-benzopyran-methanesulfonate

Mixture of 5.56 g of intermediate XLIII as base, 4.58 g

2- (p-toluenesulfonyloxymethyl) -1,4-benzodioxane and 1.9 g of anhydrous potassium carbonate in 80 ml of anhydrous dimethylformamide were stirred for 5 hours at 110 ° C, the reaction mixture was cooled to room temperature, poured into water and extracted with dichloromethane . The organic phase was washed with water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness in vacuo. The residue was purified by flash chromatography using a silica gel column with eluant ethyl acetate: methanol 95: 5, the fractions containing the title compound as the base were evaporated to dryness in vacuo. The residue was dissolved in ethanol and 1 equivalent of methanesulfonic acid dissolved in ethyl acetate was added. The crystallized substance was filtered off and recrystallized from ethanol. 2.4 g of the title compound are obtained, m.p. 172-174

S.

143

Example 53

8- {4- [4_ (2-Methoxyphenyl) -1-piperazinyl] -butyl} -3-methyl-4-oxo-

2-Phenyl-4H-1-benzopyran-methanesafonate

A solution of 2.8 g of intermediate XLVI and 0.13 g of p-toluenesulfonic acid in 150 ml of methanol was refluxed for 5 hours. After cooling to 20-25 ° C, 0.8 g of anhydrous potassium carbonate is added and stirring is continued for another 3 hours. After filtration, the reaction mixture was evaporated to dryness in vacuo. 2.5 g of 8- (4,4-dimethoxybutyl) -3-methyl-4-oxo-2-phenyl4H-1-benzopyran are obtained.

NMR (CDCl ₃ , δ)

1.6-1.9 (4H, t, CHCH ₂ CH ₂ CH)

2.2 (3H, s, flavon CH ₃ )

2.9 (2H, t, F1- CH ₂₎

3.3. (6H, s, 2 x OCH ₃ )

4.4 (1Η, t, CH (O CH ₃ ) τ)

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

7.5-7.8 (6H, m, flavone CH in 7 and 5 x phenyl CH)

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

A solution of 2.5 g of the compound thus obtained in 10 mJ. water and 30 ml of acetic acid were heated at 50 ° C for 2% hours. The reaction mixture was cooled to room temperature, diluted with ice water, basified with aqueous sodium carbonate solution and extracted with chloroform. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to dryness in vacuo. The residue was purified by flash chromatography on silica gel with eluent petroleum ether: ethyl acetate 3: 1. They are obtained

2.1 g of 8- (4-oxobutyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (> 75% yield). It is used without further purification in the next step.

144

NMR (CDCl ₃ , δ) 1.9-2.1 (2H, dd, CH ₂ CH ₂ CH ₂ CH) 2.2 (3H, s, flavon CH ₃ ) 2.5 (2H, t, CH ₂ CHO) 2.9 (2H, t, FL-CH ₂ ) 7.3 (1H, dd, Flavon CH in 6) 7.5-7.7 (6H, t, flavone CH in 7 and 5 x phenyl CH) 8.1 (1H, dd, CH flavon in 5) 9.7 (lH, s, CHO)

2.3 ml of 6 N hydrochloric acid in ethanol, a solution of 2.1 g of the compound thus obtained in 40 ml of methanol and 0.45 g of sodium cyanoborohydride are added sequentially to a solution of 8 g

1- (2-Methoxyphenyl) -piperazine in 30 ml of methanol. The reaction mixture was stirred for 24 hours at room temperature, poured into 500 ml of ice water and extracted with dichloromethane. The organic phase was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The residue was purified by flash chromatography using a silica gel column and ethyl acetate eluent: 9: 1 petroleum ether, the fractions containing the title compound as a base were evaporated to dryness in vacuo. The residue was dissolved in 30 ml of dichloromethane and 1 equivalent of methanesulfonic acid was added to the solution. The solvent was evaporated in vacuo and the residue was crystallized from acetone. 2.35 g of the title compound are obtained, m.p. 141-143 ° C,

Example 54 8- [3- (4-Phenyl-1-piperidinA) -propylcarbamoyl] -3-phenyl-4-oxo-2-phenyl-4H-1-benzopyran-methanesulfonate

This compound was prepared by the method described in Example 11 using 4-phenylpiperidine instead of 1- (2-methoxyphenyl) piperazine and the reaction was carried out for 1 hour instead of 5 hours.

145

Purification was performed by flash chromatography using a silica gel column and eluent dichloromethane: methanol 100: 5. Melting point: 157-159 ° C (ethyl acetate). The corresponding base melts at (127) 147-149 ° C (ethanol).

Example 55 8- [3- (4,4-Diphenyl-1-piperidinA) -propylcarbamoyl] -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-methanesulfonate

This compound was prepared by the method described in Example 11 using 4,4-diphenylpiperidine instead of 1- (2-methoxyphenyl) piperazine and the reaction was carried out for 2 hours instead of 5 hours. Melting point: 221-223 ° C (ethyl acetate).

Example 56 8- {3- [4- (4-Fluorobenzoyl) -1-piperidinA] -propylcarbamoyl} -3methyl-4-oxo-2-phenyl-4H-1-benzopyran

This compound was prepared by the method described in Example 11 using 4- (4-fluorobenzoyl) -piperidine instead of 1- (2-methoxyphenyl) -piperazine and the reaction was carried out for 30 minutes instead of 5 hours. Purification was performed by flash chromatography using a silica gel column and eluent guxAopoMemaH: 5N methanolic ammonia in a ratio of 100: 1 to 100: 20. Melting point: 181-183 ° C (ethanol).

Example 57 8- {3- [4- (2-Oxo-1-benzimidazolinyl) -1-piperidinyl] propylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran

This compound was prepared by the method described in Example 11 using 4- (2-oxo-1-benzimidazolinyl) -piperidine instead of 1- (2-methoxyphenyl) -piperazine Purification was performed by flash chromatography using a column with silica gel and eluent chloroform: 5N methanol ammonia 100: 3. Melting point: 238-241 ° C (ethanol).

146

Example 58

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

This compound was prepared by the method described in Example 11 using 1- (2-pyrimidinyl) -piperazine instead of 1- (2-methoxyphenyl) -piperazine and the reaction was carried out for 2 hours. Purification was performed by flash chromatography using a silica gel column and eluent chloroform: methanol 100: 3. The desired fractions were dissolved in dichloromethane and 1 equivalent of methanesulfonic acid was added to the solution. After evaporation of the solvent in vacuo, the residue was boiled for 1 hour with ethyl acetate and then removed by filtration. Melting point: 209-210 ° C. The substance contains 0.2 equivalents of ethyl acetate and 0.1 equivalents of water. The corresponding base was melted at 178-180 ° C (ethanol).

Example 59

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

Proceed as described in Example 11 but using 1- (2-hydroxyphenyl) -piperazine instead of 1- (2methoxyphenyl) -piperazine, heat P / ₉ hours instead of 5 hours and use dichloromethane: methanol 100: 3 to 100: 10 as eluent for column chromatography to afford the title compound. Melting point: 118-120 ° C (ethanol 95%).

Example 60

8- {4- [4- (2-Methoxyphenyl) -1-piperazinyl] -butylcarbamoyl} -3methyl-4-ocean-2-phenyl-4H-1-benzopyran-methanesulfonate

This compound was prepared according to the procedure described in Example 12, but 4- [4- (2-methoxyphenyl) -1-piperazinyl] -by-tylamine was used instead of 3- [4- (2-methoxyphenyl) -1. -Piperinyl] -propylamine.

The reaction mixture was stirred at room temperature for 22 hours,

147 is diluted with water and filtered under vacuum, the insoluble solids are washed with water. The crude residue was dried and purified by column chromatography on silica gel with eluant ethyl acetate: methanol 9: 1. The fractions containing the pure substance as the base were collected, evaporated to dryness in vacuo and dissolved in dichloromethane. Methanesulfonic acid was added to the solution and the salt was precipitated by the addition of 2 volumes of ethyl acetate. filtered and recrystallized from ethanol. The title compound is obtained, m.p. Mp 230-232 ° C. This substance contains 0.3 molar equivalents of ethanol.

Example 61 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propionazufamoyl} -3methyl-4-oxo-2-phenyl-4H-1-benzopyran-methanesulfonate

This compound was prepared as described in Example 12, but using intermediate VIII instead of 8chlorocarbonyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran and stirred for 24 hours instead of 2% hours. The crude compound was purified by column chromatography on silica gel, eluting with ethyl acetate: methanol 98.5: 1.5. The combined fractions containing the pure substance as a base were evaporated to dryness in vacuo and dissolved in dichloromethane. Methanesulfonic acid was added to the solution and the solvent was removed by evaporation in vacuo. The crude salt was crystallized from ethanol to give the title compound, m.p. (196) 198-200 ° C.

Example 62 8- {3- [N-Methyl-2- (2-methoxyphenoxy) -ethylamio] -propylcarbamoyl} -3-mexa-4-oxo-2-phenyl-4H-1-benzopyran-hydrochloride

A solution of 10.5 ml of 40% formaldehyde in water was added to a suspension of 6.66 g of the compound obtained in Example 14 in 55 ml of acetonitrile and 20 ml of water. After stirring for 15 minutes at room

To the red solution was added 2.70 g of 95% sodium cyanoborohydride and after stirring for 15 minutes under the same conditions, 1.38 ml of acetic acid were added. After stirring for 3 hours, the solvents were removed in vacuo and the residue was washed with 250 ml water and 250 ml chloroform. After addition of 3N sodium hydroxide, the organic phase was separated and the aqueous phase extracted 2 times with chloroform. The solvent was removed from the combined organic phases by evaporation in vacuo and the residue was purified by flash chromatography on silica gel with eluent chloroform: 5.2N methanolic ammonia 100: 0.5 to 100: 2. The combined fractions containing the pure title compound as a base were evaporated to dryness in vacuo and the residue was dissolved in hot ethanol. The solution was acidified with ethanol hydrogen chloride and after evaporation of the solvent in vacuo, the residue was washed with diethyl ether and stirred at room temperature. The crude material was separated by filtration and crystallized from acetonitrile. 3.1 g of the title compound are obtained. Melting point: 146-148 ° C.

Example 63 8- {X-methyl-3- [4- (2-methoxyphenyl) -1-piperazinyl] propionamido} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyranmethanesulfonate

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 yields the title compound as a base. Purification by column chromatography on silica gel eluting with ethyl acetate: methanol 95: 5 afforded the crude methanesulfonate as described in Example 61 and crystallized from acetone. The title compound is obtained, m.p. 200-202 ° C.

149

Example 64 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3-phenyl-4-oxo-4H-1-benzoyl-dimethane

This compound was prepared as described in Example 12, but using Intermediate LVI instead 8hlorokarbonil-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran and stirring for 24 hours instead of 2 ¹ ^ h. The crude compound was purified by column chromatography eluting with ethyl acetate: methanol 92: 8. The combined fractions containing the pure substance as a base were evaporated to dryness in vacuo and dissolved in dichloromethane. To the solution were added 2 equivalents of methanesulfonic acid. The crude dimethanesulfonate obtained by evaporation of the solvent was crystallized from acetone, m.p. (200) 153-156 ° C. Example 65 8- {3 - [(3,4-Dihydro-1-oxo-2H-naphthyl) -methylamino] -propylcarbam (III) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran- methanesulfonate

A mixture of 6 g of intermediate XLIII, 2.4 g of 2-methylene-tetralone (prepared as described in Org. Synth., 60, 88, 1981) and

3.14 ml of triethylamine in 48 ml of anhydrous dimethylformamide was stirred for 6 hours at room temperature and then for 1 hour at 50 ° C. The reaction mixture was diluted with water and extracted with dichloromethane. The organic phases are washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The crude residue was purified twice by column chromatography, first with eluent dichloromethane: methanol 95: 5 and then with eluent dichloromethane: methanol: 5.8X methanolic ammonia 98: 2: 0.2, 1.74 g of the title compound was obtained as a base. The base was converted to methanesulfonate according to the procedure described in Example 61. The salt was recrystallized from acetone and then from acetonitrile. The title compound is obtained, m.p. (60) 157-159 p.

150

Example 66

8- {2- | 4- (2-methoxyphenyl) -1-piperazinyl-epoxycarbonylmethyl} -

3-Methyl-4-oxo-2-phenyl-4H-1-benzopyran-dihydro-aoride

The title compound was prepared by the method described in Example 5, but using intermediate XLVII instead of 8-carboxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran and 1- (2-chloroethyl) - 4- (2-methoxyphenyl) -piperazine instead of 1- (3-chloropropyl) -4- (2-methoxyphenyl) -piperazine. Melting point: 193-196 ° C from ethanol: diethyl ether.

Example 67 8- {4- [4- (2-Methoxyphenyl) -1-piperazinyl] -butylsulfamoyl} -3methyl-4-oxo-2-phenyl-4H-1-benzopyran-dimethane-affonate

The title compound was prepared by the method described in Example 61, but as piper azinyl] -butylamine piper azinyl] -propylamine.

is used instead of Raw

4- [4- (2-Methoxy phenyl) -1-

3- [4- (2-Methyl phenyl) -1 dimethanesulfonate was first crystallized from acetonitrile and then from ethanol.

Melting point: 172-174 ° C.

Example 68 8- {X- (2-Tetrahydropyranoxoxy) -3- [4- (2-methoxyphenyl) -1piperazinyl] -propylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-1benzopyran-methanesulfonate hemihydrate

A solution of 3.6 g of 1- (3-chloropropyl) -4- (2-methoxyphenyl) piperazine in 30 ml of anhydrous dimethylformamide was added dropwise at 0 ° C to a mixture of 3.92 g of O- (2-tetrahydropyranyl) -hydroxylamine ( obtained as described in

R. N. Watrener at al., Angewandte Chem. Ini. 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 cooled to room temperature and

151 Dimethylformamide is removed by vacuum distillation. The residue was washed with water and extracted with ethyl acetate. The combined organic phases are washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo to give 4.39 g of 1- [3- (2-tetrahydropyranyloxy amino) -propyl] -

4- (2-Methoxyphenyl) -piper azine.

¹ H-NMR (CDCl ₃ , δ)

6.50-6.75 (t, 4H,

5.20 (bs, 1H,

4.60 (m, 1H, (m, 4H, aromatic protons) (bs, 1H, NH) (m, 1H, O-CH-O)

3.30- 4.00 (t, 5H, OCH ₃ and tetrahydropyran CH ₉ O)

2.80-3.20 (t, 6H, piperazine 2 x CH ₂ , alkyl chain CH ₂ N)

2.20-2.80 (m, 6H, piperazine 2 x CH ₉ , alkyl chain CH ₉ N)

1.30-2.00 (t, 8H, tetrahydropyran 3 x CH _? , alkyl chain

A solution of 2.79 g of 8-chlorocarbonyl-3-methyl-4-oxo-2-phenyl4H-1-benzopyran in 47 ml of chloroform was added dropwise at room temperature to a mixture of 3.26 g of the compound thus obtained and 1.42 g of potassium carbonate in 47 ml of chloroform. The reaction mixture was stirred for 3 hours and diluted with 75 ml of chloroform and washed three times with 1M sodium hydroxide. The organic phase was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The crude residue was purified by column chromatography on silica gel with eluant ethyl acetate: methanol 98: 2. The combined fractions were evaporated to dryness under wax. 2.99 g of pure title compound are obtained as a base. The base was dissolved in dichloromethane and methanesulfonic acid was added to the solution. The solvent was removed by evaporation in vacuo and the crude salt was crystallized from ethyl acetate. The title compound is obtained, m.p. Mp 159-160 ° C.

152

Example 69 8- {4- [4- (2-Methoxyphenyl) -1-operazinyl] -butyramido} -3-methyl-4oxo-2-phenyl-4H-1-benzopyran-methanesulfonate hemihydrate

The title compound was prepared according to the method described in Example 38, but using intermediate XLVIII instead of intermediate XLIV and stirred for 1 hour at 70 ° C and 2 hours at 130 ° C instead of 7 hours at 100 ° C. After the usual treatment, the crude residue was purified by column chromatography on silica gel using ethyl acetate: methanol 95: 5 as eluent. The fractions containing the pure title compound as a base were combined and evaporated to dryness in vacuo. The residue was dissolved in dichloromethane and 1 equivalent of methanesulfonic acid was added to the solution. After evaporation of the solvent to dryness in vacuo, the crude salt was crystallized from acetone, m.p. 175176 С.

Example 70 E-8- {2- [4- (2-Methoxyphenyl) -1-piperazinyl] -ethoxyiminomethyl} -

3-methyl-4-ocean-2-phenyl-4H-1-benzopyran

A solution of 5.4 g of 8-formyl-3-methyl-4-oxo-2-phenyl-4H-1benzopyran and 5.13 g of intermediate LII in 10 ml of chloroform containing the molecular sieve 3A was stirred at reflux for 6 hours. The molecular sieve was removed by filtration and the solution was evaporated to dryness in vacuo. The crude material was purified by column chromatography on silica gel with eluant ethyl acetate: petroleum ether 7: 3. Two groups of fractions were combined and evaporated to dryness in vacuo. The first eluted group of fractions (less polar) contains the almost pure title compound; the second group (more polar) is a 1: 1 mixture of E and Z diastereomers as determined by NMR.

1 H-NMR (CDCl 3, δ)

8.75 (del. 0.5Η, benzopyran CH at 7, δ)

153

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

8.30 (dd, 1H, benzopyran CH at 5, E + Z)

8.15 (dd, 0.5H, benzopyran CH at 7, E) 8.00 (s, 0.5H, imine CH, Z)

7.60-7.75 (m, 2H, phenyl CH at 2 'in 6', E + Z)

7.50-7.60 (m, 3H, phenyl CH at 3 ', 4' and 5 ', E + Z)

7.45 (dd, 0.5H, benzopyran CH at 6, Z)

7.41 (dd, 0.5H, benzopyran CH at 6, E)

6.70-7.10 (m, 4H, phenyl protons, E + Z)

4.41 (t, 2H, CH ₂ O, E + Z)

3.86 (s, 3H, CH ₃ O, E + Z)

3.05-3.20 (m, 4H, piperazine 2 x CH ₂ , E + Z)

2.70- 2.90 (t, 6H, piperazine 2 x CH _{? In} CH ₂ N, E + Z)

2.20 (s, 1.5H, benzopyran CH ₃ in 3, Z)

2.18 (s, 1.5H, benzopyran CH ₃ in 3, E)

Diastereomer E was crystallized from ethanol: water 2: 1 and 2.5 g of pure title compound were obtained, m.p. Mp 107-109 ° C.

Example 71 8- {51-Hydroxy-3- [4- (2-methoxyphenyl) -1-piperazinyl] propylcarbamoyl} -3-methyl-4-ox () - 2-phenyl-4H-1-benzopyranethanesulfonate 0.25 H ₂ O

A solution of 2.04 g of the compound of Example 68 as a base in 104 ml of 1.6N ethanol was stirred for 12 hours at room temperature. The ethanol was removed by evaporation in vacuo and the residue was washed with 1N sodium hydroxide and dichloromethane. The organic phase was separated, washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. To the solution of the residue in dichloromethane was added 1 molar equivalent of methanesulfonic acid. The solvent was removed and the crude methanesulfonate was crystallized from acetone to give

154 is 1.02 g of the title compound, m.m. 211-213 ° C. The substance contains 0.25 moles of water.

Example 72 E-8- <2- {2- [4- (2-megpoxyphenyl) -1-piperazinyl] -ethylacarbamoyl} ethenyl> -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-methanesulfonate

1.2 H ₂ O

The title compound was prepared by the method described in Example 61, but using intermediate IV instead of intermediate VIII and 2- [4- (2-methoxyphenyl) -1-piperazinyl] ethylamine instead of the corresponding propylamine in 1,1,2,2tetrachloroethylene as solvent. Finally, the reaction mixture was diluted with water and chloroform and washed with 1N aqueous sodium hydroxide solution, then with water. After drying over anhydrous sodium sulfate, methanesulfonic acid was added to the organic phase and the solvents were evaporated in vacuo. The crude material was crystallized 2 times from isopropanol. The title compound was obtained containing 1.2 molar equivalents of water, m.p. 124-127 ° C.

Example 73 8- {4- [4- (2-Methoxyphenyl) -1-piperazinyl] -butylAsulfinyl} -3methyl-4-oxo-2-phenyl-4H-1-benzopyran-methanesulfonate

The title compound was prepared according to Example 38, but using intermediate LIV instead of intermediate XLIV, with stirring for 3 hours at 70 ° C and another 3 hours at 90 ° C after the addition of a catalytic amount (0.01 equivalents) of potassium iodide. Purification by column chromatography on silica gel with 9: 1 ethyl acetate-methanol eluent afforded the title compound as the base. To the crude base dissolved in dichloromethane was added 1 molar equivalent of methanesulfonic acid. After removal of solvent

155 By evaporation of the nog vacuum, the resulting salt was recrystallized from acetone to give the title compound, m.p. 183-184 ° C.

EXAMPLE 74 8- {3- [3- (2-Methoxyphenoxy) -propylamino] -propylcarbamoyl} -3methyl-4-oxo-2-phenyl-4H-1-benzopyran-methanesAuhydrate Aphonate

The title compound was prepared by the method described in Example 76 but using 3- (2-methoxyphenoxy) -propyl chloride (prepared as described in B. Willhalm, Tetrahedron, 20, 1185, 1964) instead of 2- (2,6- dimethoxyphenoxy) -ethyl bromide. The extraction residue with dichloromethane was purified by column chromatography on silica gel eluting with dichloromethane: methanol: 5X methanol ammonia 9: 1: 0.3; the pure base was converted to methanesulfonate, which was crystallized 2 times from ethyl acetate: acetonitrile 9: 1 to give the title compound, m.p. (60) 87-90 ° C.

Example 75 8- {3- [2- (2-Methoxyphenoxy) -ethylamino] -propylcarbamoyl} -3methyl-4-oxo-2-phenyl-4H-1-benzopyran-methanesulfonate

1.85 g of 95% sodium borohydride are added to a solution of 7 g of intermediate LIX in 70 ml of methanol with stirring and 0 ° C. After stirring at the same temperature for 1 hour, the solvent was removed by evaporation in vacuo. The residue was diluted with water and 2N hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo to give 6.6 g of pure 2- (2-methylthiophenoxy) ethanol as an oil. 8.57 g of p-toluenesulfonyl chloride are added portionwise to a solution of the compound thus obtained in 35 ml of pyridine, with stirring and 0 ⁰ C. After 14 hours stirring, at room temperature, the reaction mixture is poured into cold 2N hydrochloric acid and extracted with

156 dichloromethane. The organic phase was washed twice with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. 7.8 g of a 3: 1 mixture of 2- (2-methylthiophenoxy) -ethyl-toluenesulfonate and 2- (2-methylthiophenoxy) -ethyl chloride (analyzed by NMR) were obtained as a low-melting solid, which was used without further purification.

A homogeneous mixture of 3.3 g of the above mixture and 8 g of intermediate XLIII was held for 20 minutes in an oil bath at 140 ° C. The molten mass was then cooled to room temperature and solidified. The solid residue was washed with dichloromethane and 4N sodium hydroxide. The organic phase was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo.

The crude material was purified by column chromatography on silica gel eluting with dichloromethane: methanol 9: 1. 2.7 g of the title compound are obtained as a base. It is converted in the usual way to crude methanesulfonate, which is first crystallized from acetone and then from acetonitrile. Melting point: 143-146 ° C.

Example 76 8- {3- [2- (2,6-dimethoxyphenoxy) -ethylamino] -propionecarbamoyl} -3methyl-4-oxo-2-phenyl-4H-1-benzopyran-hydrochloride

A homogeneous mixture of 3.3, g 2- (2,6-dimethoxyphenoxy) ethyl bromide (prepared as described in J. Augstein et al., J. Med. Chem., 8, 356, 1965) and 8.4 g of intermediate XLIII was heated 10 minutes in an oil bath at 150 ° C. The molten mass was cooled to room temperature and solidified. The solid residue was washed with ethyl acetate and 2N sodium hydroxide. The organic phase was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The oily residue was purified 2 times by column chromatography on silica gel eluting with ethyl acetate: methanol: 51M methanol ammonia 97: 3: 0.3 and then with

157 dichloromethane: methanol: triethylamine 90: 10: 0.3. obtained 3.3. g pure title compound as base. The crude hydrochloride obtained by the conventional method was crystallized from acetone and then from acetonitrile. Melting point: 179-181 ° C.

Example 77 8- {3- [4- (5-HAOro-2-methoxyphenyl) -1-piperazinyl] propylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran

This compound was prepared by the method described in Example 11, but using 1- (5-chloro-2-methoxyphenyl) -piperazine instead of 1 (2-mpaoxyphenyl) -piperazine and the reaction was carried out for 6 hours instead of 5 hours. Purification is carried out by flash chromatography on silica gel with eluent ΧΛοροφορΜ: 5Ν methanolic ammonia 100: 1. The title compound was melted at 163-166 ° C after crystallization from 95% ethanol.

Example 78 (E) -8- {4- [4- (2-methoxyphenyl) -1-piperazinyl] -1-butenyl} -3-methyl-

4-oxo-2-phenyl-4H-1-benzopyran

33.4 ml of a one-molar solution of lithium bis (trimethylsilyl) amide in anhydrous tetrahydrofuran are added dropwise over a period of 15 minutes to a suspension of 6.4 g of 3hydroxypropyltriphenylphosphonium bromide in 60 ml of anhydrous tetrahydrofuran, cooled to -15 ° C. of 4 g of 8-formyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran in 40 ml of tetrahydrofuran. The reaction mixture was stirred for 30 minutes at 0 ° C, then P / ₉ hours at room temperature.

Termination of the reaction with methanol and evaporation to dryness in vacuo gave a residue which was purified by column chromatography on silica gel using ethyl acetate: petroleum ether 6: 4 as eluent. The combined fractions were evaporated in vacuo. 4.17 g of 8- (4-hydroxy-1-butenyl) -3-methyl-4-oxo-2 is obtained

158 phenyl-4H-1-benzopyran as an E-Z-diastereomeric mixture with a ratio of 3.5: 1 as determined by NMR.

1 H-NMR, 200 MHz (CDCl ₃ , δ)

8.10-8.20 (d, 1H, benzopyran CH in 5, E + 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-CH ₂ , E) 5.90 (dt, 0.22H, CH-CH ₂ , E) 3.60-3.80 (m, 2H, CH ₂ O, E + Z) 2.45-2.60 (m, 2H, CH-CH ₂ , E + Z) 2.18 (s, 3H, benzopyran CH ₃ in 3, E + Z) 1.60-1.90 (sa, 1H, OH, E + Z)

1.65 g of p-toluenesulfonyl chloride was added to a solution of 2.2 g of the above mixture in 24 ml of anhydrous pyridine, with stirring and 0 ° C. Stirring was continued for 48 hours at the same temperature. The reaction mixture was then poured into cold 1N hydrochloric acid and filtered under vacuum. The resinous solid was washed with water and washed with dichloromethane. The solution was dried over anhydrous sodium sulfate and evaporated in vacuo to dryness. 2.30 g of (E, 2) -4- {8- [3-methyl-4-oxo-2-phenyl-4H-1-benzopyranyl]} - 3-butenyl-p-toluenesulfonate are obtained with the same diastereoisomeric composition as the above intermediate .

A solution of 2.85 g of the p-toluenesulfonic acid ester above and 2.98 g of 1- (2-methoxyphenyl) -piperazine in anhydrous dimethylformamide was stirred for 48 hours at room temperature. The mixture was then poured into 250 ml of water and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous sodium sulfate and evaporated in vacuo to dryness. A residue was obtained which was purified by column chromatography on silica gel using ethyl acetate as eluant: petroleum

159 ethers 6: 4. The separated fractions were evaporated in vacuo to dryness and the crude product was crystallized from 70% ethanol. 1.48 g of the title compound are obtained, m.p. 119-121 ° C ¹ 1I-NMR, 200MHz (CDC1 _3, δ)

8.14 (dd, 1Η, benzopyran CH in 5)

7.85 (dd, 1H, benzopyran CH at 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, J = 16.5 Hz, CH-CH ₂ )

3.86 (s, 3H, CH ₃ O)

3.00-3.15 (m, 4H, 2 piperazine CH ₂ )

2.50-2.80 (m, 8H, 2 piperazine CH ₂ , CHCH ₂ CH ₂ N)

Example 79 (E) -8- <2- {2- [4- (2-methoxyphenyl) -1-piperazinyl] ethoxycarbonyl} -ethenyl> -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-methanesulfonate

The title compound was prepared according to Example 6 but using intermediate III instead of 8-carboxy-3-methyl-4oxo-2-phenyl-4H-1-benzopyran. After the usual treatment, the residue was crystallized 2 times from ethanol; the resulting solid was purified by column chromatography on silica gel with eluent chloroform: ethyl acetate 8: 2. A pure base was obtained which was dissolved in chloroform: ethanol 1: 1. Methanesulfonic acid was added to the solution and the solvents were removed by evaporation in vacuo. The crude salt was crystallized from isopropanol to give the title compound, m.p. Mp 193-195 ° C. this compound contains 0.33 equivalents of isopropanol and 0.25 equivalents of water.

160

Example 80 8- {2- [4 (2-Methoxyphenyl) -1-piperazinyl] -ethylacarbamoylAmethyl} -

4-Oxo-2-phenyl-4H-1-benzopyran-methanesulfonate hydrate

A mixture of 2.8 g of intermediate XLVII and 1.28 g of 1-hydroxybenzotriazole in 20 ml of anhydrous dimethylformamide was stirred for 15 minutes at 0-5 ° C. To the mixture was added dropwise a solution of

1.96 g of dicyclohexylcarbodiimide in 20 ml of anhydrous dimethylformamide for 40 minutes. After 8 hours of stirring at room temperature, a solution of 2.24 g of 1- (2aminoethyl) -4- (2-methoxyphenyl) -piperazine in 15 ml of anhydrous dimethylformamide was added. After stirring for 8 hours and staying overnight at the same temperature, the insoluble material was filtered off and the filtrate was poured into about 300 ml of water and basified by the addition of 1N sodium hydroxide. The mixture was extracted with dichloromethane and the organic phase separated, dried over anhydrous sodium sulfate and evaporated in vacuo. The crude material was purified by flash chromatography on silica gel with eluant chloroform: methanol 95: 5. To a solution of the crude base in ethanol is added 1 molar equivalent of methanesulfonic _acid; Diethyl ether was added until the salt crystallized. The salt was then filtered and recrystallized from ethanol: diethyl ether 1: 2. 1.15 g of the title compound are obtained, m.p. Mp 160-162 ° C.

Example 81 8- {N-acetyl-3- [4- (2-methoxyphenyl) -1-piperazinyl] propylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran

A solution of 2.86 g of LVII intermediate, 5.04 g of 1- (3-chloropropyl-4- (2-methoxyphenyl) -piperazine and 2.58 g of anhydrous potassium carbonate in 50 ml of dimethylformamide was stirred for 7 hours at 90 C. After cooling to room temperature, the reaction mixture was stirred. is poured into 500 ml of water and extracted with dichloromethane The organic phase is washed with water, dried over anhydrous sodium sulfate and evaporated

161 go dry foot vacuum. The residue was purified by column chromatography on silica gel using eluant ethyl acetate: petroleum ether 7: 3. 1.89 g of the title compound are obtained, m.p. (55) 62-63 ° C.

Example 82 8- {2- [4- (2-Methoxyphenyl) -1-piperazinyl] -ethylAsulfonylamino} -3methyl-4-oxo-2-phenyl-4H-1-benzopyran-methanesulfonate

1.05 ml of 2-chloroethanesulfonyl chloride was added dropwise to a solution of 5 g of 8-amino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran and

1.4 ml of triethylamine with stirring and 0 ° C. The reaction mixture was stirred for two days at room temperature. After filtration of the precipitated solids, the solution was evaporated to dryness in vacuo. A crude residue was obtained containing 8 (ethenylsulfonylamino) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, which was used without further purification. A mixture of 7.54 g of this residue and 5.8 g of 1- (2-methoxyphenyl) -piperazine and 4.15 g of potassium carbonate in 100 ml of dimethylformamide was stirred for 4 hours at room temperature, poured into 600 ml of water and extracted with ethyl acetate. The organic phase was evaporated to dryness in vacuo and the residue was purified by column chromatography on silica gel with eluent petroleum ether: acetone 8: 2. The combined fractions were evaporated to dryness in vacuo and crystallized from 70% ethanol. 0.75 g of the title compound is obtained as a base. This solid was dissolved in dichloromethane and 1 equivalent of methanesulfonic acid was added to the solution. The crude methanesulfonate obtained by evaporation in vacuo was crystallized from acetone. 0.6 g of the title compound are obtained, m.p. 202-203 ° C.

Example 83

8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propionylcarbamoyl} 3-methyl-4-ocean-2-phenyl-4H-1-benzopyran-methanesulfonate

162

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-methoxyphenyl) -piperazine and 0.14 g of sulfur in 5 ml pyridine, refluxed for 6 hours with stirring. After evaporation of the solvent in vacuo, the residue was purified by flash chromatography on silica gel eluting with chloroform. The resulting title compound was dissolved as a base in dichloromethane and 1 equivalent of methanesulfonic acid was added to the solution. Evaporation under vacuum and crystallization of the acetonitrile residue afforded the title compound. Yield: 0.7 g, m.p. Mp 189-190 ° C.

Example 84 8- {4- [4- (2-Methoxyphenyl) -1-piperazinyl] -butylAphonyl} -3methyl-4-oxo-2-phenyl-4H-1-benzopyran-methanesulfonate. 1 / d H ₂ O

The title compound was prepared according to Example 73, but using intermediate LX instead of intermediate L1V. Purification is carried out by column chromatography on silica gel with eluant ethyl acetate: petroleum ether 7: 3. To the crude base solution in dichloromethane was added 1 molar equivalent of methanesulfonic acid. After removal of the solvent by evaporation in vacuo, the resulting salt was crystallized from acetone to give the title compound, mp 212-214 ° C.

Example 85 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3-hydroxymethyl-4-oxo-2-phenyl-4H-1-benzopyran. 0.4 ethanol

A mixture of 3.6 g of XCV intermediate and 1.65 g of 1 hydroxybenzotriazole in 35 ml of anhydrous dimethylformamide was stirred for 15 minutes at 0-5 ° C. A solution of 2.5 g of dicyclohexylcarbodiimide in 35 ml of anhydrous dimethylformamide was added dropwise. After stirring for 1 hour at the same temperature, a solution of 1- ('3-aminopropyl) -4- (2-methoxyphenyl) -piperazine was added. After 2 hours

After stirring at the same temperature and staying overnight at room temperature, the reaction mixture was evaporated to dryness in vacuo. The residue was purified by flash chromatography on silica gel eluting with dichloromethane: methanol 100: 3 and then crystallized from ethanol. 2.5 g of the title compound are obtained, m.p. Mp 152-154 ° C.

Example 86 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -4-oxo-2-phenyl-4H-1-benzopyran-methanesulfonate. V4 H ₂ O 2 * 3.6 ml of diethyl cyanophosphonate are added dropwise at 0-5 ⁰

C and stirring to a solution of 4 g of 8-carboxy-4-oxo-2-phenyl-4H1-benzopyran (prepared as described in Da Re et al., Veg., 99, 1962, 1966) and 3.75 g of 1- (3 -aminopropyl) -4- (2-methoxyphenyl) -piperazine in 35 ml of anhydrous dimethylformamide. 2.5 ml of triethylamine are then added dropwise at the same temperature. After 30 minutes of stirring at 0-5 ° C and 1 hour at room temperature, the reaction mixture was poured into 350 ml of 2.5% aqueous sodium carbonate. The resulting precipitate was stirred for 1 hour at room temperature, separated by vacuum filtration and crystallized from ethanol. The base compound thus obtained is dissolved in dichloromethane and one equivalent of methanesulfonic acid is added to the solution. Evaporation in vacuo gave a glassy substance which was crushed and boiled for 1 hour in acetone under reflux. 5 g of the title compound are obtained, m.p. 191-194 ° C.

Example 87 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} 2,3-dihydro-4-oxo-4H-1-benzopyran-methanesulfonate

A solution of 0.84 ml of thionyl chloride in 17 ml of anhydrous dichloromethane was added dropwise to a solution of 2.0 g of 8-carboxy-

2,3-Dihydro-4-oxo-4H-1-benzopyran (prepared according to Lichtenberger

164 et al., Bull. Chem. Soc. Fr., 275, 1963) in 1.75 ml of triethylamine in 17 ml of dichloromethane with stirring and room temperature. Stirring was continued for 1 hour at the same temperature and then the reaction mixture was evaporated to dryness in vacuo to give the crude 8-chlorocarbonyl-2,3-dihydro-4-oxo-4H-1 benzopyran. It is used by the method of Example 10 instead of 8chlorocarbonyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran to give the title compound, which is purified by column chromatography on silica gel using ethyl acetate: ethanol as eluent 85:15. 1.91 g of pure base are obtained. After being dissolved in dichloromethane, acidified with methanesulfonic acid and evaporated to dryness in vacuo, the crude salt obtained is crystallized from acetonitrile. 1.57 g of the title compound are obtained, m.p. 175-177 ° C.

Example 88

8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -4-oxo-4H-1-benzopyran-methane-sulfonate. 1.25 N ₂ O

The title compound was prepared by the method described in Example 87, but using intermediate LXII instead of 8 ** carboxy-2,3-dihydro-4-oxo-4H-1-benzopyran. The crude methanesulfonate was washed with diethyl ether, filtered and repeatedly crystallized from acetonitrile, m.p. Mp 155-157 ° C

Example 89 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -6-bromo-3-methyl-4-ocean-2-phenyl-4H-1-benzopyran

This compound was prepared according to Example 86, but using 8-arboxy-6-bromo-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (prepared as described in EP 107804) instead of 8carboxy-4 -oxo-2-phenyl-4H-1-benzopyran. It is purified as a base by flash chromatography on silica gel with eluent

165 dichloromethane: methanol 100: 3 and crystallized from 95% ethanol, mp (150) 154-159 ° C.

Example 90 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -6-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-methanesulfonate

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 (obtained as described in JP 6115880) and 1.51 g of 1- (2 -methoxyphenyl) -4- (3-aminopropyl) -piperazine in 20 ml of anhydrous dimethylformamide under stirring at 0 ° C. After stirring for 1 hour at 0 ° C to room temperature, the reaction mixture was poured into a mixture of 100 ml of water and 10 ml of 1N sodium hydroxide. The base of the title compound precipitates; it is filtered and washed with water. After drying in a desiccator, it is normally converted to methanesulfonate, which is crystallized from acetonitrile. Yield: 1.7 g; mp Mp 185-186 ° C.

Example 91 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -6-hydroxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyranethanesulfonate

0.8 g of the compound obtained in Example 114 and 5.8 ml of 1N sodium hydroxide in 10 ml of methanol were stirred for 4 hours at room temperature. After standing overnight, 15 ml of 1N sodium hydroxide and 15 ml of methanol are added and the mixture is stirred for 1 hour at room temperature. The methanol was evaporated in vacuo and water was added to the residue. The suspension was filtered under vacuum to give 0.48 g of the title compound. It is converted by the usual procedure into methanesulfonate, recrystallized from acetonitrile. Melting point: 200-202 ° C.

166

Example 92 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3,6 dimethyl-4-oxo-2-phenyl-4H-1-benzopyran-methanesafonate

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-2phenyl-4H-1-benzopyran. The crude methanesulfonate was crystallized from acetonitrile. Melting point: 196-197 ° C.

Example 93 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3methyl-6-nitro-4-oxo-2-phenyl-4H-1-benzopyran

This substance was prepared according to the procedure described in Example 12 but using intermediate LXVIII instead of 8chloro arbonyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran and 1,1,2trichloroethane instead of chloroform. After the usual treatment, the crude material was purified by column chromatography eluting with dichloromethane: methanol 98: 2. Evaporation to dryness of the combined fractions and crystallization from ethanol afforded the title compound, m.p. Mp 159.5-161 ° C.

Example 94 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -6amino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran

A mixture of 33 g of the compound obtained 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 was hydrogenated in a Parr apparatus, hydrogen pressure 2 atmospheres, 12 hours stirring at 40 ° C. The catalyst was then filtered and washed with 80% ethanol. The mother liquor was evaporated in vacuo to 80 ml volume and filtered. The crude substance is washed with water and suspended in water; 37% hydrochloric acid is added until the pH reaches 1. The insoluble matter is filtered off under vacuum and

167 The filtrate was basified by the addition of 35% sodium xugpokcug. The title compound precipitates. Separate by filtration and wash with water. After drying in a desiccator, 26 g of m.p. (108) 215-217.5 ° C, which was used in Example 95 without further purification. For analysis, 4.7 g of the compound was crystallized first 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 was prepared according to the procedure described in Example 36, but using the compound obtained in Example 94 instead of that obtained in Example 33. The reaction mixture was diluted with water and filtered under vacuum, the solid was washed with water. After drying in a desiccator at 80 ° C, this material was purified by column chromatography on silica gel with eluant chloroform: methanol 95: 5; (150) 218-220 ⁰ <* - C.

Example 96

8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propionecarbamoyl} -6ethylamino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran

A mixture of 8.42 g of the compound of Example 94, 0.45 ml of acetaldehyde, 0.59 g of 85% sodium cyanoborohydride and 3.3 ml of 4.85N ethanol hydrochloride in 73 ml of methanol was stirred for 5 days at room temperature. The reaction mixture was then poured into cold 1.5N sodium hydroxide; the suspension is diluted with water and filtered under vacuum. After desiccator drying, the residue was purified by column chromatography on silica gel with eluant chloroform: methanol 100: 3. (.'after evaporation in vacuo and a

The 168 combined fractions afford 6 g of the compound of Example 94 and 2.67 g of the title compound, m.p. 198-201 ° C after recrystallization from ethanol.

Example 97 8- {3- [4- (2-Megpoxyphenyl) -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 obtained in Example 94, instead of the compound obtained in Example 33, 10 molar equivalents of 40% formaldehyde instead of 7 molar equivalents and 3 moles of sodium cyanoborohydride instead of 2 mol were reacted and stirred. 18 hours at room temperature instead of 4 ^ / ₂ hours. After the usual treatment and purification by column chromatography on silica gel with eluent chloroform: methanol 97: 3, evaporation in vacuo of the combined fractions and crystallization of the ethanol residue, the title compound is obtained, m.p. 183-186 ° C.

Example 98 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -7methoxy-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 treatment, the solid residue was purified by column chromatography on silica gel with ethyl acetapamethanol 8: 2 eluent. The separated fractions were evaporated to dryness in vacuo and the residue was crystallized from acetonitrile to give the title compound, m.p. Mp 151-152 ° C

Example 99 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbam (IIIA) -3methyl-4-oxo-2- (4-trifluoromethylphenyl) -4H-1-benzopyranomethate sulfonate eu to 6 their id

169

The title compound was prepared following the procedure described in Example 90 but starting from intermediate LXXII instead of 8-carboxy-6-methoxy-3-methyl-4-oxo-2-phenyl4H-1-benzopyran. After crystallization, the acetonitrile methanesulfonate was m.p. (85) 90-120 ° C (dec).

Example 100 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -2- (4benz (CHAPHENA) -3-methyl-4-oxo-4H-1-benzopyran-methanesulfonate hemihydrate)

The title compound was prepared by following the procedure described in Example 90, but starting from intermediate LXXIV instead of 8-carboxy-6-methoxy-3-methyl-4-oxo-2-phenyl4H-1-benzopyran. The crude methanesulfonate was crystallized from acetonitrile. M.P. 208-210 ('.

Example 101 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl-1-propylcarbamoyl} -3methyl-4-oxo-2- (4-phenoxyphenyl) -4H-1-benzopyranethanesulfonate. 0.25 N ₂ O

The title compound was prepared following the procedure described in Example 90 but starting from intermediate LXXVII instead of 8-carboxy-6-methoxy-3-methyl-4-oxo-2-phenyl4H-1-benzopyran. The crude methanesulfonate was crystallized from acetonitrile. M.P. 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-oxyl. 411-1-benzopyran (prepared according to Da Re, Farmaco Ed. Sci., 11, 678, 1956 ) instead of 8-carboxy-4-oxo-2-phenyl-4H-1-benzopyran and the reaction was carried out for 5 hours at room temperature. Purify by flash chromatography

170 on silica gel with eluent chloroform: methanol 98: 2 and crystallized from acetone, m.p. 155-158.5 ° C.

Example 103 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -2 (tert-butyl) -3-methyl-4-oxo-4H-1-benzopyran-dihydro-aoride guxugpam

This compound was prepared according to Example 86, but using intermediate LXXVIII instead of 8-carboxy-4-oxo-

2-phenyl-4H-1-benzopyran. The base was purified by flash chromatography on silica gel with eluant chloroform: methanol 49: 1 and converted to dihydrochloride in methanol: diethyl ether. Melts at 226-229.5 ° C after recrystallization from methanol: diethyl ether 1: 1. Example 104

8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -2cyclohexa-3-methyl-4-ocean-4H-1-benzopyran

This compound was prepared according to Example 86, but using TXXIX intermediate instead of 8-carboxy-4-oxo-2phenyl-4H-1-benzopyran and the reaction was carried out for 5 hours at room temperature. It was purified by flash chromatography on silica gel with eluent chloroform: methanol 49: 1 and crystallized from acetonitrile (mp 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 LXXXI instead of 8-carboxy-4-oxo-2phenyl-4H-1-benzopyran and the reaction was complete in 5 hours at room temperature. After interruption, the title compound was isolated by chloroform extraction and purified by flash chromatography on silica gel with chloroform: methanol 49: 1 eluent and crystallized from acetonitrile. M.P. 151-153 ^1> C.

171

Example 106 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3methyl-4-oxo-2-thienyl-4H-1-benzopyran

This compound was prepared according to Example 86 but using intermediate LXXXIII instead of 8-carboxy-4-oxo-

2-phenyl-4H-1-benzopyran. It was purified by stirring in water (completely removing the dimethylformamide) and then by column chromatography on silica gel with eluant chloroform: methanol 49: 1, crystallized from acetonitrile. M.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 Gcarbonyldiimidazole in 60 ml of anhydrous dimethylformamide was stirred 1% at room temperature under nitrogen atmosphere. Then, 2.7 g of 1- (3-aminopropyl) -4- (2-methoxyphenyl) piperazine are added. After stirring at room temperature for 2 hours, the reaction mixture was poured into 300 ml of water and extracted with chloroform. The organic phase was dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by flash chromatography on silica gel eluting with chloroform: methanol 49: 1, washed with water and crystallized from acetonitrile. 2 g of the title compound are obtained, m.p. 144-146 ° C,

Example 108 (E) -8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3methyl-4-oxo-2- (2-styrene) -4H-1-benzopyran

This compound was prepared according to Example 86, but using LXXXVI intermediate instead of 8-carboxy-4-oxo-

2-phenyl-4H-1-benzopyran. It is purified by crystallization from acetonitrile. Mp 191-194 ° C

172

Example 109 8- {3- [4- (2-Methoxyphenyl) -1-iperazinyl] -propionecarbamoyl} -3methyl-2- (4-methylphenyl) -4-oxo-4H-1-benzopyran

This compound was prepared according to Example 86 but using intermediate LXXXVII instead of 8-carboxy-4-oxo-2-phenyl-4H-1-benzopyran and the reaction was complete in 4 hours at room temperature. After interruption, the title compound was isolated by extraction with ethyl acetate, dried over anhydrous sodium sulfate and evaporated in vacuo, then washed with diethyl ether and crystallized from acetonitrile. M.P. 161-163 ° C.

Example 110 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -2- (4methoxyphenyl) -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 the reaction is complete in 3% hours at room temperature. It is purified by flash chromatography on silica gel with eluent chloroform: methanol 49: 1 and crystallized from acetonitrile. M.P. 158-16 GS.

Example 111 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -2- (4fluorophenyl) -3-methyl-4-oxo-4H-1-benzopyran

This compound was prepared according to Example 86, but using intermediate L.XXXIX instead of 8-carboxy-4-oxo-

2-phenyl-4H-1-benzopyran and complete the reaction in 5 hours at room temperature. It was purified by flash chromatography on silica gel with eluant chloroform: methanol 100: 2 to 100: 6 and crystallized from 95% ethanol. M.P. 166-168 ° C2

173

Example 112 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -6-methanesulfonylamino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyranxyl] oxide

0.032 ml of methanesulfonyl chloride 6 1 ml of dimethylformamide are added dropwise over 10 minutes to a solution of 0.21 g of the compound of Example 94 and 0.062 ml of triethylamine in 4 ml of dimethylformamide with stirring at -20 ° C. Stirring was continued for ¹ H-h at the same temperature. The reaction mixture was then poured into water and the suspension filtered under vacuum. 0.1 g of the title compound is obtained which is recrystallized from 80% ethanol. M.P. Mp 272-275 ° C.

Example 113 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3methyl-2- (4-nitrophenyl) -4-oxo-4H-1-benzopyran

This 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-1benzopyran. After stirring at room temperature for 1 hour, the reaction mixture was poured into cold 2% sodium carbonate solution and the precipitated solid was isolated by filtration under vacuum. Desiccation and ethanol crystallization afforded the title compound, m.p. (60) 185-187 ° C.

Example 114 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -6-diethoxyphosphonyloxy-3-lessA-4-oxo-2-phenyl-4I-1-benzopyran

This compound was prepared according to the procedure described in Example 90 but starting from intermediate LXI11 instead of 8-arboxy-6-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran and using 2 equivalents of diethyl cyanophosphate

174 instead of 1.1 equivalent. Filtration from water gave the title compound, m.p. 48-50 ° C. The title compound can be regarded as a prodrug of 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propyl} carbamoyl} -6-hydroxy-3methyl-4-oxo-2-phenyl-4H-1- chainsaw en.

Example 115 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3methyl-4-oxo-2-trifluoromethyl-4H-1-benzopyranmethanesulfonate

Proceeding as described in Example 90, but using intermediate C instead of 8-carboxy-6-methoxy-3methyl-4-oxo-2-phenyl-4H-1-benzopyran, the crude base of the title compound was obtained. After the usual treatment by extraction with ethyl acetate, the residue was purified by column chromatography on silica gel, eluting with ethyl acetate methanol 9: 1. It is converted to methanesulfonate by the usual procedure and recrystallized from ethyl acetate. Melting point: 145-148 ° C.

Example 116 8- {N-Methyl-3- [4- (2-methoxyphenyl) L-piperazinyl] -3-propylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyranhydrochloride

This compound was prepared according to Example 12, but using intermediate C1 instead of 3- [4- (2-methoxyphenyl) -1piperazinyl] propylamine. The crude base was purified by flash chromatography on silica gel, eluent ΝοροφορΜ: 5Ν methanolic ammonia 100: 1 and converted to the hydrochloride in a conventional manner. After crystallization from acetone, m.p. 195-198 S.

Example 117 7- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -2benzoyl-3-yl-benzo [b] furan

175

This compound was prepared according to Example 86 but using intermediate CX instead of 8-carboxy-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic acid and the reaction was complete within 4 hours at room temperature. It is purified by crystallization from ethanol. Melting point: 165-166 ° C.

Example 118 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} 2- (4biphenyl) -3-methyl-4-oxo-4H-1-benzopyran

The title compound was prepared according to Example 86 but using CVI intermediate instead of 8-carboxy-4-oxo-2-phenyl-4H-1-benzopyran. The reaction was continued for 20 hours at room temperature. The base was purified by crystallization from ethanol (mp 164-166 ° C).

Example 119 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3methyl-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 anhydrous pyridine was stirred and heated at 100 ° C for 2 hours under nitrogen. Then 16 ml of triethylamine are added and heating is continued for one hour at the same temperature. The reaction mixture was cooled to room temperature and poured into 600 ml of water. The precipitate was removed by vacuum filtration, washed with water to give 5.4 g of methyl-2-hydroxy-3- (2-nicotinoylpropionyl) benzoate, which was used in the next step without further purification. 3.4 g of the compound thus obtained is heated 1 ^l /? hours at 100 ° C after dissolution in a mixture containing 15 ml of acetic acid and 1 ml of 37% hydrochloric acid. After cooling to room temperature, the mixture was poured into 150 ml of water and extracted with ethyl acetate. The organic phase is washed with 5% aqueous sodium hydrogen carbonate solution and then with water, dried over anhydrous

176 sodium sulfate and evaporated in vacuo. 1.3 g of crude 8-methoxycarbonyl-3-methyl-4-oxo-2- (3-pyridyl) -4H-1-benzopyran are obtained.

g of this ester was dissolved in 9 ml of methanol and 15 ml of 1,4 dioxane and slowly added 1.7 ml of 10N sodium hydroxide while maintaining the temperature between 20 and 25 ° C. After 1 hour at 50 ° C, the reaction mixture was poured into 150 ml of water and extracted with ethyl acetate. The aqueous phase was acidified with 1N hydrochloric acid. The precipitate was removed by vacuum filtration. 0.6 g of 8-carboxy-3-methyl-4-oxo-2- (3-pyridyl) -4H-1-benzopyran are obtained, which is used in the next step without further purification.

The title compound was prepared according to Example 86, but using the acid thus obtained instead of 8-carboxy-4-oxo-2-phenyl-4H-1-benzopyran and carrying out the reaction for 2 hours at room temperature. The base was purified by flash chromatography on silica gel with eluent chloroform: methanol 98: 2 and crystallization from acetone. Yield: 0.15 g, m.p. 134.5-137 ° C.

Example 120 8- {3- [4- (2-Acetoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran g of the compound of Example 59 and 0.32 g of 4-dimethylaminopyridine dissolved in 10 ml of dichloromethane. While maintaining the temperature between 8 and 10 ° C, 0.15 ml of acetyl chloride was slowly added. After 2 hours at room temperature, the reaction mixture was poured into 70 ml of water and extracted with dichloromethane. The organic phase was washed with 5% aqueous sodium bicarbonate and then with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo, the crude base was purified by flash chromatography on silica gel with ethyl acetate-methanol 9: 1, then crystallized of ethanol. Yield: 0.74 g of the title compound, m.p. 120-123 ° C.

177

Example 121

8- {3- [4- (2-Methylaminocarbonyloxyphenyl) -1-piperazinyl] propylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran g of the compound of Example 59 and 1.8 ml of methylisocyanate were dissolved in 30 ml of dry dimethylformamide and stirred at room temperature for 24 hours. The mixture was diluted with water, stirred for two hours, then filtered under vacuum. The crude base was purified by flash chromatography on silica gel with chloroform eluent: 5A and methanolic ammonia 100: 3. After crystallization from ethanol, the title compound has m.p. Mp 132-135 ° C.

Example 122 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -6acetoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran

0.17 ml of acetyl chloride were added dropwise over 5 minutes with stirring and 0 ° C to a solution of 1 g of compound of Example 91 and 0.32 ml of triethylamine in 36 ml of chloroform. After stirring at the same temperature for 2 hours, the reaction mixture was diluted with dichloromethane and water. The organic phase was separated, washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. Crystallization of the acetonitrile residue afforded 0.8 g of the title compound, m.p. Mp 148-149 ° C.

Example 123 (N, S) -8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] propylcarbamoyl} -2,3-dihydro-4-hydroxy-4H-1-benzopyranethanesulfonate

The title compound was prepared by the method described in Example 17, but using the compound of Example 87 instead of the compound of Example 1. The reaction mixture was dissolved in water and stirred for 15 minutes; then extracted with ethyl acetate. After the usual treatment a crude product is obtained which is purified by flash chromatography on silica gel with eluent

178 dichloromethane: methanol 95: 5. Evaporation of the separated fractions in vacuo gave a pure base which was converted to methanesulfonate and crystallized from acetonitrile. Melting point: 172-175 ° C.

Example 124 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -2- (4-aminophenyl) -3-methyl-4-oxo-4H-1-benzopyran

2.22 g of the compound of Example 113 and 0.56 g of Raney nickel in 96 ml of ethanol and 4.8 ml of acetic acid were hydrogenated in a Parr apparatus (hydrogen pressure = 1 atmosphere) at room temperature. After 6 hours of shaking, the catalyst was filtered off, the filtrate was basified with 3N sodium hydroxide and diluted with water. After 2 days of standing, the precipitated title compound was removed by vacuum filtration, washed with water, dried in a desiccator and recrystallized first from ethyl acetate and then from ethanol. Yield: 1.5 g, m.p. Mp 192-194 ° C.

Example 125 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -2- (4acetylaminophenyl) -3-mepsha-4H-1-benzopyran

The title compound was prepared by the method described in Example 36, but using the compound obtained in Example 124 instead of that obtained in Example 33. Purified by crystallization from 95% ethanol. Melting point: 207-209 ° C.

EXAMPLE 126 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -2- (4hydroxyphenyl) -3-methyl-4H-1-benzopyran-dihydro-aoride monohydrate

The title compound was prepared according to the method described in Example 86, but using CVII intermediate instead of 8-carboxy-4-oxo-2-phenyl-4H-1-benzopyran, and the reaction was carried out for 14 hours at room temperature. used

179 Hexamethylphosphoramide as co-solvent, The isolated diethylphosphonyl ester of the title compound is hydrolyzed by alkaline treatment and then neutralized with dilute hydrochloric acid. The crude base was extracted with chloroform. The organic phase was washed with water and evaporated in vacuo. The salt is obtained by the addition of ethanol hydrogen chloride to a solution of the base in acetone, evaporation to dryness and washing with acetone. Melting point: 193-205 ° C.

Example 127 8- {3- [4- (2-megpoksifeniA) -1-piperazinyl] -propylcarbamoyl} -2feniA-4, M ^1, M ⁴ -triokso-4H-1-benzothiopyran monohydrate

0.32 ml of 30% hydrogen peroxide were added to 0.8 g of the compound of Example 107 in 15 ml of acetic acid. The mixture was stirred at 50 ° C for 3 hours. To the mixture was added 0.48 ml of 30% hydrogen peroxide in three equal portions over 2 hours. After cooling, the mixture was poured into 240 ml of water, neutralized (pH = 7) with 5% aqueous sodium bicarbonate solution and extracted with chloroform. The organic phase was washed with water, dried over anhydrous sodium sulfate and evaporated in vacuo. 0.18 g of the title compound are obtained, mp 172-175 ° C after crystallization from acetonitrile.

Example 128

7- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -2-phenyl-benzo [b] furan

The title compound was prepared by the method described in Example 86, but using 7-carboxy-2-phenyl-benzo [b] furan (prepared as described in EP U306226) instead of 8-carboxy-4-oxo-2-phenyl-4H- 1-benzopyran and carrying out the reaction for 1¼ hours at room temperature. It is purified by crystallization from tetrachloromethane. Melting point: 132-136 ° C.

180

Example 129

8- {N-MemuA-3- [4- (2-Memoxy (|) eHUA) -1-pyridin-3-yl] -piperazu-Aphamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyranethanesulfonate

2.29 g of intermediate VIII was added portionwise with stirring and 0 ° C to a solution of 1.5 g of intermediate CI and 0.95 g of triethylamine in 30 ml of chloroform. After stirring at room temperature for 2 hours, the reaction mixture was diluted with dichloromethane, water and 0.5N sodium hydroxide. The organic phase was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate: methanol 96: 4. Evaporation of the separated fractions in vacuo gave the pure title compound as a base. It is converted to methanesulfonate by the conventional method. The salt was then crystallized from ethyl acetate. 2.75 g of m.p. 135-141 ° C (dec,).

Example 130 8- {N-Methyl-4- [4- (2-methoxyphenyl) -1-pyerazinyl] -butylsulfamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzoylmethanesulfonate

The title compound was prepared by the method described in Example 129 but using intermediate CVIII instead of intermediate ('1. Crystallized from acetonitrile. Melting point: 173-175 ° C.

pharmacological data

Methodology

Sprague Dawley male rats [Crl: CD 'BR) weighing 20 () - 300 g, female Albino Swiss mice [Crl: CD-I (ICR) BR] weighing 20-30 gu male Beagle dogs (weighing 10-12 kg) were obtained from Charles River, Italy and respectively from Nossan (Correzana, Milan, Italy).

181

The animals were kept under free access to food and water, and in an accelerated light-dark cycle, at 22-24 ° C until the day of the experiments. Acute toxicity

The acute toxicity of the synthesized compounds was evaluated in albino Swiss female mice after intraperitoneal and oral administration. Four logarithmic doses of the compounds were dissolved or suspended in 0.5% Methocel and given in a volume of 10 ml / kg to groups of 4 mice / dose. Mortality was recorded 7 days after administration. Data analysis: LD ^ q values and their baseline values are calculated using the Weil method (Biometrics, 8, 249, 1952).

Research on. receptor binding:

- [Hprazosin binding (α-receptors)

The rat cerebral cortices were homogenized in 50 volumes, relative to the original wet weight, of ice-cold 50 mM mpuc-HCL buffer pH 7.4. Homogenized samples were centrifuged at 48,000 x g for 10 minutes and the precipitated material was resuspended in the same volume of ice-cold buffer, centrifuged and resuspended 2 more times. The resulting final precipitates were resuspended in the same volume of buffer and incubated according to the conditions given in the table below.

The above receptor binding studies, as well as the experimental dog data reported below, prove that the compounds of the invention are α-blockers, i.e. they belong to a class of substances that are widely used as antihypertensive and anti-BPH agents. See, e.g. Frishman, W. H. et al., Medical Clinics of N. America, 72, 427, 1988 and references cited therein.

T binding (5HT receptor)

Rat hippocampi in the rat were homogenized in 5U volume, relative to the original wet weight, of ice cold 5 (1

182 mM mpuc-HCL buffer pH 7.4. The homogenized samples were centrifuged at 48,000 x g for 10 minutes and the precipitated material was resuspended in the same volume of ice-cold buffer, incubated for 10 minutes at 37 ° C, centrifuged and resuspended 2 more times. The resulting final precipitates were resuspended in the same volume of buffer and incubated according to the conditions given in the table below.

These receptor binding studies help to demonstrate that the compounds of the present invention represent ligands for the 5HT _1A receptor. As previously reported, compounds that are 5HT _1A ligands exhibit anxiolytic and antidepressant effects in animals and humans (Hamon, M. et al., Ann. Ac. Acad. Sci., 600, 114, 1990; Traber J. et al., TIPS, 8, 437, 1987)

Reception p / li g and Conditions Receptor binding studies a, adrenergic f-H] prazosin 5-HT _1E p otoner d ir en fH] 8-OH-DPAT [tM] lig and 0.35 1.0 drug (bp) 1 ml 1ml 10 mg / ml 10 mg / ml incubation buffer * tris- H Cl trie-H Cl 50mM 50 mM pH 7.4 pH 7.4 nonspecific prazosin 5-HT connection 2 μΜ 10 μ Μ incubation 25 ° C 25 (' 30 minutes 30 minutes

н.Х.М. = preparation of untreated membranes * = contains 1% ascorbic acid and 10 μΜ pargillin

183

Incubations are completed after a specified time (see table) by rapid filtration through Whatman GF / B filters using a Brandel apparatus. the filters are washed twice with 15 ml of ice-cold buffer (see table). Radioactivity remaining on the filters is determined by scintillation counting. Non-specific binding (which usually amounts to 10-30%) is evaluated by the addition of high concentrations of specific substituents (see table). All compounds were tested initially at a concentration of 1x10 &lt; ⁶ & gt ^; M and in the presence of significant displacement activity. A complete competition curve is obtained (down to a concentration of 10 ^'11 M). All samples were run three times.

The competition curves were always analyzed (to estimate IC ^ q) by nonlinear matching of the logistic equation curves according to the method reported by De Lean et al. (Am. J. Phisiol., 235, E96, 1978) using the ALLFIT program [available at National Institutes of Health (N.I.H.) Bethesda, Maryland, USA] for an IBM personal computer.

Bladder contractions of K ⁺ -induced rats

The whole rat bladder was removed and immediately placed in a Krebs solution heated to 37 ° C. Strips of urine release muscle (detrusor) (20-30 m in length and 1-2 m in width) are cut from the bladder vault. Each strip was placed in a 10 ml organ bath and coupled at a constant load of 1 g with an isometric stretch measuring device (DY-1 Basile, Comerio, Varese, Italy). Contractions are recorded using a Rasilie 7o70 polygraph. After a 60 min equilibrium period, the bands were exposed to 80 mM KCl (final concentration). This causes rapid phase contraction, followed by slow onset and maintaining tonic

184 components. When the tonic contraction becomes stable, the bands are washed and a new contraction is induced after 30 minutes. After registering two or more reproducible results, one concentration of the tested drugs was added to the bath and a new contraction was initiated 30 minutes later. The experimental groups consist of at least two preparations taken from different animals for each concentration of drug tested. The values of IC ₃₀ inhibition of agonist-induced contractions were evaluated by linear regression analysis.

Effects on urethral contractions and blood pressure in dogs

The experiments were conducted according to the method of Imagawa et al. (J. Pharmacol. Methods, 22, 103-111, 1989) with substantial modifications as follows: Adult male beagle dogs weighing 8-10 kg are anesthetized with sodium pentobarbital (30mg / kg iv and 2 mg / kg) / h iv) are intubated and spontaneously ventilated with ambient air. To monitor the blood pressure of the entire organism, a RE catheter was inserted into the aorta through the right carotid artery.

Collateral on the left femoral vein is an anesthetic infusion cannula and the right femoral vein is a medication cannula. For intra-arterial injection (1.a.) of norepinephrine (NA), a PE catheter is inserted into the lower abdominal aorta through the right external iliac artery. Through this procedure, NA is selectively distributed in the lower urinary tract. The bladder and proximal urethra are revealed by a midline laparotomy. To prevent the bladder from filling, a cannula is placed on both the urethra and the urine is allowed to flow out. To record the urethral pressure of the prostate, a Mikro-tip catheter is inserted into the bladder through the urethra.

185 (6 F) u is withdrawn when the pressure sensor is positioned in the urethra of the prostate gland. A ligature is provided between the bladder neck and the urethra to isolate the reaction of the bladder and to avoid any interaction with the bladder. Another ligature was placed around the MiJkro-tip catheter on the external urethral canal to provide the catheter itself. After a period of stabilization following the surgical procedure (30 minutes), during which blood pressure and urethral pressure of the prostate were continuously monitored as basal values, i.a. norepinephrine. The selected 'Nm ·' dose of norepinephrine is such as to cause at least 100% increase in urethral pressure. Test compounds were administered

iv cumulatively at intervals of 15-20 minutes. Intra-arterial injections of NA were repeated approximately 5 minutes after each dose of test compound. Dose-effect curves were plotted by calculating the percentage inhibition against urethral pressure elevation (NA induced) and the percent blood pressure drop induced by the test compound. By linear regression analysis are the EDs calculated _? for diastolic blood pressure (dose inducing 25% reduction) and ID _S q (dose inducing 50%> inhibition of urethral pressure elevation induced by NA).

Results

The compounds prepared according to the examples were tested by the methods reported above and the results are presented in the tables below together with the comparative results for the cited standards used. Clitl compounds have receptor affinity (IC ₅₀ values) lower than about SCO nM, generally considered to have good affinity. Compounds with IC ₅₀ values less than 100 nM are generally preferred.

w »·

186

Table I

Compound Example No. Receptor binding IC _sn (nM) Acute toxicity in mice K + stimulation of rat bladder ^1c , 7tm) Contractions ld ₅₀ ι.ρ. (mg / kg) p.o. ^α ι 5-HT 1a phase tonic 4 550 55 346 1732 5 20 19 621 > 3000 6 107 1000 233 7 8 6 155 384 1915 8 66 111 > 500 1915 11 29 9 247 297 2.9 3.0 13 68 ; 229 > 1000 > 3000 10.0 10.0 14 61 1 6 140 559 15 8 131 306 496 16 220 1050 345 778 1.6 2.2 17 59 910 299 608 8.8 3 .8 18 270 > 1000 457 3000 19 165 340 > 1000 > 3000 2 0 169 85 297 594 2.7 2.5 21 17 33 297 566 2 2 117 . 48 > 500 > 2000 24 690 212 > 1000 > 3000 2 6 270 > 1000 > 500 > 2000 2 7 23 124 399 > 3000 1.0 0.8 2 8 120 96 203 1127 29 86 45 730 > 3000 10.0 10.0 3 2 119 46 301 > 2000 10.0 > 10 3 3 17 38 399 > 2000 10.0 10.0 3 4 30 34 > 500 2.8 3.6 3 5 15 8 329 959 3 6 18 54 > 500 > 2000 3 7 32 77 > 500 > 2000 3 8 20 344 > 500 > 2000 3 9 90 170 > 1000 > 3000 4 0 75 83 140 349 0.5 0.9 41 43 53 399 2241 0.7 1.4 4 2 111 39 459 2163 10.0 10.0 4 3 166 > 1000 4 4 685 201 84 399 0. 6 0.5 4 5 15 106 329 1727 4 6 86 23 4 7 36 23 330 1047 2. 7 5.2 4 8 104 5 500 1914 4 9 152 9 432 > 2000 5 0 39 300 211 299 51 22 84 > 500 > 2000 5 2 89 2 127 224 5 3 7 4 1 127 1020 5 4 35 14 3 10 6 421 5 5 291 > 1000 128 > 2000 5 6 25 748 > 500 ----------------—- __________________ — ....... _________________________________________ ____________________________________.

187

Table 1 (continued)

Compound Example No. Receptor binding 1C < _n (nM) Acute toxicity in mice K + urinary bladder stimulation in rat 1C ₅₀ (μ Кон) ι.ρ. (mg / kg) p.o. ^α ι 5-HT, 1a 57 69 > 1000 500 > 2000 58 > 1000 126 258 508 59 5 9 > 500 278 60 25 45 203 329 61 36 11 315 592 62 252 278 128 344 --- 63 194 99 309 479 , .. _r 64 40 ii i 65 113 26 - 66 57 56 601 67 4 4 508 1868 68 29 13 69 16 87 344 70 53 85 > 500 1868 71 108 69 72 145 111 479 > 2000 73 '6 89 202 462 74 178 482 75 147 15 78 18 116 79 77 141 > 500 > 2000 80 28 162 81 13 81 83 30 5 84 5 2 85 16 14 86 48 20 87 119 107 237 > 500 88 216 11 93 47 38 94 39 66 98 103 12 99 44 5 ! 102 56 18 ί 104 9 15 ! 107 37 16 110 26 15 1! Flavoxate >> 1000 >> 1000 385 808

Table II

Effects on the pancreas ability of the urethra and blood pressure in dogs

Compound Example No. Urethra ED _sn (pg / kg) DBP ED, _S (pg / kg) DBP / ypempa ratio 5 37.0 1074 29.0 11 1.4 390 278.6 13 16.0 215 13.4 17 10.0 6.2 0.6 * 21 6.6 127 19.2 27 3.2 9.8 3.1 * 40 11.0 152 13.8 41 57.0 745 13.1 42 31.0 404 13.0 45 16.4 186 11.3 47 35.0 530 15.1 Prazosin 3.6 6.6 1.8 * Terflavoxate > 10000 6060 -

Urethra: active dose when inhibiting 50% of urethral contractions. caused by norepinephrine DBP: active dose in reducing diastolic blood pressure by 25% DBP / ypemp: ι: active dose ratio (selectivity index) * non-selective: significant effect on ^d urethra and DBP

Effective quantities

The following are instructions for effective oral, parenteral, intravenous doses, expressed in mg / kg body weight per day, for the following applications:

189 (a) In obstructive disorders of the lower urinary tract:

Usually 0.001 - 20

Preferred 0.05 - 1

Highly preferred * * 0.3 (b) As antihypertensive agents:

Usually 0.01 -20

Preferably 0.1 -5

H and preferably * * 1 (c) As anxiolytics - antidepressants:

Usually 0.01 -20

Preferably 0.05-5

Highly preferred * * 0.5 (d) As bladder spasmolytics:

Usually 0.01 -20

Preferably 0.02 -10

N or Preferred * * 2 ** Most preferred oral dosage values. Intravenous doses should be 10 to 100 times lower.

Patients requiring treatment with the present compounds and compositions also include people who have one or more symptoms of depression (as defined e.g. in! 1 arrison's Principles of Internal Medicine, XII Ed., McGrow-NSH, Inc., p. 2124) or people who exhibit symptoms of depression (Harrison's, supra, pp. 2131-2134).

Doses for selective administration, i. doses that are active in the lower urinary tract without a significant effect on blood pressure depending on the compound used, but typically by selective compound can be administered up to four times ED ₃ 0 without a significant effect on blood pressure. Further refinement and optimization of doses is possible using only routine experiments.

190

The active compounds of the invention may be administered orally, e.g. with an inert diluent or an edible carrier, or they may be included in gelatin capsules or compressed into tablets. For the purposes of oral therapeutic administration, the active substances of the invention may be combined with excipients and used in the form of tablets, pastilles, capsules, tinctures, suspensions, syrups, wafers, chewing gums and the like. similar. These dosage forms should contain at least 0.5% of the active substance, but the amount of the active ingredient may vary depending on the formulation and may be between 5% to about 70% by weight of one dosage form. The amount of active substance in such compositions is such that a suitable dosage is obtained, although the desired dose can be obtained by administering a greater amount of dosage forms. Preferred compositions and dosage forms of the invention are prepared so that an oral dosage unit contains between 1.0-300 milligrams of active compound.

Tablets, pills, capsules, lozenges and the like may also contain e.g. the following ingredients: a binder such as microcrystalline cellulose, tragacanth or gelatin; an excipient such as starch or lactose, a disintegrant such as alginic acid, Primogel, cereal starch and the like; a lubricant such as magnesium you are Art or Sterotex; lubricant such as colloidal silica; a sweetener such as sucrose or saccharin may be added or a flavoring such as peppermint, methyl salicylate or orange flavoring. When the dosage form is a capsule, it may contain, in addition to the substances of the above type, a liquid carrier such as oil. Other dosage forms may contain other various substances that modify the form of the drug unit, e.g.

191 coatings. Thus, the tablets or pills may be coated with sugar, shellac or other enteric coating. In addition to the active substances, the syrup may also contain sucrose and some preservatives, dyes, colorants and flavors as a sweetener. The substances used in the preparation of these various compositions should be pharmaceutically pure and not toxic in the quantities in which they are administered.

For the purposes of parenteral treatment, the active substances of the invention may be incorporated into a solution or suspension. These preparations must contain at least 0.1% of the active substance, but may vary between 0.5 and about 30% by weight. The amount of active substance in such compositions is such that a suitable dose is obtained. Preferred compositions and dosage forms according to the invention are prepared in such a way that a parenteral unit dose contains between 0.2-100 milligrams of active compound. The solutions or suspensions may also contain the following ingredients: a sterile diluent such as water for injections, saline solution, stable oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial substances such as benzyl alcohol; antioxidants such as ascorbic acid or sodium bisulfite; he flap agents such as ethylenediaminetetraacetic acid; buffers such as acetates; citrates or phosphates and voltage regulators such as sodium chloride or dextrose. Repeated dose vials may be glass or plastic.

Claims (16)

Patent Claims A compound of general formula I Y-Z-B 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 _? represents a hydrogen atom or an alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, substituted heterocyclyl or aroyl group; the substituents of the above substituted groups are one or more halogen atoms and / or one or more alkyl, cyano, hydroxy, alkoxy, phenyl, phenoxy, trifluoromethyl, nitro, amino, alkyl n-, e and alkylamino-, acylamino-, alkylsulfonylamino- or benzoyl groups; R; represents a hydrogen atom or an alkyl atom. hydroxyalkyl, alkoxyalkyl, aralkoxyalkyl, phenyl, hydroxy, alkoxy or aralkoxy; R ₆ represents a hydrogen or halogen atom, or a nitro-, amino-alkylamino-, dialkyl, amino-, acylamino-, alkylsulfonylamino-, cyano-hydroxy-, alkoxy- or alkyl group, R ₇ represents a hydrogen atom or an alkoxy group; Y represents one of the following groups, each of which is connected at its left end with the heterobicyclic ring and at its right end with the Z group: (Ύ1) -CO-, (Y2) -COO-, (Ύ3) -CONH-, (Y4) -CON (CH ₃ ) - (Y5) -CON (OH) - (Y6) -CH (OH) -, (Y7) -CH (Oalkyl) -, (Y8) -CH = CH-, (Y9) -ch = ch-so-> (Y10) -CH = CH-CONH- (Y11) -CH-NO-, (Y12) -CH ₃ ~, (Ύ13) - SI ₂ co-, (Y14) -CH ₂ CONH-, (Y15) -CH.NH-. * (Y16) -CH ₂ N (CH ₃ ) -, (Ύ17) -CH ₂ N (COCH ₃ ) -, (Y18) -CH ₂ N (CONH ₂ ) -, (Ύ19) -CH ₂ NHCO-, (Y20) -CH ₂ N (CH ₃ ) CO-, (Y21) -CH ₂ NH-CC) NH-, <Y22) -CH ₂ NHSO ₂ -, (Y23) -CH ₂ O- (Y24) -CH ₂ S-, (Y25) -CHoSO-, L. (Y26) -CH ₂ SOy (Y27) -CH% O, NH-, with (Y28) -CH ₂ SO ₂ N (CH ₃ ) - (Y29) -NH-, (Y30) -N (CH ₃ ) -> (Y31) -N (COCH ₃ ) -, (Y32) -N (CONH ₂ ) -> (Y33) -NHCO-, (Y34) -N (CH ₃ ) CO-, (Y35) -NH-CONH- (Y36) -nhso ₂ -, (Y37) -0-, (Y38) -S-, (Y39) -SO-, (Y40) -SO ₂ -, (Y41) (Y42) -SO _? NH-, -SO ₂ N (CH ₃ ) -, (Y43) (Y44) -COM 1 () -, -CON (COCH ₃ ) -, (Y45) (Y46) -CSNH-, -CSN (CH ₃ ) -, (Y47) O -CON (Ο _Ί - ' ^Χ (¥ 48) -NHCOO-, and (Y49) -COS-; Z represents a linear or branched alkylene chain group of 1 to 6 carbon atoms and optionally a hydroxyl substituent; and B represents one of the following groups; (In | \ N— A / Q in which Q represents a methylene or ethylene group and A represents one of the following groups: (Aj) a phenyl group substituted by one or more halogen atoms and / or one or more alkyl, alkoxy or hydroxy groups, (A ₂ ) one 2-pyrimidinyl group and (A ₃ ) one group of the general formula Ahh I I I in which ------ has the meaning defined above and E represents an oxygen atom or a valence bond (B ₂ ) in which each L ₃ and L _? independently represents a hydrogen atom, a phenyl, 4-fluorobenzoyl or 2-oxo-1-benzimidazolinyl group or a group of the general formula (CH ₇ ) -O-A, in which n is U, 1 or 2, and A is defined in this claim provided that C and L _? does not enter into a atomic atom, (B ₃ ) R-io _x -ν- (ϊ: ή ₂ ) _{Γ Γ} ---- 4 * 12. ... R11 in which each Rj _f) and Rj ^ independently represents a hydrogen atom or an alkoxy or alkylthio group, R ₁₂ represents a hydrogen atom or an alkyl group, an is 2 or 3, in which R | ₂ is defined in this claim, and R ₁₃ represents a hydrogen atom or an alkoxy group, and (B ₅ ) 0 -N-Cll _: ... I ... wherein R ₁₂ is as defined in this claim. or a prodrug, enantiomer, diastereoisomer, oxide or pharmaceutically acceptable salt of such compound. 9 Compound, co according to claim I, wherein -: is a double bond, X: represents an oxygen atom. W: represents a carbonyl group, R ₂ : represents a phenyl group, R ₃ : represents a methyl group, Ο represents a hydrogen atom, and R ₇ ; n peg cm a left hydrogen atom. P. L, Compound, ei Claim 1 or Claim 2, where before < .you go into a one with :> t groups ¥ 2, Y3, ¥ 37, ¥ 40, or ¥ 41. A compound according to any preceding claim, wherein Z represents a trimethylene or tetramethylene group. A compound according to any preceding claim, wherein B represents one of the groups B1 or B3. A compound according to any preceding claim, wherein B represents a 4- (2-methoxyphenyl) -1-piperazinyl group. A compound according to any preceding claim, wherein Υ, Z and B together represent a 3- [4- (2-methoxyphenyl) -1piperazinyl] propylcarbamoyl group. 8. Each of the following compounds: 8- {2- [4- (2-methoxyphenyl) -1-piperazinyl] 1-oxoethyl} -3-methyl-4oxo-2-phenyl-4H-1-benzopyran, 8- {2- [4- (2-methylphenyl) -1-piperazinyl] -1-oxoethyl} -3-methyl-4-oxo- 2 - phenyl-4H-1 - enzyme assay, 8-12- [4- (2-ethoxyphenyl) -1,1-piperazinyl | -1,1-oxoethyl} -3-methyl-4-oxo2-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} -3methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {2- [4- (2-Methoxyphenyl) -1-piperazinyl] -ethoxycarbonyl} -3-methyl4-oxo-2-phenyl-4H-1-benzopyran, 8- {3- [4- (2-chlorophenyl) -1-piperazinyl] -propoxycarbonyl} -3-methyl-4oxo-2-phenyl-4H-1-benzopyran, 8- [3- (4-phenyl-1-piperazinyl) -propoxy arbonyl] -3-methyl-4-oxo-2phenyl-4H-1-benzopyran, B- 3- [4- (2-methoxyphenyl) -1-piperazinyl] -propoxycarbonyl} -3methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -2-methyl-2-propoxycarbonyl] -3-methyl-4-oxo-2-phenylA-4H-1-benzopyran} 8 - {3- [4- (2-methoxy phenyl) -1-piperazinyl] -propyl arb amoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {2- [4- (2-Methoxyphenyl) -1-piperazinyl] -ethylcarbamoyl} -3-methyl4-oxo-2-phenyl-4H-1-benzopyran, 8- {3- [2- (2-methoxyphenoxy) -ethylamino] -propylcarbamoyl} -3-methyl4-oxo-2-phenyl-4H-1-benzopyran, 8- [3- (4-phenyl-1-piperazinyl) -propylcarbamoyl] -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {N-methyl-2- [4- (2-methoxyphenyl) -1-piperazinyl] -ethyl arb amoyl} - 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {1-hydroxy-2- [4- (2-methoxyphenyl) -1-piperazinyl] -ethyl} -3-methyl- 4- ok co -2- f enyl-4 H -1-6 enopyran, 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} -3methyl-4-oxo-2-phenyl-4 H -1-benzyl, 8- {1-hydroxy-4- [4- (2-methoxyphenyl) -1-piperazinyl] -butyl} -3methyl-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- 14 - (2-methoxyphenyl) -1-piperazinyl] -ethyl aminomethyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {N-acetyl-2- [4- (2-methyl-siphenyl) -1-piperazinyl] -ethyl aminomethyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran. 8- [4- (2-methoxyphenyl) -1-piperazinylacetamidomethyl] -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- ί N-methyl-N- [4- (2-methoxyphenyl) -1-piperazinyl] -acetamidomethyl and l) - 3-methyl-4 - o k s o - 2 - phenyl-4 N -1 - benz ο п і р а н 8- {2- [4- (2-Methoxyphenyl) -1-piperazinyl] -ethoxymethyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {2- [2- (2-Ethoxyphenoxy) -ethylamino] -ethoxymethyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride, 8- {2- [4- (2-Methoxyphenyl) -1-piperazinyl] -ethylthiomethyl} -3-methyl4-oxo-2-phenyl-4H-1-benzopyran, 8- {2- [4- (2-methoxyphenyl) -1-piperazinyl] -ethylsulfinylmethyl} -3methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {2- [4- (2-methoxyphenyl) -1-piperazinyl] -ethylsulfonylmethyl} -3w methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {2- [4- (2-Methoxyphenyl) -1-piperazinyl] J-ethylamino} -3-methyl-4oxo-2-phenyl-4H-1-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylamino} -3-methyl-4oxy with o-2-phenyl-4H-1-benzoxypropyl, 8- {4- [4- (2-methoxyphenyl) -1-piperazinyl] -butylamino} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8 - {N-methyl-3- [4- (2-methoxyphenyl) -1-piperazinyl] -propyl amino} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {N-acetyl-3- [4- (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] -ethoxy} -3-methyl-4-oxo-2phenyl-4H-1-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propoxy} -3-methyl-4-oxo-phenyl-4H-1-benzopyran, 8- {4- [4- (2-Methoxyphenyl) -1-piperazinyl] -butoxy} -3-methyl-4-oxo-phenyl-4-l-benzopene and wound, 8- { 5- [4- (2-methoxyphenyl) -1-piperazinyl] -phenyloxy} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-oxo-1-piperazinyl] -propoxy} -3-methyl4-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- [4- (2-methoxyphenyl) -1-piperazinyl] -propoxy} -3methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylthio} -3-methyl-4oxo-2-phenyl-4H-1-benzopyran, 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylsulfonyl} -3-methyl4-oxo-2-phenyl-4H-1-benzopyran, 8- {2- [4- (2-methoxyphenyl) -1-piperazinyl] -ethylsulfamoyl} -3-methyl4-oxo-2-phenyl-4H-1-benzopyran, 8- {N-methyl-2- [4- (2-methoxyphenyl) -1-piperazinyl] -ethylsulfamoyl} - 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {Nk arb amoyl-3- [4- (2-methoxyphenyl) -1-piperazinyl] propylamino} -3-methyl-4-oxo-2-phenyl-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} -3methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {4- [4- (2-methoxyphenyl) -1-piperazinyl] -butyl} -3-methyl-4-oxo-2phenyl-4H-1-benzopyran, 8- [3- (4-phenyl-1-piperidinyl) -propylcarbamoyl] -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- [3- (4,4-diphenyl-1-piperidinyl) -propyl arbamyl] -3-methyl-4-oxo-phenyl-4H-1-benzopyran, 8- {3- [4- (4-fluorobenzoyl) -1-piperidinyl] -propyl arb amoyl} -3methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {3- [4- (2-Oxo-1-benzimide azolinyl) -1-piperidinyl] -propylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {3- [4 ~ (2-pyrimidinyl) -1-piperazinyl] -propylcarbamoyl} -3-methyl4-oxo-2-phenyl-4H-1-benzopyran, 8- {3- [4- (2-hydroxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {4- [4- (2-Methoxyphenyl) -1-piperazinyl] -butylcarbamoyl} -3-methyl- 4-oxo-2-phenyl-4H-1-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylsulfamoyl} -3, methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {3- [N-methyl- 2- (2-methoxyphenoxy) -ethylamino] -propylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {X-methyl-3- [4- (2-methoxyphenyl) - 1-piperazinyl] -propionamido} -3methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3-phenyl4-oxo-4H-1-benzopyran, 8- {3 - [(3,4-dihydro-1-oxo-2H-naphthyl) -methylamino] -propyl arb amoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {2- [4- (2-Methoxyphenyl) -1-piperazinide] -ethoxycarbonylmethyl} -3methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {4- [4- (2-Methyl siphenyl) -1-piperazinyl] -butylsulfoyl} -3-methyl4-oxo-2-phenyl-4H-1-benzopyran, 8- {N- (2-membered hydropropyloxy) -3- [4- (2-methoxyphenyl) -1piperazinyl] -propyl arbamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {4- [4- (2-Methyl siphenyl) -1-piperazinyl] -butyramido} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyr. E-8- {2- [4- (2-methoxyphenyl) -1-piperazinyl] -ethoxyiminomethyl} -3methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {N-hydroxy-3- [4- (2-methoxyphenyl) -1-piperazinyl] propyl arb amoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, E-8- <2- {2- (4- (2-methoxyphenyl) -1-piperazinyl] -ethylcarbamoyl} ethenyl> -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- (4- (4- (2-methoxyphenyl) -1-piperazinyl] -butylsulfinyl} -3-methyl4-oxo-2-phenyl-4H-1-benzopyran, 8- {3- [3- (2- methoxyphenoxy) -propylamino] -propylcarbamoyl} -3methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {3- [2- (2-methylthiophenoxy) -ethylamino] -propylcarbamoyl} -3methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- (3- (2- (2,6-dimethoxyphenoxy) -ethylamino] -propylcarbamoyl} -3W methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {3- [4- (5-Chloro-2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} - 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, (E) -8- {4- [4- (2-methoxyphenyl) -1-piperazinyl] -1-butenyl} -3-methyl- 4oox-2-phenyl-4H-1-benzopyran, (E) -8- <2- (2- [4- (2-methoxyphenyl) -1-piperazinyl] -ethoxycarbonyl} ethenyl> -3-methyl-4-oxo -2-phenyl-4H-1-benzopyran, 8- {2- (4- (2-methoxyphenyl) -1-piperazinyl] -ethyl arbamylmethyl} -4oxo-2-phenyl-4H-1-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] -ethylsulfonylamino} -3methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylthio arbamyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- (4- [4- (2-methoxyphenyl) -1-piperazinyl] -butylsulfonyl} -3-methyl- 4- oxo-2-phenyl-4H-1-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propyl arb amoyl} -3-hydroxymethyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propyl arbamoyl} -4-oxo-phenyl-4H-1-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -2,3-methoxy-4-oxo-4H-1-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -4-oxo4H-1-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-phenyl] -propylcarbamoyl} -6-bromo-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propyl arbamyl} -6methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -6 **** hydroxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 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} -3methyl-6-nitro-4-oxo-2-phenyl-4H-1-benzopyran, 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -6amino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -6-acetamido-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -6ethylamino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1- piperazinyl] -propylcarbamoyl} -6-dimethylamino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {3- [4- (2-Methyl siphenyl) -1-piperazinyl] -propyl arb amoyl} -7methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propyl arbamoyl} -3methyl-4-oxo-2- (4-trifluoromethylphenyl) -4H-1-benzopyran, 8- {3- [4- (2-Methyl siphenyl) -1-piperazinyl] -propyl arb amoyl} -2- (4-benzoylphenyl) -3-methyl-4-oxo-4H-1-benzopyran, 8- {3 - [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3methyl-4-oxo-2- (4-phenoxyphenyl) -4H-1-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -2,3 dimethyl-4-oxo-4H-1-benzopyran, 8- {3- [4- (2-methoxyphenyl) - 1-piperazinyl] -propylcarbamoyl} -2 (tert-butyl) -3-methyl-4-oxo-4H-1-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -2-cyclohexyl-3-methyl-4-oxo-4H-1-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -2- (2-furyl) -3-methyl-4-oxo-4H-1-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3H-methyl-4-oxo-2-thienyl-4H-1-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -4-oxo2-phenyl-4H-1-benzothiopyran, (E) -8- {3- [4- (2-methoxyphenyl) ) -1-piperazinyl] -propylcarbamoyl} -3methyl-4-oxo-2- (2-styryl) -4H-1-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propyl arbamyl} -3methyl-2- (4-methylphenyl) -4-oxo-4H-1-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propyl arb amoyl} -2- (4methoxyphenyl) -3-methyl-4-oxo-4H-1-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -2- (4 ^w fluorophenyl) -3-methyl-4-oxo-4H-1-benzopyran, 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -6-methanesulfonylamino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propyl arbamyl} -3methyl-2- (4-nitrophenyl) -4-oxo-4H-1-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -6-diethoxyphosphonyloxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3methyl-4-oxo-2-trifluoromethyl-4H-1-benzopyran, 8- {N-MemuA-3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 7- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propyl arb amoyl} -2-benzoyl-3-ethyl-benzo [b] furan, 8- (3- (4- (2-methoxyphenyl) -1-piperazinyl] -propyl arbamoyl} -2- (4-biphenylyl) -3-methyl-4-oxo-4H-1-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3methyl-4-oxo-2- (3-pyridyl) -4H-1-benzopyran, 8- {3- [4- (2-acetoxyphenyl) -1-piperazinyl] -propyl arb amoyl} -3methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {3- [4- (2-methylaminocarbonyloxyphenyl) -1-piperazinyl] propylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- (3- [4- (2- methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -6acetoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, (K., 8) -8- (3- [4- (2-methoxyphenyl) ) -1-piperazinyl] -propylcarbamoyl} - 2,3-dihydro-4-hydroxy-4H-1-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propyl arbamoyl} -2- (4aminophenyl) -3-methyl-4-oxo-4H-1-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -2- (4-acetylaminophenyl) -3-methyl-4H-1-benzopyran, 8- (3- (4- (2-methoxyphenyl) -1-piperazinyl] -propyl arb amoyl} -2- (4-hydroxyphenyl) -3-methyl-4H-1-benzopyran 8- (3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -2-phenyl-4, Ν ^1, N ⁴ -mpuokco-4H -1-benzoyl thiopyran 7- (3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -2-phenylbenzo [b] furan and 8- (N-MemuA-4- [4- (2-methoxyphenyl) -1-piperazinyl] -butylsulfamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran; or a prodrug, enantiomer, diastereoisomer, oxide or pharmaceutically acceptable salt of such compound. A pharmaceutical composition comprising a compound according to any preceding claim, or a prodrug, enantiomer, diastereoisomer, N-oxide, or pharmaceutically acceptable salt of such compound, in admixture with a pharmaceutically acceptable diluent or carrier. A process for the preparation of compound Fl-YZ-B, wherein Y, Z and B have the meanings defined in claim 1, and F1 represents a group of the general formula wherein -----, X, W, R ₂ , R ₃ , R ₆ and R _? have the meanings defined in claim 1, characterized in that the method involves the condensation of a compound of general formula F1-YZL, wherein L represents a halogen atom or a leaving group, with a compound of general formula H-B, A process for the preparation of compound Fl-Y-Z-B as defined in claim 10, characterized in that the method involves the condensation of compound Fl-Y-H with compound L-Z-B, wherein L has the meaning defined in claim 10. 12. A process for the preparation of compound Fl-YZ-B, wherein Z and B have the meanings defined in claim 1, F1 has the meaning defined in claim 10 and Y represents one of the groups Y3, Y4, Y5, ΥΙΟ, Y14, Y27 , Y28, Y41, Y42 or Y44 as defined in claim 1, characterized in that the method involves condensation of compounds of the general formula F1-XQ-C1, wherein X represents a valence bond or a methylene or vinyl group, and Q represents a carbonyl or a sulfonyl group having a compound of the general formula A-NH-ZB, wherein A represents a hydrogen atom, an alkyl group or an OP group, wherein P ₂ is a protecting group. A method according to any one of claims 10 to 13, characterized in that it is carried out in polar solvents in the presence of a base at a temperature of 20 to 140 ° C. A method according to claim 13, wherein the base is potassium carbonate or triethylamine. A process according to claim 13 or claim 14, wherein the solvent is dimethylformamide, chloroform, dichloromethane or methanol. A process for the preparation of a compound Fl-YZ-B as defined in claim 10, characterized in that the method involves reacting a compound of the general formula Fl-X-COOH, F1-XCHO, F1-X-COC1, F1- X-NH ₂ or F1-X-OH, where X has the meaning defined in claim 12, with a suitable compound such as HZB, LZ-B, HS-ZB, HO-ZB, H ₂ NO-ZB, A-NH-ZB , or HCO-ZB, wherein L and A have the meanings defined in claims 10 and