SK100794A3 - Heterocyclic compounds - Google Patents

Abstract

There are disclosed compounds of the general formula <CHEM> The heteroatom X is preferably oxygen, but may have other values. The group W is preferably a carbonyl group, but may have other values. The preferred heterocyclic ring is thus a 4-oxo-4H-1-benzopyran ring. This may have a wide range of R2, R3, R6 and R7 substituents. Y is a linking group, chosen from a wide range, but including -COO- , -CONH- , -O- , -SO2- and -SO2NH-. Z is an alkylene chain, and B is a complex amine. These compounds and their prodrugs, enantiomers, diastereoisomers, N-oxides and pharmaceutically acceptable salts are useful for the treatment of hypertension and urinary tract troubles associated with benign prostatic hypertrophy, and for the treatment of other diseases.

Description

Technical field

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

BACKGROUND OF THE INVENTION

Flavoxate = 8- (2-piperidinoethoxycarbonyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran having the formula

is used as a pharmaceutical agent for urinary tract disorders because it exhibits a smooth muscle relaxation activity attributed to its activity by calcium antagonists. This activity is manifested on the smooth muscles of the bladder top or may be related to the urinary center of the central nervous system.

The compounds of the present invention described below essentially comprise multiple amino group complexes instead of a piperidino group. Other changes include alternatives to the ethoxycarbonyl group that separates the amino group from the benzopyran ring, alternatively the 2-, 3-, 6- and 7- benzopyran ring substitutions, the replacement of the ring heteroatom with a sulfur atom or a sulfinyl, sulfonyl or imino group and / or

2,3-dehydrogenation of the benzopyran ring. These structural variations provide novel compounds with the ability to interact with various biological systems, as confirmed by their affinity for α-adrenergic and 5HT _1A -serotinergic receptors. Flavoxate virtually lacks the affinity for these receptors.

SUMMARY OF THE INVENTION

The compounds of the invention have the general formula I

(I) where

- - - represents a single or double bond,

X represents an oxygen or sulfur atom or an imino, alkylimino group,

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

R ₂ is H or an alkyl, trifluoromethyl, phenethyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, carbocyclyl, substituted carbocyclyl, 2-furyl, 2-thienyl, 3-pyridyl or aroyl, where the substituents of the above mentioned groups, one or a plurality of halogen atoms and / or one or more alkyl, cyano, hydroxy, alkoxy, phenyl, phenoxy, trifluoromethyl, nitro, amino, alkylamino, dialkylamino, acylamino, alkylsulfonylamino or benzoyl groups, r ₃ represents a hydrogen atom or alkyl, hydroxyalkyl, alkoxyalkyl, aralkoxyalkyl , phenyl, hydroxy, alkoxy or aralkoxy,

R 8 represents a hydrogen or halogen atom or a nitro, amino, alkylamino, dialkylamino, 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 shown to be attached to a heterobicyclic ring from its left end and to its Z end from its right end:

(Y1) (Y2) (Y3) (Y4) (Y5) (Y7) (Y8) (Y9) (Y10) (Y11) (Y12) (Y13) (Y14) (Y15) (Y16) (Y17) (Y18) (Y19) (Y20) (Y21)

-WHAT-,

COO,

-CONH-, -CON _(CH3) -, -CON (OH) -,

-CH (OH) -, -CH (Oalkyl) -, -CH = CH-, -CH = CH-COO-, -CH = CH-CONH-, -CH = NO-,

-ch ₂ -,

-CH ₂ COO-, -CH ₂ CONH-, -CH ₂ NH-, -CH ₂ N _(CH3) -, _-CH2 N _(COCH3) -, _-CH2 N (CONH ₂₎ -, -CH ₂ NHCO-, -CH ₂ N (CH ₃₎ -CO-, -CH ₂ NH-CONH-, hs';, ^ & 5aäá Sfi »íiÄÍÍÍ iíAi4 *» 4> * i * N "." »» ... and

(Y22) CH ₂ NHSO ₂ -, (Y23) -ch ₂ o-, (Y24) -ch ₂ s-, (Y25) -ch ₂ so-, (Y26) -CH 2 SO 2 ^- t (Y27) -ch ₂ with ₂ nh-, (Y28) -ch ₂ with ₂ n (ch ₃ ) (Y29) NH, (Y30) -N _(CH3) -, (Y31) -n (coch ₃ ) -, (Y32) -n (conh ₂ ) -, (Y33) -NHCO- (Y34) -N _(CH3) -CO-, (Y35) NH-CONH-, (Y36) -nhso ₂ -, (Y37) -about-, (Y38) -with-, (Y39) -SO-, (Y40) -s ° ₂ -, (Y41) -so ₂ nh-, (Y4 2) -SO ₂ N (CH ₃ ) -, (Y43) -con (coch ₃ ) -, (Y44) -CSNH-. (Y45) -en (ch ₃ ) -, (Y46) 0 -CON (O-X 'X)

(Y47) -NHCOO-, and (Y48) -COS-;

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

B represents one of the following groups (BI) / N-N -A

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

(A1) phenyl substituted by one or more halogen atoms and / or one or more alkyl, alkoxy or hydroxy groups, phenyl, (A2) 2-pyrimidinyl, (A3) a group of the general formula

wherein - - - is as defined above and E represents an oxygen atom or a valence bond, (B2)

wherein each L 1 and L 2 independently represents a hydrogen atom, a phenyl, 4-fluorobenzyoyl or a 2-oxo-1-benzimidazolinyl group of the general formula (C 1 -P-OA, where n is 0, 1 or 2 and A is as defined above) with the proviso that L1 and L2 are not hydrogen atoms, (Β3)

wherein each R ₁₀ and R ₁₀ independently represents a hydrogen atom or an alkoxy or alkylthio group, ^R 12 represents a hydrogen atom or an alkyl group and n is 2 or 3, (Β4)

wherein R ₁₂ is as defined above and R ₁₃ is hydrogen or alkoxy and (Β5)

If - where R _{12 is} as defined above.

- represents a double bond, W represents a carbonyl group and X represents an imino group, the ring may be. tautomerized to form a 4-hydroxyquinoline structure, such compounds are included within the scope of the invention.

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

The term prodrung as used herein refers to derivatives of compounds of formula I in which there have been reactive groups such as amino, imino or hydroxy groups (particularly as or in W, R ₂ , R ₃ , R ₆ , Z, BI and B2 groups) or acidic amino groups (e.g., those present in Y3, ΥΙΟ, Y19, Y27, Y36 and Y41) masked; the derivatives release the compound itself in the living body and thus have the same pharmacological effect on the body as the compound itself. Prodrugs may be prepared by varying the pharmacokinetic properties of the compound, for example by preparing a delayed release or sustained release form of the compound or otherwise modifying the metabolism, absorption, distribution or plasma shelf life of the compound. The compounds further prepared in Examples 114 and 120 to 122 are examples of prodrugs.

The group of formulas will hereinafter be abbreviated as F1. Preferred meanings of substituents in the F1 group are as follows:

- - - double bond of an oxygen atom,

W: a carbonyl group, R ₂ phenyl,

R ₃ a methyl group,

R ₆ is a hydrogen atom;

R? hydrogen atom.

A group having all these preferred substituents is

3-Methyl-4-oxo-phenyl-4H-1-benzopyran-8-yl group.

Preferred groups for Z are trimethylene and tetramethylene. Y preferably represents one or more Y2, Y3, Y37, Y40, Y41 or Y42. B preferably represents one of groups B1 or B3, in particular a 1- (2-methoxyphenyl) -piperazinyl group.

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

The adrenergic antagonistic activity of the compounds of the invention makes them useful as agents affecting the body tissue, particularly rich in α-adrenergic receptors (such as blood vessels, prostate and urethra). Accordingly, the anti-adrenergic compounds of the invention, evaluated on the basis of their receptor binding profile, may be useful as therapeutic agents, for example, for the treatment of hypertension and micturition problems associated with obstructive lower urinary tract disorders, including but not limited to benign hypertrophy prostate.

The serotoninergic activity of the compounds of the invention makes them suitable as tissue-acting agents, particularly in the central nervous system where ^5HT 1α receptors act. 0 ^5-HT IA receptors are believed to regulate the action and release of serotonin as well as the release of other neuromediators and are found as the pre- and postsynaptic. The compounds of the invention have biological activity in blocking the binding between these receptors and their various specific ligands (e.g. serotonin). Accordingly, compounds of the invention that interact with the 5HT _1A receptor (evaluated based on their receptor binding profile) may be useful therapeutic agents in the treatment of anxiety and depression.

Surprisingly, the compounds of the invention (particularly those that exhibit affinity for both α-β-aderenergic and 5HT _1A- serotoninergic receptors) exhibit high selectivity for the mammalian lower urinary tract, i.e., are more active in anthrophizing urethral contractions than lowering blood pressure. In contrast, known α-antagonists such as prazosin, which is 1- (4-amino-6,7-dimethoxy-2-quinazolinyl) -4- (2-furoyl) -piperazine (GB 1156973), do not show such selectivity (av indeed, they cause hypotension (the most common side effect), while flavone derivatives structurally similar to flavoxate, such as terflavoxate, which is 8- (1,1-dimethyl-2-piperidinoethoxycarbonyl) -3-methyl-4-oxo-2-phenyl -4H-1-benzopyran hydrochloride (EP 0072620), does not cause urethral contractions. Naturally, the compounds of the invention that are not selective for the lower urinary tract are preferred as antihypertensive agents, but selective compounds can often be used as antihypertensive agents because of their low toxicity.

The compounds of the invention also exhibit good antagonistic activity against potassium chloride induced bladder contractions. This effect may be attributed to calcium antagonist activity and makes the novel compounds useful as lower urinary tract spasmolytics (i.e., useful in the treatment of urinary incontinence, compulsion syndrome, and the like).

Most of the compounds of the invention exhibit low toxicity. Thus, they can be used in larger amounts, preferably by often compensating for the relatively low level of activity some of these compounds possess. Naturally, those compounds that exhibit both high activity and low toxicity are preferred.

?

The invention further provides a pharmaceutical composition comprising a compound of the invention, or a prodrug, enantiomer, diastereomer, N-oxide, or a pharmaceutically acceptable salt of such a compound, in admixture with a pharmaceutically acceptable diluent or carrier.

Synthesis of compounds of the invention.

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

Procedure a:

Condensation of compounds of formula F1-Y-Z-L wherein L represents a halogen atom or a leaving group such as tosyloxy with a compound of formula H-B. The condensation is preferably, but not necessarily, carried out at a temperature in the range of 20-140 ° C in a polar solvent such as dimethylformamide or methanol, usually in the presence of a base such as potassium carbonate. Such condensations are illustrated in Examples 1 to 3, 7 to 9, 11 13 to 16, 21, 23 to 31, 38 to 42, 46 to 49, 54 to 59, 69, 73, 77, 78 and 84 below. See also Gibson's chapter in Patai, The Chemistry of the Amino Group, p. 45 et seq., Wiley Interscience, New York, 1968.

An alternative method for preparing the compounds of the invention is by condensation (under the same conditions as described in the previous paragraph) of compound F1-Y-H with compound L-Z-B, wherein L is as 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 also be prepared (see Gibson's chapter in Patai, supra).

Compounds of formula I bearing an NH ₂ group in R 8 or as a substituent in R ₂ may be prepared by reduction of the corresponding compounds I wherein R 8 or a substituent in R ₂ are NO ₂ groups. Such a reduction can be performed by:

I with a Ni-Raney catalyst in a protic solvent selected i

from methanol, ethanol, isopropanol, water and mixtures thereof, or;

J with SnCl ₂ , H ₂ O, optionally in the presence of hydrochloric acid, either as a protic solvent such as methanol, ethanol, isopropanol, water, acetic acid and mixtures 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 mixtures thereof. J

P

I

The temperatures of the above reactions will be selected within the range of &lt; RTI ID = 0.0 &gt; 100 C. &lt; / RTI &gt; Examples of this reduction are given in Examples 94 and 124.

I

The compounds of formula I having a NHAlk group as the R substituent can be prepared by monoalkylation, starting from the corresponding starting compounds of the formula I, wherein R = NH _second For example, the amino compound of formula I can first be reacted with an excess of trifluoroacetic anhydride, followed by reacting the obtained trifluoroacetyl derivative with an alkyl-L reagent and finally deprotecting the trifluoroacetyl alkylated derivative thus obtained by treatment with potassium carbonate in methanol or sodium borohydride or methanol. These reactions are described in Examples 32 and 33, where they were performed on Y groups.

Alternatively, compounds of formula I with NHAlk or N (Alk) ₂ groups, as Rg substituents, or as a phenyl group substituent in R ₂ , may be obtained by alkylation of the corresponding starting compounds of formula I wherein Rg = NH ₂ with appropriate alkanals in the presence of a reducing agent , such as sodium cyanoborohydride. Descriptions of these reactions are given in Examples 96 and 97 below.

Compounds bearing an OH group as R g or as a substituent in R ₂ may be prepared from the corresponding starting compounds of formula I alkoxy-substituted at the indicated positions. This may be accomplished by treating the starting compounds, for example, BBr ₃ in dichloromethane at 0-40 ° C (TWGreene, Protective Groups in Organic Synthesis, p. 87, Wiley Interscience, 1981) or other methods described in the same reference.

Compounds of formula (I) wherein - - - represents a single bond may be obtained either by selective hydrogenation of the corresponding compounds wherein - - - represents a double bond, or by conversion of suitable starting materials in which the 2,3-bond is already saturated, such substances being readily available. according to Reaction Schemes 4, 6 to 9, 11, 12 and 14. The latter is illustrated in Example 87 and is particularly preferred when the compound contains a nitro group because by hydrogenation the nitro group can be converted to an amino acid. Selective hydrogenations can be performed using an alternative application:

hydrogen in the presence of a metal or metal oxide catalyst (e.g. palladium on carbon or platinum oxide) in a protic solvent at 20-120 ° C (EH Rodd, Chemistry of Carbon Compounds, Vol. IVB, p. 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 et al., J. Med. Chem., 33, 1859, 1990).

Compounds in which W represents a hydroxymethylene group and the 2,3-bond is saturated can be obtained by reduction of the β 13 with sodium hydride of the corresponding compounds wherein W represents a carbonyl group and the 2,3-bond is saturated as described in Example 123 below.

In some cases, a compound of Formula I may be prepared by converting other (starting) compounds of the invention. Such conversions include:

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

Procedure c: by reduction as illustrated below in Examples 17 to 20, Fl-CH (OH) -Z-B → Fl-CH (Oalkyl) -Z-B by etherification as illustrated in Example 22,

Procedure d: Fl- _{(CH2) n-NH-ZB} -> Fl _{(CH2) n} N (CH ₃₎ -ZB

wherein n = 0 or 1, by N-methylation as illustrated in Example 35, procedure e: _N 1 - (CH ₂ ) _n -NH-ZB -> _N 1 - (CH ₂ ) _n -N (COCH ₃ ) -ZB where n = 0 or 1, by N-acylation as illustrated in Example 36 below, procedure f: Fl- _{(CH2) n-NH-ZB} -> Fl _{(CH2) n} N (CONH ₂₎ -ZB wherein n = 0 or 1, by reaction with potassium isocyanate as illustrated in Example 50 below. Procedure g: F1-CH (OH) -Z-B → F1-CO-Z-B by oxidation as illustrated below in Example 51, procedure h: Fl-Y-Z-B-> Fl-Y-Z-B (N-oxide) by oxidation as illustrated in Examples 43 below

and 122, method i: h ₂ n-f-yzb → ch ₃ conh-f-yzb (where H ₂ N-F1 is an F1 group in which R 8 is amino or R ₂ contains amino) using the N-acylation method described in Examples 36 and 95).

Procedure j: F1 (R ₆ = NH ₂ ) -YZB → F1 (R ₆ = CH ₃ SO ₂ NH) -YZB by amidification using the method described in Example 112.

procedure to:

or

_F1-YZ-NH-CH2 - ^ ⁰ '13 8

-> ^Γ1 - ^ ~ Ζ-Ν (Α1λ) -θΗ ₂ χΟ

or

Fl-YZN (Alk) -CH ₂ ^R 'Vx

Fl-YZ-NH- _(CH2) noQ

II

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

Some compounds may be prepared by further reactions. For example, those wherein Z contains a hydroxy substituent may be prepared further via an epoxy group.

Procedure 1: _{F1-y-CH2-CH-CH2} + HB -> _F1-y-CH2 -CH (OH) -CH ₂ -B

O as illustrated below in Example 45.

Further reaction via double bond is also possible, eg:

Procedure N: F1-Y-CH = _CH2 + HB -> _{F1-y-CH2-CH2-B} as illustrated in Examples 37, 63 and 82.

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

Procedure · n: F1- (X) - (Q) -C 1 + A-HN-ss -> F1- (X) - (Q) -N (A) -ZB (wherein X = bond, _CH2 or CH CH, Q = CO or SO ₂ , and A = H, alkyl or OPr, where Pr is a protecting group, as described in Example 12 (particularly preferred) and in Examples 60, 61, 64, 67, 68, 72, 87 , 88, 93, 98, 116, 129, and 130).

The same compounds can also be prepared by other procedures, including:

F1- (X) -COOH + A-NH-ZB in the presence of a coupling agent (e.g. dicyclohexylcarbodiimide, N, N'-carbonyl-diimidazole or diethylcyanosphonate) optionally in the presence of a promoter (e.g. 4-dimethylaminopyridine or N-hydroxybenzotriazole) in an aprotic or 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. Org. Chem., 5, 61, 1968, Ishihara, Chem. Pharm. Bull., 39, 3236,

1991) as illustrated in Examples 80, 86, 89, 90, 92, 99-111, 113-115, 117-119 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 ethereal solvents (e.g. diglyme); Fl- (X) -COO-Alk + A-NH-ZB optionally in the presence of a coupling agent (e.g. trimethylaluminium) in an aprotic and / or chlorinated solvent (e.g. hexane, dichloromethane) at -10/80 ° C, or without solvents at 80-180 ° C (SMWeinreb 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 addition of A-NH-Z-B at 0-80 ° C; optionally, a promoter (e.g., 1-hydroxypiperidine) may be added prior to the addition of the amine (Albertson, Org. React., 12, 157, 1962).

Procedure o: F1-COC1 + HS-Z-B → F1-Y48-Z-B Procedure p: F1-COC1 + HO-Z-B → F1-Y2-Z-B as illustrated below in Example 10.

Procedure q: Fl-CHO + H ₂ NO-ZB → Fl-Y11-ZB as illustrated below in Example 70.

Procedure r: F1-CHO + A-NH-Z-B → F1-CS-N (A) -Z-B (where A = H or CH-j) 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) such as illustrated further in Example 83.

procedure: F1-NH ₂ + HCO-AB -> F1-Y29-ZB as illustrated below in Example 34th

Procedure T: F1-Y-CH ₃ - _HO-CH2-B -> _{F1-y-CH2-CH2-B} as illustrated below in Example 4th

procedure u: F1-CH = CH-CONH ₂ + HOCH ₂ -B-> Fl-Y10-CH ₂ -3 procedure in: Fl-YZN ₃ + HC0-CH ₂ -0

F1-Y-Z-B3 procedure procedure under reducing conditions as illustrated in Example 44.

w: _{F1-YZ-NH2-L- (CH2) n} _ .o.ZA>

^F1-YZ-l B3 II as illustrated in Examples 74, 75 and 76th

f-yz-nh ₂ + 1-ch ₂ R

F1-Y-Z-B4 as illustrated in Example 52.

x: _F1-YZ-NH2 +

F1-Y-Z-B5 as illustrated in Example 65.

Procedure y: Fl-Y-Z-CHO + HB → Fl-Y-Z-B as illustrated in Example 53.

It will be appreciated by those skilled in the art that all of the above synthetic routes b) to y) could be simplified provided that the reactive intermediates do not carry additional groups sensitive to the same reactants (e.g., CO, NH ₂ , NHAlk or OH groups). Compounds of formula I bearing such reactive groups may be prepared by processes b) to y) provided that the reactive groups present in the starting materials are pre-protected and then deprotected after the reaction, as illustrated in Example 71. Some examples of protection and removal protecting groups for various reactive groups can be found in TWGreen, Protective Groups in Organic Synthesis, Wiley Interscience, 1981 (2nd edition 1991).

Alternatively, non-reactive groups (e.g. NO ₂ ) can be left unconverted during the first reaction and then converted to a reactive group (e.g. NH ₂ ) as a final step in the process. See e.g. Procedure (a).

The synthesis technique will depend on the desired compound being synthesized, but process n) is generally preferred for compounds that can be produced by it. Additional synthetic methods will be apparent to those skilled in the art.

Starting materials

The starting materials (Fl-YZL and Fl-YH and the like) used in the above-described preparations may themselves be prepared from simple compounds such as Fl-COOH, Fl-CHO, Fl-COCl, _F1-NH2 and Fl-OH by transformations known to those skilled in the art. Many such transformations are described in detail below. Many of these simple compounds (Fl-COOH, Fl-CHO, Fl-COCl, _F1-NH2 and Fl-OH) are commercially available or their synthesis reported in the literature. Those that are unavailable can be synthesized according to one or more of the following Reaction Schemes 1 to 16.

Reaction Scheme 1 leads to compounds that form a carbonyl group, and X is in which W represents an oxygen atom.

Scheme 1

a = co ₂ ch ₃ , co ₂ c ₂ h ₅ , no ₂ , ch = ch ₃ , = co ₂ h, nh ₂ .

Grade la

Procedure without isolation of the phenyl ester intermediate:

- R ₃ CH ₂ COCl or (R ₃ CH ₂ CO) ₂ O and a Lewis acid (e.g. AlCl ₃ or ZnCl ₂ ), without solvent or in an apritic solvent (e.g. nitrobenzene or chlorinated solvent) at 20-180 ° C.

Procedure for isolation of the phenyl ester intermediate:

- R ₃ CH ₂ COCl or (R ₃ CH ₂ CO) ₂ O is heated with starting material or other esterification methods such as the Schotten-Bauman procedure. The isolated ester is then heated in nitrobenzene or other non-protic solvent (e.g., chlorinated solvent), or without any solvent, at 20-180 ° C, in the presence of a Lewis acid such as AlCl ₃ or ZnCl ₂ (AMBlatt, Org., React., 1, 342 (1942).

Step 1b

R ₂ COCl or (R ₂ CO) ₂ O and R ₂ COONa alone or in a high boiling non-protic solvent (such as o-dichlorobenzene) at 150-220 ° C; this reaction also provides a direct transformation of compounds (2) to compounds (6) when compounds (2) have A = COOH;

- R ₂ C (OAlk) ₃ in the presence of HClO ₄ at 20-40 ° C or in pyridine in the presence of piperidine at 60 to 80 ° C,

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

Grade lc

- R ₂ COCl in pyridine at 20-100 ° C or a non-protic solvent at 0-80 ° C, optionally in the presence of a base such as

NET ₃ or 4-dimethylaminopyridine.

Stage 1 d

- K ₂ CO ₃ in acetone or methyl ethyl ketone at 20-80 ° C,

- NaH in DMSO or THF at 0 - 40 C C,

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

Stage 1 e

- HCl or H ₂ SO ₄ in AcOH at reflux or in alcohol (MeOH, EtOH, isopropanol) at 20 ° C at reflux temperature,

- CF ₃ COOH in dichloromethane at 20-40 ° C,

p-toluenesulfonic acid in the pool or toluene under reflux.

Stage 1 f

- R ₂ COCl and K ₂ CO ₃ or KOH in water and phase transfer catalyst in benzene or toluene under reflux,

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

Grade 1 g

If A is COOCH ₃ or COOC ₂ H ₅ group:

- NaOH in aqueous EtOH at 0 - 75 ’C,

- LiOH in aqueous DMF, MeOH or THF or mixtures thereof at 10-100 CC,

- HCl in an aprotic solvent such as dioxane at 60 - 120 C.

If A is N0 ₂ :

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

- reduction with hydrogen and a catalyst (e.g. Ni-Raney or Pd / C) in a protic solvent (e.g. MeOH ₂ , EtOH, isopropanol or mixtures thereof) at 20-100 C,

- reduction with SnCl ₂ in the presence of aqueous HCl in a protic solvent (e.g. AcOH) at 20-100 ° C,

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

If A is CH = CHCH ₃ group:

oxidation with Na ₂ Cr ₂ O ₇ or other oxidizing agents such as KMnO ₄ in acetone / H ₂ SO ₄ at 0 - 100 ° C

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

1953).

Scheme 2

ABOUT

co ₂ h 3

Stage 2a

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

- R ₂ C = c-COOAlk and Al ₂ O ₃ in an aprotic solvent (eg Et ₂ O) at 0-40 ° C,

R ₂ C = C-COOAlk and a base in an aprotic solvent (e.g. THF or DMF) at 20-140 ° C.

The last two options are both followed by treatment with polyphosphoric acid at 50-120 ° C.

Stage 2b

NaOH in aqueous EtOH at 40-75 ° C,

LiOH in aqueous DMF at 40-100 ° C.

Grade 2c stoichiometrically 30% H ₂ O ₂ in AcOH at 25-60 ° C, m-chlorobenzoic acid in chloroform at 0-30 ° C.

Stage 2d

- 30% H ₂ O ₂ in AcOH at 50-80 ° C.

Reaction Scheme 3 leads to compounds (2) wherein R ₇ is methoxy, W is carbonyl and X is oxygen or sulfur. Compounds (1) can be prepared according to Reaction Schemes 1 and 2 starting from suitable phenols or thiophenols (unsubstituted at the 2 or 6 position of COOAlk or NO ₂ ).

Scheme 3

Step 3a

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

This method can be used when R ₃ is other than H or ch ₂ OH.

Simple 2,3-dihydro intermediates (- - - = single bond) can be prepared according to Reaction Scheme 4, with the proviso that other reactive groups that might be present (e.g. NH ₂ , OH) were pre-protected as already has been described. The compounds (4) thus obtained can be converted to the corresponding derivatives with A = COOH or NH ₂ according to the method of step 1g.

Scheme 4

Step 4a

R ₂ -CHO, aqueous NaOH in EtOH or another protic solvent,

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

Step 4b

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

Step 4c

R ₂ -CHO, 0, 1N to 1Ν aqueous NaOH or another 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 an organic base (e.g. NEt ₃ ) (SE Kelly et al., J. Org. Chem., 56, 1325, 1991).

Step 4e

R ₂ -CHO in a chlorinated solvent (e.g. dichloromethane) at -78 ° C, then TiCl ₄ or Lewis acid (SEKelly et al., J. Org. Chem., 56, 1325, 1991).

Stage 4f

lithium diisopropylamide in THF at -78 ° C, then R ₂ -CHO (A. Baneri et al., Tetrahedron Letter, 1979, 3685).

Grade 4g

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

Grade 4h

R ₂ CH = CR ₃ COOAlk, triethylbenzylammonium hydroxide in an aprotic solvent (e.g. 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 with A = COOCH ₃ or COOC ₂ H ₅ are also hydrolyzed to compounds with A = COOH).

Step 4i concentrated H ₂ SO ₄ or P ₂ O ₅ or polyphosphoric acid or Lewis acid in nitrobenzene or toluene or without solvent at 0 - 180 ° C. (Also in this case, hydrolysis of A = COOAlk to A = COOH occurs).

Simple starting materials where R ₃ = OH or OR _g where

R _g is alkyl or aralkyl, can be prepared according to Reaction Scheme 5 wherein A is as defined in Reaction Scheme 1. Compounds (I) and (2) (which is the same as (2) and (4) in Reaction Scheme 4 but with R ₃ = H) may be prepared according to Reaction Scheme 4 using the appropriate phenols or thiophenols with R ₃ = H as starting materials. Compounds (4) used in Reaction Scheme 5 may be prepared by known methods from the corresponding salycilates or thiosalyciates ( see J. March, Advanced Organic Chemistry, 486, John Wiley and Sons, New York, 1985, L. Rene et al., Eur. J. Med. Chem.-Chim.Ter., 4, 385, 1977 and herein quoted works). Substituent A in compounds (3) and (6) of Reaction Scheme 5 can be transformed by the methods of Step 2g to Substituent B as defined in Reaction Scheme 1.

Step 5a aqueous NaOH in an alcoholic solvent (e.g. MeOH or EtOH), then 30% H ₂ O ₂ at -10 to -78 ° C (NDMeyer et al., J. Med. Chem., 34, 736, 1991 and cited therein) work). (Not when A is CH = CH-CH ₃ ; if A = COOR is simultaneously transformed into COOH).

Step 5b

If - - - - single bond:

Amyl nitrite or other alkyl nitrite without solvent or in a suitable solvent (e.g. EtOH or benzene) in the presence of a catalyst such as 37% HCl (Org. React., 7, 327, 1953 and references cited herein), then aqueous H ₂ SO ₄ in protic a solvent (e.g. AcOH) at 10-100 ° C (Acheson RM, An Introduction to The Chemistry of Heterocyclic Compounds, 347, John Wiley &amp; Sons, New York, 1976).

If - - - = double bond:

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

Stage 5c

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

Step 5d% ^H 2 ° ^2'NaOH or other base (e.g. NEt ₃ ) in a protic solvent such as MeOH at 20-100 ° C (SRDeshpande et al., Synthesis, 835, 1983) or photolysis and 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, Heterocycles, 26, 2117, 1987). (Not when A is CH = CH-CH ₃ ; if A = COOR is simultaneously transformed into COOH).

Step 5e

RgL, wherein L represents a leaving group (e.g. alkyl sulfate, halogen, tosyl) and a base (e.g. K ₂ CO ₃ , NaH, KOH, NaOH or LiOH) in an aqueous solvent (e.g. THF, DMSO, DMF, benzene) in the presence of a phase transfer catalyst (e.g., benzyltriethylammonium bromide) at 0-180 ° C.

Stage 5f

By methods according to step 1b.

Reaction Scheme 6, in which A has the same meaning as in Reaction Scheme 1, leads to compounds in which W represents a thiocarbonyl group. Compounds (1) and (2) of Reaction Scheme 6 can be prepared according to Reaction Schemes 1, 2, 4 and 5. Substituent A in Compound (4) of Reaction Scheme 6 can be transformed by procedures from step 1g to substituent B as defined in Reaction Scheme. 1.

Scheme 6

O O

Grade 6a ^P 2 ^S 5 ⁱⁿ Pyridine at 50-100 ° C (Stavaux et al., Bull. Soc. Chim. Fr., 2082, 1967).

Step 6b

P ₂ S ₅ or B ₂ S ₃ or SiS ₂ or Lawesson's reagent in a chlorinated solvent (e.g. chloroform) or an aromatic solvent (e.g. benzene, toluene, xylene) under reflux (Dean et al., J.Chem.Soc.C. 2192, 1963;

R. K. Razdan et al., J. Med. Chem., 21, 643, 1978; K. Clausen et al., Tetrahedron, 37, 3635 (1991).

Step 6c

COCl ₂ without a solvent or with an inert solvent (e.g. benzene) at 40-90 ° C (A.Schonberg et al., Chem.Ber., 101, 701, 1968).

Stage 6d

Thioacetic or thiobenzoic acid or potassium diethyl xanthogenate in a suitable solvent (e.g. benzene) at reflux (A.Schonberg, supra).

Reaction Scheme 7, in which A has the same meaning as in Reaction Scheme 1, leads to compounds in which W represents a methylene or hydroxymethylene group. Compounds (1), (2) and (4) of Reaction Scheme 7 can be prepared according to Reaction Schemes 1, 2, 5 and 6. Substituent A in compounds (7) of Reaction Scheme 7 can be transformed by procedures of step 1g to a substituent 3 such as as defined in Reaction Scheme 1.

Scheme 7

5

Step 7a

1,2-ethanedithiol or 1,3-propanedithiol in an aprotic solvent (e.g. dichloromethane or benzene or toluene) at 0-110 ° C in the presence of a catalyst (e.g. p-toluenesulfonic acid or boron trifluoride etherate).

Step 7b

R ₂ COCH ₂ R 3 in a suitable solvent mixture (e.g. EtOAc or dichloromethane plus EtOH or MeOH) saturated with HCl gas at 0-40 ^° C; then aqueous HCl ₄ in AcOH at 20-100 ° C (L. Jurd, Tetrahedron, 28, 493, 1972).

Step 7c

LiAlH ₄ in THF at reflux (if A is other than COOR and NO ₂ ),

ZnJ ₂ and sodium cyanoborohydride (6 equivalents) in a chlorinated solvent (e.g., 1,2-dichloroethane) at room temperature to reflux (CKLau et al., J. Org. Chem., 51, 3083, 1986).

Stage 7d

- Raney-Ni in an alcoholic solvent (e.g. isopropanol) at room temperature to reflux (Hilton et al.,

Soc., 90, 6887 (1968).

Step 7e

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

LiAlH ₄ in THF (or other suitable solvent) at 0-50 ° C (when A is other than COOR or NO ₂ ) (Degani et al., Ann.Chim., 61, 793, 1971; Kurosawa, Bul1. Chem. Soc. Jn., 51, 1175 (1978).

Grade 7f

Trityl perchlorate in acetonitrile at room temperature (Degani et al., Supra).

Grade 7g

Melting of the P ₂ O ₅ at ^80-180 ° C (Hortmann, et al., J. Am Soc., 96, 6118, 1974).

Grade 7h

NaBH ₄ in EtOH or other suitable solvent at 0 ° C to reflux (K.Anaya, Bull. Chem. Soc.Jpn., 40, 1884, 1967). Hydrogen (1-10 atm) in EtOH (or other suitable solvent) in the presence of a catalyst such as 5% or 10% Pd / C or Raney-Ni or PtO ₂ at rt to 80 ° C (K. Hanaya, supra). Not when A is CH = CH.CH-j. When A = NO ₂ is simultaneously reduced to NH ₂ .

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

Reaction Scheme 8 represents the preparation of simple starting materials such as (4), (5), (6) and (9), wherein A has the same meanings as in Reaction Scheme 1. Compounds (1), (2), (3) (7), (8) can be prepared according to the reaction scheme

1,2,4,5,7,9,11. Substituent A in compounds (4), (5), (6) and (9) of Reaction Scheme 8 can be transformed by procedures from step 1g to substituent B as defined in Scheme 1.

reaction

Scheme 8

Rg-H, Ac

Step 8a

Pb (OAc) ₄ in a suitable solvent (e.g. benzene, toluene) at reflux (GARussel et al., J. Am. Chem. Soc., 1906, 1975).

Step 8b

NaBH ₄ in alcohols (see Reaction Scheme 7, step 7a), then alkaline hydrolysis (if A = COOR, can be simultaneously converted to COOH), aluminum isopropoxide as described in Reaction Scheme 7, step 7f, diborane in THF at - 10 ° C to rt, then aqueous H ₂ O ₂ in the presence of NaOH (not when A is CH = CH-CH ₃ ; if A = COOR can be simultaneously converted to COOH). (Kirkiacharian et al., CRHebd.Seances Acad.Sci.Ser. C, 289, 227, 1979),

LiAlH ₄ and AlCl ₃ in a suitable solvent (e.g. THF) at 0 ° C to reflux (not for A = COOR or NO ₂ ) (Bokadia et al., J. Chem. Soc., 4663, 1961).

Grade 8c

Hydrogen (100 atm), copper chromite in EtOH at 140 [deg.] C, cf. MA Vickars, Tetrahedron, 20, 2873, 1964. When A = N0 ₂ it is simultaneously converted to _NH2 group.

Stage 8d

KM0 ₄ in terc. 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). (Unless A = CH = CH-CH ₃ ). (See also AHHaines, Methods for the Oxidation of Organic

Compounds, Academic Press Inc, (London), 1985, p. 3.2.2). osmium tetroxide (see AHHaines, supra, chapter 3.2.1) in a suitable solvent (e.g. Et ₂ O) at room temperature (Baranton et al., Bull. Soc. Chim. Fr., 4203, 1968) (no, if A is CH = CH-CH ₃ ), aqueous H ₂ O ₂ in formic or acetic acid at -20 to -50 ° C, then NaOH, H ₂ O, 45 ° C (Baraton et al., supra, AH Haines , supra, chapter 3.2.7) (not if A is CH = CH-CH ₃ if A = COOR is simultaneously converted to COOH), silver acetate and iodine in wet AcOH at 0-20 ° C (K.Hanaya, supra; AH Haines, supra, chapters 3.2.3, 3.2.4, 3.2.9) (not if A is CH = CH-CH ₃ ).

Step 8e% H ₂ O ₂ in the presence of NaHCO ₃ in benzonitrile at 0 to 110 ° C, then LiAlH ₄ in THF at 0-40 ° C (not for A = COOR and CH = CH-CH ₃ ) (Clark et al. Journ. Of Chem., 27, 865 (1974).

Grade 8f

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

Step 8b

See step 8b (Clark et al., Supra).

Grade 8h

0.4 M cerium chloride heptahydrate in MeOH, in a suitable solvent (e.g. MeOH); then NaBH ₄ at 0 ° C to 78 ° C. (WO 89/06650);

NaBH ₄ in diglyme at 0 ° C under reflux (GPThakar, Indian J.Chem., 3, 74, 1965) (when A = NO ₂ is converted to NH ₂ ); NaBH ₄ and AlCl ₃ in a suitable solvent (e.g. THF or benzene) at 0 ° C under reflux (not with A = COOR) (GPThakar, supra);

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

Simple starting materials with W = CH ₂ and a single bond at position 2,3 can be prepared according to Reaction Scheme 9, wherein A has the same meanings as in Reaction Scheme 1. Compounds (1) of Reaction Scheme 9 can be prepared according to Reaction Scheme 6 Compounds (1) of Reaction Scheme 9 can alternatively be obtained from compounds (2) by converting the latter to a 4-toluenesulfonic acid ester or a methanesulfonic acid ester or a halogen derivative which can be transformed into thioether derivatives (1) by nucleophilic thiol substitution. . These simple conversions can be performed by techniques known to those skilled. Compounds of Reaction Scheme 9 can be prepared according to Reaction Scheme 7. Compounds (3) of Reaction Scheme 9, P = OC (S) -aryl, or OC (S) -heteroaryl, or OC (S) O-aryl, or OC (S) S-alkyl, may be obtained by reacting compounds (2) with a suitable chlorothioformate or chlorothiocarbonate or 1,1-thiocarbonyl-diimidazole as described in J. Org. Chem., 55, 924, 1990 and Synthesis, 362, 1991 and references cited therein. Compounds (4) can be obtained from compounds (1) or (3) by simple elimination reactions with bases. Compound (5) may be obtained according to scheme 4. The substituent A in compounds (6) of Reaction Scheme 9 can be transformed by the processes of Step lg into a substituent B as defined in Reaction Scheme first

Scheme 9

R 8 = alkyl, aryl, heteroaryl or nothing,

P = halogen, O-tosyl, O-mesyl, OC (S) aryl, OC (S) heteroaryl, 1-imidoazolyl, OC (S) O-aryl, OC (S) O-heteroaryl

Step 9a

Raney-Ni in a suitable solvent (e.g. isopropanol) at rt to 100 ° C. When A is N0 ₂ is simultaneously converted to _NH2; triethyltin hydride in benzene or other aromatic solvent at 30-150 ° C. For other methods like nickel chloride and _NaBH4 in MeOH or boron-pyridine complex in trifluoracetic acid or in dichloromethane in the presence of A1C1 _3, see J. March, Advanced Organic Chemistry, p. 728, J. Wiley and Sons, New York, 1992, and references cited therein (not when A is CH = CH-CH ₃ ).

Step 9b

Hydrogen with a catalyst according to Reaction Scheme 8, step 8f. If A is NO _{2, it} is similarly converted to NH ₂ .

Step 9c

If P is an O-C derivative:

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

silane (e.g. triethylsilane or diphenylsilane) in a suitable solvent (e.g. dichloromethane) at -20 ° C to reflux in the presence of CF ₃ COOH or BF ₃ (FMMauser, J. Org. Chem., 55, 555, 1990);

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

If P is halogen or O-S derivative:

a reducing agent (e.g., sodium cyanoborohydride in hexamethylphosphoric triamide or NaBH ₄ in DMSO) selected from the agents cited in J.March, Advanc.Org.Chem., J.Wiley, New York, 1992, Chap. 0-76, 0-77.

Stage 9d

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 is simultaneously converted to 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 is simultaneously converted to NH ₂ ),

- hydrazine, NaOH in ethane-1,2-diol at 200 DEG C. (Chemical Abstracts, 74 (1971): 22699) (not for A = COOR, N0 _2), or other methods cited in J.March, supra (not for A = COOR, N0 _2);

- Stage Step 7c (not for A = N0 _2).

Reaction Scheme 10 represents pathways to compounds wherein W represents a valence bond and X represents an oxygen atom or a sulfur atom.

Scheme 10

A = COOAlk, NO ₂ , CH ₃ , B = COOH, NH ₂ .

Step 10a according to Step 1a, but using R ₃ COCl or (R ₃ CO) ₂ O instead of R ₃ CH ₂ COCl or (R ₃ CH ₂ CO) ₂ O with or without isolation of the phenyl ester intermediate, hexamethylenetetramine in CF ₃ COOH at reflux followed by the addition of aqueous HCl. If A = COOAlk, it may be hydrolysed to COOH in such strong acid conditions, that need re-esterification with a suitable alcohol (e.g. using thionyl chloride at reflux temperature) before Step 10c.

Step 10b

R ₃ COCH _(R2) Hal in acetone or methyl ethyl ketone or dichloromethane or chloroform with a suitable base such as K ₂ CO _{3, NEt3} or NaH, at 20-80 ° C

Step 10c

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

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

Using ArCOCH ₂ Br and K ₂ CO ₃ in acetone under reflux gives compounds (4) with R ₂ = ArCO.

Degree 10d

Intensive mixing in preheated polyphosphoric acid at 90 - 140 C,

Lewis acid (e.g. AlCl ₃ ) in chlorobenzene at 70-90 ° C. Cyclization carried out on compound (3) with R ₃ = C1 with a Lewis acid (e.g. AlCl ₃ ) in o-dichlorobenzene at 45 ° C or with BF ₃ in Et ₂ O at 20-25 ° C gives compounds (4), wherein R ₃ = OH, as reported by K. Davies, J. Chem. Soc. PT, 1, 2624, 1957, for compounds having X = S and _R2 = H.

Grade 10e sodium alcoholate (1 equivalent) in the same alcohol at 0-90 ° C; when A = COOAlk, it may be appropriate to use the corresponding AlkOH as the reaction solvent;

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

Grade 10f

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

Grade 10g

If A - COOAlk or NO ₂ , the methods described in step 1g can be used. It should be noted that reduction of the NO ₂ group to the NH ₂ group can be accomplished by catalytic hydrogenation simultaneously with hydrogenation of the double bond at the 2-3 position, as reported by SLMeisel et al., Heterocyclic Compounds, eds. Interscience Publ .: Compounds with Condensed Thiophene Rings p. 34 (1954) and M. Ahmed, ibidem, eds. Wiley-Interscience: Benzofurans, p. 56 (1974).

When A - NO ₂ and R ₂ = COAr, reduction is carried out with hydrogen, in the presence of Pt on carbon catalyst, to form

2,3-dihydro compounds (5) wherein B = NH ₂ and R ₂ = CH ₂ Ar as disclosed in WO 86/07056;

if A = CH ₂ and R ₂ , R 1, R ₆ are not CH ₃ or R ₂ does not carry a CH ₃ group, the compounds may be transformed to the corresponding:

A = CH ₂ Br by reaction with N-bromosuccinimide in CC1 ₄ and 2,2-azobisisobutyronitrilen or benzoyl peroxide as catalysts at reflux.

A - CHO reaction of the above compounds with hexamethylenetetramine in refluxing chloroform followed by acidic hydrolysis of the salt in boiling AcOH or by reaction of compounds containing A = CH ₃ with tetrabutylammonium dichromate in refluxing chloroform according to Valenti et al. Forsch. Forsch., 40, 122 (1990).

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

Compounds (4) of the above Reaction Scheme 10 containing R ₃ = C ₆ H ₅ or tert. butyl, R ₂ = H and X = O can be transformed into the corresponding intermediates containing R ₂ = 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 is an imino or alkylimino group and W is as defined above, simple starting materials can be prepared according to the following Reaction Scheme 11:

Scheme 11

A = COOAlk, NO ₂

R = H, alkyl

Step 11a

EtOC _(R2) = C (COOEt) ₂ at 80-140 ° C neat or in a polar solvent (e.g. isopropanol).

Step 11b

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

Step 11c 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), by heating in a high boiling solvent (e.g. Ph ₂ O) followed by hydrolysis of non-isolated compounds (4) (R ₃ = COOEt) with a strong acid (e.g. HCl) in a protic solvent (e.g. acetic acid) under reflux to give compounds (4) wherein R ₃ = COOH. The above isolated acids can be decarboxylated by heating in a high boiling solvent (e.g. Ph ₂ O) to give compounds (4) wherein R ₃ = H according to R. Albrecht et al. Ber. 105, 3118 (1972).

Step IIId heating in a high boiling solvent (e.g., Ph ₂ O) at 255 ° C, when R = Alk, compounds (4) are obtained directly from compounds (1) without isolation of compounds (3) by condensation with R ₂ COCH (R). ₃ ) COOAlk in polyphosphoric acid at 90-150 ° C according to F. Piozzi et al., Gazz. Chim. It., 100, 678 (1970).

Degree Ile

Al / Hg amalgam in aqueous EtOH solution under reflux followed by acidification with strong acid (e.g. HCl) and treatment with FeCl ₃ P ° ^d reflux by WADenny et al., J. Med. Chem., 32, 396, 1989.

If A = COOAlk, the compounds (4) can be hydrolyzed to the corresponding A = COOH before carrying out the step IIe.

If A = NO ₂ , intermediates (5) with A = NH _{2 are obtained} .

Stage IIIf

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

If A = COOAlk, compounds (1) could be hydrolyzed to the corresponding A = COOH before carrying out step f. All the compounds (1) have R = H and the obtained Compounds (5) have R ₃ = H,

Grade 11g

R ₂ CH (Hal) -CH (R ₃ ) COOH in a protic solvent (e.g. water) in the presence of a strong base such as NaOH at 100-125 ° C followed by cyclization of isolated anilinopropionic acid compounds with preheated polyphosphoric acid at 120- 125 ° C or with phosphorus pentoxide in a high boiling aprotic solvent (eg xylene) at 120 to

140 ’C. In some cases, it is useful to start with compounds (1) wherein R = tosyl or other suitable protecting groups; the obtained compounds (6), wherein R = tosyl, can be readily converted to compounds (6), wherein R = H, by hydrolysis with a strong acid (e.g. HCl) in a protic solvent (e.g. AcOH) under reflux. When A = COOAlk, compounds (6) having A = COOH are obtained.

Degree llh

R ₂ CHO and ethylene in AcOH and HCl at 25-30 ° C according to

KDHesse, Liebigs Ann.Chem. 741,117 (1970). If compounds (1) have R = H starting materials (7), R = R ₃ = H.

Epichlorohydrin followed by cyclization of isolated anilinopropanol derivatives in refluxing N, N-diethylaniline or o-dichlorobenzene in the presence of proton acceptors (e.g. NEt ₃ ) according to SDBoyd et al., J. Org. 30, 2801 (1965). In this case, Compounds (7) having R = _R2 = H and _R3 = OH.

Step 11i by hydrogenation in the presence of a catalyst (e.g. platinum oxide) in a protic solvent (e.g. EtOH) at 20-30 ° C and 2-4 atm according to G.M.Coppola, J.Heter.Chem. 15, 645 (1978).

If A = NO ₂ , compounds (7) having A = NH _{2 are obtained} . The thus obtained compounds (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 1g.

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

Scheme 12

Rs

R /

W - CH ₂ or a bond

Step 12a Oxalyl chloride in a polar solvent (e.g. THF) under reflux followed by internal Fridel-Crafts acylation of crude chloro-hydroxylamide with Lewis acid (e.g. AlCl ₃ ) in a nonpolar solvent (e.g. CS ₂ ) under reflux, according to EP 0402859,

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 addition of a strong acid (e.g. HCl) as described in EP 0402859.

Reaction Schemes 13 and 14 provide simple starting materials in which X is an imino group and W is a valence bond. In these two reaction schemes, A has the same meanings as in reaction scheme 1.

Scheme 13

Step 13a

ClCH ₂ C (Cl) = CH ₂ in the presence of K ₂ CO ₃ at 40-80 ° C acc

L. Purdie, J. Chem. (C) 1970, 1126.

Step 13b

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

Step 13c

BF ₃ in MeOH at 130-155 ° C, heating at 100-110 ° C.

Compound (5) obtained by Step 13c always have _R2 = CH ₃ ·

Stage 13d

R ₂ COCH (OAlk) ₂ in a non-polar solvent (e.g. toluene) in the presence of iodine as catalyst at reflux in azeotropic conditions followed by reduction of the isolated (or not isolated) imino Compound by NaBH ₄ in a polar solvent (e.g. MeOH) in the presence of NaOH as catalyst for reflux. If A = COOAlk, it will be hydrolysed to COOH.

Step 13e sodium amide in a high boiling solvent (e.g., N, N-diethylaniline) at 220-250 ° C by F. Piozzi et al., Gazz. potassium budoxide in a polar solvent (e.g. DMF) at 20-100 ° C according to EP 0042298.

Stage 13f

BF ₃ in a non-polar solvent (e.g. benzene) at 5 to 10 ° C.

Grade 13g

Zn or Fe dust in an acidic medium (e.g. AcOH) and water at 70-100 C. If A = NO ₂ is reduced to the NH ₂ ·

Step 13h Thionyl chloride under reflux. The resulting acyl chlorides are isolated and reacted with sodium azide in an acidic medium (e.g., AcOH) at 10-20 ° C followed by heating to 50-70 ° C.

Step 13i Diazotization with NaNO ₂ in concentrated H ₂ SO ₄ followed by addition of ZnCl ₂ at 5-10 ° C and reaction of the isolated diazonium salts with CH ₂ = C (R ₂ ) COOH in a polar solvent (e.g. acetone) in the presence of copper salt (e.g. 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.

Stage 13j

R ₂ CH ₂ NO ₂ in a polar solvent (e.g. EtOH) in the presence of 60% base (e.g. n-butylamine) and catalytic amounts of acid (e.g. AcOH) under reflux.

The thus obtained compounds (5) can be converted to the corresponding derivatives containing A = COOH or NH _{2 by the} methods of Reaction Scheme 1 step 1g.

In Scheme 14, compounds (4) containing R ₃ = H correspond to compounds (5) of Scheme 13.

Scheme 14

Step 14a

NaOH ₂ in aqueous acidic medium (e.g. HCl) at -5 to + 5 ° C, isoamylnitrite in polar solvent (e.g. EtOH) at 5 ° 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 HCl solution under reflux according to Horner et al., Ber. 85, 1073 (1953).

Stage 14c

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

R ₃ COCH (R ₂ ) Hal in a polar solvent (e.g. acetone) in the presence of a suitable proton acceptor (e.g. K ₂ CO ₃ ) under reflux followed by cyclization of isolated B-anilinoketone intermediates with freshly melted ZnCl ₂ in a protic solvent (e.g. EtOH) under reflux,

- R ₂ CH (Hal) CN in the presence of BC1 ₃ and a Lewis acid (e.g. _TiCl4) in an apolar solvent (e.g. benzene) at reflux followed by cyclization of the isolated 2-amino-a-halogénacetofenonových compound with a suitable reducing agent (e.g. NaBH ₄₎ in a polar medium (e.g. dioxane-water) at reflux, according to T. Sagusawa, et al., J. Org. Chem., 44, 578, 1979. The above method yields compounds (4) having R ₃ = H,

- R ₂ COCH (R ₃ ) Hal (half equivalent) in a polar solvent (eg MeOH) under reflux followed by cyclization of the isolated Schiff base intermediates with a strong acid (eg CF ₃ COOH at 20-30 ° C),

Stage 14d

R ₂ COCH ₂ R ₃ when heated to 100 ° C without solvents or at reflux in a polar solvent (eg MeOH) followed by cyclization of the isolated hydrazone compounds with polyphosphoric acid at 100 - 130 ° C or simple heating in ethylene glycol or aqueous formic or ethanolic acid formic acid.

The cyclization can also be carried out by heating in ethanolic HCl under reflux or in an AcOH / HCl mixture under reflux or in orthophosphoric acid at 95-105 ° C or by simple heating with anhydrous ZnCl ₂ at 100-200 ° C. If A = COOAlk, compounds (4) having A = COOH can be obtained.

Grade 14e borane-pyridine complex at 0-30 ° C followed by addition of a protonating agent (e.g. HCl), tin or zinc and aqueous HCl at 50-100 ° C,

_NaBH4 in the presence of a Lewis acid (e.g. A1C1 ₃₎ ret pyridine at 0-30 ° C or alternatively in the presence of a salt like cobalt or zinc chloride, sodium borohydride 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 general methods are disclosed by Houlihan in the Heterocyclic Compounds, Part One, eds. Wiley-Interscience: Indoles, p. 462 (1972). When A = NO ₂ , compounds (4) can be reduced to the corresponding compounds (5) having A = NH ₂ .

Stage 14f

NaH and RHal in an aqueous polar solvent (e.g. DMF) at 20-80 ° C,

RHal in the presence of potassium carbonate in a polar solvent (e.g. acetone) under reflux, sodium amide and RHal in a polar anhydrous solvent (e.g. THF) at low temperature (-70 ° C).

Compounds (4) bearing other reactive groups such as NH ₂ or OH should be protected using suitable protecting groups which can be selectively cleaved at the end using deprotection methods.

Grade 14g

RHal in the presence of an alkali metal carbonate (e.g. potassium carbonate) as reported Houlihan in Heterocyclic Compounds, part two, Ed. Wiley-Interscience: Indoles, p. 90 (1972) and references cited therein, the compound (5), bearing other reactive groups such as _NH2 or OH, have to be protected as described above,

Grade 14h

tetrachloro- [1,4] benzoquinone in a polar solvent (e.g. ethylene glycol monomethyl ether) under reflux, copper chloride in pyridine under reflux according to Kikugaw et al., J. Jeter. Chem., 16, 1325 (1979).

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

Compounds (4) of Reaction Scheme 14 having R ₂ = 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 ring contraction using an oxidant ( e.g. sodium periodate) and a base (e.g. NaOH) in aqueous EtOH at reflux according to SDBoyda 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 ₂ according to the method of Reaction Scheme 1, step 1g and from them to alternative final products. If NH is present and could interfere with the following reactions, it may be protected as described by TW-Green in Protective Groups in Organic Synthesis, Wiley Interscience, 1981. Alternatively, non-reactive groups (e.g. NO ₂ ) may be converted to reactive groups (e.g. NH ₂ ) as the final preparation step.

Starting materials in which W represents a valence bond, X represents an imino group and the 7-substituent is a carboxymethyl group, can be obtained according to Reaction Scheme 15.

Scheme 15

Step 15a

Hydrogen in the presence of 10% Pd / C as a catalyst at 45 lbs in water containing one equivalent of NaOH followed by diazotization with sodium nitrite in HCl at 0-5 ° C and stannous chloride. The cyclization is carried out during acidification of stannous salts using H ₂ S terminates and refluxed in xylene, are not HEBaumgarten, et al., J. Am., 82, 3977, 1960.

Step 15b

- R ₃ CH ₂ COR ₂ in the presence of acid (e.g. acetic acid) in a polar solvent (e.g. EtOH) at reflux as shown in the work-WJWelstead and et al., J.Med.Chem., 22, 1074 ( 1979) for r ₂ = CH ₃ and R ₃ = C ₆ H ₅ , where steps 15c and 15d are also given,

Step 15c lower alkanol (e.g. MeOH, EtOH) under reflux in the presence of a stream of hydrogen chloride,

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

The preparation of simple starting materials having R ₃ = hydroxyalkyl and / or the corresponding ethers can be carried out by reacting either compounds (3) of Scheme 1, compounds (2), (4) or (5) of Scheme 2, compounds (4) of the reaction schemes 6, 10, 11 and 15, the compounds (5) of reaction scheme 13 and compounds (4) and (6) of reaction scheme 14 having _R3 = H, C-j according re68 action scheme 16, wherein a and B are the same as in Reaction Scheme 1, R ₄ represents an alkyl or aralkyl group and R ₅ represents H or an alkyl group:

Scheme 16

R ₄ = Alk, Aralk R ₅ = H, Alk

Stage 16a:

R ₃ = H, W = CO, CS (and no activated absent the 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.Jap., 57, 2323, 1984) .

R ₃ = CH ₃ , W = CO, CS, bond and no other methyl groups in the molecule:

N-bromosuccinimide in the presence of benzoyl peroxide or 2,2'-azobisisobutyronitrile in CC1 ₄ at 50-80 ° C,

Step 16b

R ₃ = H, W = bond, X = O, S, NH or N-Alk and there are no electron donor groups present on the other rings:

phosphorus oxychloride and DMF at 50 - 140 ° C or others

Vilsmeyer-Haack reagents (see Jitz, Adv.Org.Chem., 9,

225, 1976)

R ₃ = CH ₃ , W = bond, X = O, S, NH or N-Alk and no other CH ₃ groups are present:

irradiation with Hg by a high pressure lamp in a protic solvent (e.g. AcOH) at 20-100 ° C as reported by Frasca et al., Tetrahedron, 23, 603, 1973.

Stage 16c

- sodium or potassium acetate in aprotic solvents (eg acetone, DMF) at 40-120 C. C.

Stage 16d

R ₅ in compounds (5) = H:

A reducing hydride (e.g. _NaBH4) in a polar solvent (e.g. MeOH or EtOH or dioxane) at 0-80 ° C,

R ₅ in compounds (5) = alkyl:

alkylmagnesium bromide in protic solvents (e.g., Et ₂ O, THF at 0-60 ° C).

Step 16e

NaOH or LiOH in protic solvents (e.g. alcohols, water) or other mixtures at 25-50 ° C (in which case A = COOAlk may be simultaneously hydrolyzed to COOH).

Stage 16f

The same methods as described in Step 1g of Reaction Scheme 1, but oxidizing CH = CHCH ₃ to COOH for compounds (5).

Stage 16g

The strong base or púšťadlách gene (e.g. NaH) and _R4-L reagent (where L is halotosyloxyskupina) in anhydrous aprotic extended (e.g. DMF or THF) at 20-140 ° C,

Stage 16h

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

The simple compounds (6) having the hydroxyalkyl group at the 3-position obtained in this manner can be reacted as such or alternatively can be derivatized to hydroxymethyl groups by known reagents and methods such that said group does not interfere in the other reaction steps necessary to prepare the protected hydroxyalkyl group. R _3rd

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

Prodrugs as defined above may be prepared from the corresponding hydroxy compounds by Method 1 below or from the corresponding amide compounds by Method 2 below.

Method 1 by reaction with chloroforminate, isocyanate or isothiocyanate, carbonyl chloride or bromide or another activated acid derivative (e.g. anhydride) in a suitable solvent (e.g. chlorinated solvent, DMF, THF, dioxane, acetonitrile, pyridine) in the presence or absence of a base (e.g. ₃ , pyridine, 4-dimethylaminopyridine, NaOH, potassium carbonate or 1,10-diazabicycloundecene or other unspecified reagents) at -20/100 C, by reaction with carbocylic acid in the same solvents as above, in the presence of a condensing agent such as Ν, Ν ' -carbonyldiimidazole, carbodiimides or other substances known to those skilled in the art by reaction with a dialkyl or diaryl chlorophosphate or a dialkyl cyanophosphonate under the same conditions as described above (for example such derivatization methods see Example 144 and SOThorberg et al., J. Med. Chem., 30, 2008, 1987).

Method 2

Prodrugs derivatives of acidic NH groups, as described above, can be synthesized from compounds of formula I by preparing the N-hydroxy (substituted) methyl-derivative and by the same reaction as described above for oxygen derivatization.

The intermediate N-hydroxy (substituted) methyl derivative can be isolated or directly reacted to give the desired compound. N-Hydroxy (substituted) methyl derivatives of the Ny-CH type (R-JOH, where R 1 = H or CCl ₃ , can be obtained by reacting suitable compounds of formula I with formaldehyde or CCl ₃ as described in HEZaugg, Organic Reactions, 14 Chapter 2, 52 J.Wiley and Sond, New York, 1956 or JPChrupp, J. Org. Chem., 28, 2592, 1965.

In the case where R 1 = phenyl, said compounds can be synthesized by reaction with benzaldehyde and a cyclic amine (e.g. morpholine) in MeOH or dichloromethane: MeOH 1: 1 at 0 ° C to reflux and hydrolyzed intermediates 0.1 N HCl at pH 4. (O. Jacobseen, Annalen, 157, 243, 1884, H. Bundgaard et al., Int. J. Pharm., 22, 45, 1984).

All of the above processes and reaction steps are intended to be exemplary and not limiting. It will be appreciated by those skilled in the art that the above chemical transformations are carried out on polyfunctional substrates and that the reagents used could interfere, also by reaction with other groups present in the molecule. For example, catalytic hydrogenation may transform nitro groups into amino groups as desired, but it may also occur that the isolated double bonds could be hydrogenated and halogen atoms removed; Lithium aluminum hydride can reduce conjugated ketones to alkanes as desired (e.g., step 7c in Reaction Scheme 7), but also COOAlk groups to CH ₂ or NO ₂ groups to -N = N- etc. Undesirable side reactions can be avoided or minimized by selecting appropriate conditions or by using alternative reagents or other synthetic procedures. If such an alternative solution yields negative results, the unwanted intermediates obtained must be transformed into the appropriate compounds using methods known to those skilled in the art.

DETAILED DESCRIPTION OF THE INVENTION

Detailed preparation of intermediates

8- (3-Bromopropoxycarbonyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate I) 1,3-dibromopropane (g) was added dropwise at room temperature to a suspension of 30 g of 3-methyl- Sodium 4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylate in 150 ml dimethylformamide and 35 ml water. The reaction mixture was stirred at room temperature for 5 days. 100 ml of water are added and stirring is continued for a further 15 minutes. The precipitate was filtered off with suction, 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 from ethanol to give 27.7 g of the title compound, m.p. Mp 114-115 ° C.

The benzopyrancarboxylate salt used in the previous synthesis was prepared by dissolving 104 g of the corresponding acid in 560 ml of hot methanol and adding 280 ml of an aqueous solution of 31 g of sodium hydrogen carbonate. 850 ml of acetone are added to the solution to precipitate the desired salt, which is collected by suction filtration (62 g, mp 280 ° C). The corresponding acid is prepared according to Da R _e , P. et al., J. Med. Pharm. Chem. 2

263, 1960.

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

467 ml of a 1.48 N solution of sodium borohydride in anhydrous dimethylformamide are added over 30 minutes, with stirring at room temperature, to a solution of 100 g of 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carbonyl chloride in 1 liters of anhydrous dimethylformamide. The reaction mixture was stirred at room temperature for 2.5 hours. While maintaining the temperature at 0-5 ° C, 88 ml of 2N hydrochloric acid are added. 102 ml of 12.7 N sodium hydroxide solution are then added. The mixture was poured into 6 liters of water, stirred for 3 hours and filtered through a Buchner funnel. The filter cake was washed with 4N sodium hydroxide solution and then with water. The resulting white solid was crystallized from methanol to give 50 g of the title compound, m.p. Mp 145-147 ° C.

E-8- (2-Carboxytinyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (interm. III)

A mixture of 7.92 g of 8-formyl-3-methyl-4-oxo-2-phenyl-4H-1 benzopyran (prepared as described in Uneyama K. et al., Bull. Chem. Soc. Jap., 58, 2361 (1985). 3.75 g of malonic acid and 0.46 ml of piperidine in 15 ml of anhydrous pyridine were stirred at 100 DEG C. for 3 hours. After cooling to 20-25 ° C, the reaction mixture was poured into a mixture of 90 g of crushed ice and 33 ml of hydrochloric acid (d = 1.18). The resulting precipitate was collected by suction filtration, washed with water and crystallized twice from 95% ethanol to give 5.5 g of the title compound, m.p. Mp 226-229 ° C.

- 76 E-8- (2-Chlorocarbonylvinyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (interm. IV)

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 resulting crystals were collected by suction, washed with acetone and dried in vacuo to give 6.8 g of the title compound, m.p. (190) 196-198 C after recrystallization from toluene.

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

1.17 g of magnesium sawdust, 7.4 ml of anhydrous ethanol and 0.2 ml of anhydrous carbon tetrachloride were placed in a round-bottomed flask under a stream of nitrogen. As the temperature begins to rise, 7.5 ml of anhydrous chlorobenzene is added and then a solution of 5.28 ml of anhydrous diethyl malonate and 3.5 ml of anhydrous chlorobenzene in 16 ml of anhydrous ethanol is slowly added dropwise (25 minutes). The reaction flask was heated to 75 ° C for two hours, cooled to 25 ^° C, and a solution of 8.8 g of 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carbonyl chloride in 88 mL was slowly added. ml of anhydrous chlorobenzene without the temperature exceeding 35 ° C. The reaction mixture was further stirred at 35 ° C for 2 hours and then cooled to 0 ° C. 13 ml of water and 1.9 ml of sulfuric acid (d = 1.84) are added. The solution obtained is decanted from insoluble inorganic material and stripped in vacuo.

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

8-Bromoacetyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (interm. 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 at 20-25 ° C for 1 hour, the solution was washed with 400 ml of 2N aqueous sodium hydroxide solution and then repeatedly with water, dried over anhydrous sodium sulfate and stripped in vacuo. The crude product was treated with diethyl ether, collected by suction filtration and crystallized from acetone. 16 g of the title compound are obtained, mp 134-135 ° C.

8- (2-Hydroxyethylcarbamoyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (interm. VIII)

A solution of 4.55 g of sodium nitrite in 12 ml of water is added dropwise to a stirred mixture of 15.1 g of 8-amino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (prepared as described in Da Re, P. et al., Il.Farmaco (ed.Sci), 11, 670, 1956) in 150 ml of hydrochloric acid (d -1.18) at -5 ° C. Stirring is continued at 30 ° C. The solution was poured over 10 minutes at -5 to 0 ° C into 120 ml of 30 wt. solution of sulfur dioxide 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 water are added to the mixture, separated by suction filtration, washed over sodium hydroxide to a constant weight of 18 g of crude title product, m.p. 165-170 ° C, for use without further purification.

The precipitate formed is drained and dried in a desiccator

8- (3-Chloropropoxy) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (interm. IX)

This compound was prepared in the same manner as Intermediate XI, but using 1-bromo-3-chloropropane instead of 1-bromo-2-chloroethane, m.p. 98 - 102 ´C after washing 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 to a stirred mixture of 5 g of 8-amino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran and 3 ml of triethylamine in 60 ml. ml of anhydrous tetrahydrofuran. After stirring at 0 ° C for 1 hour and at room temperature for 1 hour, the reaction mixture was poured into water and filtered by suction, the filter cake was washed with water. Desiccation gave 5.5 g of the title compound, m.p. 229-230 C. C.

8- (2-Chloroethoxy) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (interm. 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, p. 506 et seq., 6.22 g of anhydrous potassium carbonate and 25.5 ml of 1-bromo-2-chloroethane in 70 ml of dimethylformamide are stirred at 60 DEG C. for 25 hours. The mixture is 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 solution and dried over anhydrous sodium sulfate. The solvents and excess 1-bromo-2-chloroethane were evaporated in vacuo to give 8.8 g of the title compound, m.p. 141-142 ° C after crystallization from chloroform: hexane.

8- (2-Azidoethoxy) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (interm. XII)

A mixture of 15.2 g of intermediate XI and 6.24 g of sodium azide in 150 ml of anhydrous dimethylformamide was stirred at 70-75 ° C for 12 hours. After cooling to 20-25 ° C, the reaction mixture was poured into 1.5 L 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 taken up in water, collected by suction and dried to give 14 g of the title compound, m.p. 119-120 C. C.

8- [N- (2-Hydroxyethyl) -N-methylcarbamoyl] -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (interm. XIII)

A solution of 1.6 ml of 2-methylamino-ethanol in 10 ml of water is added dropwise over 5 minutes to a suspension of 6 g of 8-chlorocarbonyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran and 1.52 g of carbonate of potassium in 60 ml of acetone. After stirring at 20-25 ° C for 2.5 hours, the solvent is removed in vacuo and the residue is taken up in 150 ml of acetone. The mixture was refluxed for 15 minutes and then filtered. The solvent is removed from the filtrate and the residue is dissolved in 20 ml of dimethylformamide, treated with 14 ml of 1.4% sodium carbonate solution, stirred for 10 minutes at 20-25 ° C and diluted with 150 ml of water. The mixture was extracted with chloroform and the organic layer was washed with 0.5 N hydrochloric acid and then with water. The solution was dried over anhydrous sodium sulfate and the chloroform was evaporated. The resulting oil is removed until

200 ml diethyl ether and stirred for 2 hours at 20-25 ° C. The solids were collected by filtration and crystallized from ethyl acetate to give 4.97 g of the title compound, m.p. Mp 128-130 ° C.

8- (2-Chloroethylcarbamoyl-3-methyl-4-oxo-phenyl-4H-1-benzopyran (interm. XIV)

The title compound was prepared in the same manner as intermediate XXXVII, but using intermediate VII instead of intermediate XXXVI and carrying out the reaction at room temperature, m.p. 181-182 ° C (ethyl acetate).

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

A solution of 1.1 ml of thiomyl 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 at room temperature for 4 hours. Removal of the solvent gave an oil which was taken up in diethyl ether. The title compound precipitated as a white solid, collected by filtration for use without further purification, m.p. (118) 126 - 128 ´C (diethyl ether).

8- (4-Bromobutoxy) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (interm. XVI)

A mixture of 5 g of 8-hydroxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 4.2 g of anhydrous potassium carbonate and 43.6 g of 1,4-dibromobutane in 45 ml of dimethylformamide is stirred at 75 g. ° C. The mixture is cooled to 20-25 ° C, poured into 100 ml of water and extracted with dichloromethane. The organic solution was washed with brine and dried over anhydrous sodium sulfate. The solvents and excess 1,4-dibromobutane were evaporated in vacuo. The residue is rinsed with 55 ml of petroleum ether: diethyl ether 7: 4 and collected by suction filtration. 5.6 g of the title compound, m.p. Mp 91-92 ° C.

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

This compound was prepared by the method described for the preparation of intermediate XVI but using 1,5-dibromopentane instead

1,4-dibromobutane and purification of the crude product by silica gel column chromatography (eluting with dichloromethane: ethyl acetate 99: 1), m.p. 75-76 ° C after washing with petroleum ether: diethyl ether 30: 4.

8- (2-Chloroethoxymethyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (intermediate XVIII) ml of thionyl chloride in 18 ml of chloroform was added at 0 ° C to a stirred solution of 23 g of intermediate XXII and 11 ml of triethylamine in 185 ml of chloroform. The reaction mixture was warmed to 70 ° C and stirred for 2 hours. After cooling to room temperature, it was poured into water. The organic layer 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 (interm. XIX)

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

8-Methylaminomethyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (interm. XX)

A solution of 15.1 g of anhydrous zinc chloride and 14.5 g of sodium cyanoborohydrin in 400 ml of anhydrous methanol is added dropwise at 0 ° C to a stirred 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 at 20-25 ° C for 5 hours, the solvent was evaporated in vacuo and the residue was taken up in 200 ml of water and collected by suction. The crude product was dissolved in aqueous acetic acid, washed with ethyl acetate and reprecipitated by the addition of cold 6N sodium hydroxide solution. 49 g of the title compound, m.p. 97-99 ° C after crystallization from 75% ethanol.

8- (2-Chloroethylthiomethyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (interm. 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 and spontaneously crystallized 42 g of 8-amidinothiomethyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran. A sample recrystallized from ethanol has a melting point of 233-235 ° C.

ml of 35% aqueous sodium hydroxide solution is added to a vigorously stirred suspension of 35 g of the compound thus prepared and 1.05 g of benzyltriethylammonium chloride in 440 ml of 1,2-dichloroethane. The mixture was stirred for 2.5 hours and then poured into 300 ml of water. The aqueous layer was extracted with 1,2-dichloroethane, and the extracts were added to the organic layer, which was washed with sodium chloride (solution), dried over sodium sulfate to dryness in vacuo. The residue was recrystallized from methanol to give 22 g of the title compound, m.p. 82-83 ’C.

8- (2-Hydroxyethoxymethyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (interm. XXI)

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 is dissolved in 3.10 ml of anhydrous ethylene glycol and this solution is added dropwise at room temperature to a solution of intermediate XIX. After refluxing for 5.5 hours, the reaction mixture was cooled to room temperature and poured into 50 ml of water. This was extracted with dichloromethane and the extract was washed with brine, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The solid residue was crystallized from ethanol to give 2.1 g of the title compound, m.p. 132-133 C. C.

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

A solution of 9.5 ml of trifluoroacetic anhydride in 20 ml of anhydrous dichloromethane is added dropwise at -5 to 0 ° C to a solution of 5 g of 8-amino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran in 50 ml of anhydrous. dichloromethane. The reaction mixture was stirred at 20-25 ° C for 2 hours 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 to give 5.2 g of the title compound, m.p. 175-176 C. C.

8-Aminomethyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (interm. XXIV)

A mixture of 21 g of intermediate XXIX and 19 g of triphenylphosphine in 160 ml of tetrahydrofuran is stirred at a temperature of about 8 hours. Thin layer chromatography shows the disappearance of intermediate XXIX. 3 ml of water are added and stirring is continued for another 24 hours. The solvents were removed on 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 on a Buchner funnel. The filter cake was washed with water and desiccated to give 18 g of the title compound. The hydrochloride recrystallized from ethanol has a melting point of 256-258 ° C.

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

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

8- (2-Chloroethylsulfinylimethyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (intermediate XXVI) ml of aqueous 30% hydrogen peroxide was added dropwise at 10 ° C to a solution of 12 g of intermediate XXI in 84 ml glacial acetic acid. The reaction mixture was stirred at room temperature for 4 hours and then poured into 220 ml of water. The title compound was collected by suction filtration, washed with water and dried. yield

12.4 g, m.p. 142-145 ’C (methanol).

8- (N-Methyl-N- (2-chloroethyl) aminomethyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (interm. XXVII)

A mixture of 22 g of intermediate XX, 66 ml of 1-bromo-2-chloroethane and 11 g of anhydrous potassium carbonate in 88 ml of dimethylformamide is stirred at 20-25 ° C for 12 hours. The reaction mixture was poured into 600 ml of water and extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous sodium sulfate and acidified with ethanolic hydrogen chloride. Solvent and excess 1-bromo-286

-chloroethane is distilled off under vacuum at 70 to 80 ° C. The residue was taken up in 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 under vacuum at 25-30 ° C. The crude title product was purified by flash chromatography on silica gel eluting with ethyl acetate: petroleum ether 7: 3 to give 18 g of the title compound, melting at 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 potassium carbonate, 1.75 g of potassium iodide and 5.6 ml of 1-chloro-2-methyl-2-propanol is stirred for 90 minutes at 70 ' C and an additional 6 hours at 90 ° C. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated to dryness in vacuo. The title product is obtained as an oil and is characterized as dihydrochloride, melting at 225-227 ° C after crystallization from ethanol.

8-Azidomethyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (interm. XXIX)

A mixture of 22.8 g of intermediate XIX and 6.8 g of sodium azide in 110 ml of dimethylformamide is stirred at 100 ° C for 3 hours. After cooling to ambient temperature, 130 ml of water and 88 ml of ethanol are added to the reaction mixture. After 1 hour, the crystals were collected by vacuum filtration, washed with water and dried. Yield: 22 g of the title product. A sample recrystallized from ethanol has a melting point of 132-134 ° C.

8- (N- (2-Hydroxyethyl) aminomethyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (interm. XXX)

A solution of 2.38 g of anhydrous zinc chloride and 2.30 g of sodium cyanoborohydride in 71 ml of anhydrous methanol is added dropwise with stirring to a mixture of 9.24 g of 8-formyl-3-methyl-4-oxo-2-phenyl-4H- of 1-benzopyran and 9.12 g of ethanolamine in 90 ml of anhydrous methanol. Stirring was continued at 20-25 ° C for 5 hours before the solvent was removed in vacuo. 250 ml of water are added to the residue and the insoluble material is filtered off with suction and washed with water. The crude product 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 and the precipitate was collected by suction filtration and washed with water to give 8.5 g of the title compound, m.p. 117-121 ° C after drying at 60 ° C.

8- (N-Methyl-N-chloroacetyl-aminomethyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (interm. XXXI)

A solution of 6 ml of chloroacetyl chloride in 60 ml of 1,2-dichloroethane is added dropwise at -5 to 0 ° C to a solution of 20 g of intermediate XX and 10 ml of triethylamine in 200 ml of 1,2-dichloroethane. After stirring at 20-25 ^° C for 2 hours, 150 ml of water are added to the reaction mixture and the phases are separated. The organic phase is washed with water and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was crystallized from ethanol to give 22.5 g of the title compound, mp 146-148 ° C.

8-Chloroacetamidomethyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (interm. XXXII)

A solution of 3.2 ml of chloroacetyl chloride in 32 ml of 1,2-dichloroethane is added dropwise with stirring at -5 ° C to a mixture of 10 g of intermediate XXIV and 5.5 ml of triethylamine in 80 ml of 1,2-dichloroethane. The reaction mixture is stirred at The mixture was stirred at room temperature for 1 hour and then 150 ml of water were added. The phases are separated, the aqueous phase is extracted

1.2 dichloromethane and extracts are added to the organic phase, which is then washed with cold sodium carbonate, water, dried and evaporated to dryness in vacuo. The residue was crystallized from ethanol to give 10.7 g of the title compound, m.p. Mp 152-155 ° C.

saturated sodium bicarbonate solution

8- (N-Acetyl-N- (2-chloroethyl) aminomethyl) -3-methyl-4-oxo-2-phenyl-4H-benzopyran (intermediate XXXIII)

8.65 g of intermediate XXX and 4.15 ml of triethylamine are dissolved in 70 ml of tetrahydrofuran. A solution of 2.35 ml of acetyl chloride in 23 ml of tetrahydrofuran was added dropwise at -10 ° C over 40 minutes. After stirring at 0-10 ° C for 3 hours and at 20-25 ° C for 2 hours, the solvent was evaporated in vacuo. To the residue was added 100 ml of water and extracted with dichloromethane, the obtained organic extracts were combined and then the solvent was removed in vacuo. The residue was dissolved in 50 ml of methanol and 3 g of potassium carbonate and 10 ml of water were added. After stirring at 50 ° C for 20 minutes to hydrolyze the Ν, Ο-derivatives that formed, the solvent was removed in vacuo and the residue was treated with water and dichloromethane as described above. The dichloromethane solution was again evaporated to dryness to obtain

5.9 g of 8- (N-acetyl-N- (2-hydroxyethyl) aminomethyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, m.p. 171 to 172 ’C. 3.6 ml of thionyl chloride in 30 ml of dichloromethane is added dropwise at 0 ° C to a solution of 6.1 g of the compound thus prepared in 70 ml of dichloromethane. After stirring for 90 minutes at 20-25 ° C, the reaction mixture was washed with water and dried. The solvent was removed in vacuo to give the crude title product for use without further purification.

8- (3-Chloropropyl-thi) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (interm. XXXIV)

A solution of 20.1 g of stannous chloride dihydrate in 18 ml of hydrochloric acid (d = 1.18) was added over 5 minutes at 65 DEG C. to a solution of 6 g of intermediate VII and 70 ml of acetic acid. After 10 minutes the reaction mixture was cooled to 30-35 ° C and the solvent was removed in vacuo. The residue is taken up in water and the insoluble material is separated by suction, washed with water and dried. yield

3.2 g of 8-mercapto-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, melting at 115-118 ° C after recrystallization from ethanol.

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

8- (Chloropropylsulfonyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (intermediate XXXV) ml of 30% hydrogen peroxide was added at 20-25 ° C to a solution of 3.45 g of intermediate XXXIV in 35 ml of acetic acid. After stirring at 60 ° C for 4 hours, the reaction mixture is cooled to 20-25 ° C. 30 ml of water are added. A precipitate formed and was filtered off with suction, washed with water and dried, yielding 3.4 g of the title compound. It has a melting point of 160-163 ° C after crystallization from acetone.

8- (3-Hydroxypropylcarbamoyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (interm. XXXVI)

A solution of 7.6 ml of 3-aminopropanol in 50 ml of water is added dropwise over 30 minutes to a suspension of 30 g of 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carbonyl chloride and 15.2 g of potassium carbonate in 400 ml. acetone. The thick suspension is stirred for 3 hours at 20-25 ° C. The solvents are removed in vacuo and the residue is taken up in 300 ml of water. After stirring for 1 hour, the precipitate was collected by suction and washed with water. The crude product was purified by crystallization from 95% ethanol to give 23.8 g of the title compound, m.p. 191-193 C. C. An additional 4.7 g of the title compound was obtained by concentration in vacuo of the crystalline filtrate.

8- (3-Chloropropylpropylcarbamoyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (interm. XXXVII)

A solution of 1.1 ml of thionyl chloride in 2 ml of chloroform was added to a boiling solution of 3.37 g of intermediate XXXVI in 20 ml of chloroform. After stirring at reflux for 90 minutes, the solvent was removed in vacuo and the residue was crystallized from acetonitrile to give 3 g of pure title compound, m.p. (188) 193 to

194 ’C.

8- (1-Hydroxy-4- (4-methylphenylsulfonyloxy) -butyl) -3-methyl-4-iso-2-phenyl-4H-1-benzopyran (intermediate XXXVIII)

1.12 g of sodium cyanide in 3 ml of water is added at 20-25 ° C to a stirred mixture of 3.96 g of 8-formyl-3-methyl-4-oxo-2-phenyl-4H-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 and then 10 mL of cold water was added. Tetrahydrofuran was distilled off under normal pressure and 10 ml of 1,2-dichloromethane and 10 ml of chloroform were added. The organic phase is separated, washed with aqueous sodium chloride solution, dried over anhydrous sodium sulphate and evaporated to dryness in vacuo. The residue was suspended in diethyl ether, filtered off and crystallized from chloroform: ethyl acetate. Yield: 3.55 g of 8- (morpholino-cyanomethyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, m.p. 236-238 C. C.

3.5 ml of methanol are added to a 22.8 g of anhydrous% potassium hydroxide solution in anhydrous solution with stirring at room temperature to susg of the compound prepared in 520 ml of tetrahydrofuran. 6.3 ml of acrylonitrile in 20 ml of tetrahydrofuran was added dropwise to this suspension, and the reaction mixture was stirred at ambient temperature for 1 hour. The solvents were removed in vacuo. Crystallization of the residue yielded 23.22 g of 8- (1,3-dicyano-1-morpholinopropyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran from methanol.

23.2 g of the compound thus prepared are dissolved in 250 ml of dioxane. 250 ml of 6M hydrochloric acid are added and the mixture is refluxed for 2.5 hours. After cooling to room temperature, the mixture was poured into 700 ml of aqueous sodium chloride solution and extracted with ethyl acetate for sodium chloride and sodium hydroxide. Water acidification 37 by suction and

The extracts were washed with aqueous and treated with 700 ml of 1M solution. The layer was washed with ethyl acetate and hydrochloric acid. The precipitate was collected by crystallization from ethanol to give 10.2 g

8- (3-carboxy-1-oxopropyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, m.p. 191 to 192 ’C.

Diborane generated by the dropwise addition of a solution of 2.1 ml of freshly distilled boron trifluoride etherate in 10 ml of anhydrous diglyme in 19 ml of a 0.66M solution of sodium borohydride in diglyme is bubbled through a suspension of 2.28 g of the compound thus prepared in 23 ml of anhydrous tetrahydrofuran. under a stream of nitrogen. Stirring was continued for 20 minutes at 0 ° C and for a further 20 minutes at ambient temperature. After the reaction was stopped, methanol was carefully added dropwise to the mixture at 0 ° C. The solvents were removed from the vacuum. 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 to give 2 g of 8- (1,4-dihydroxybutyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, m.p. 133-134 C. C.

2.8 g of p-toluenesulfonyl chloride are added at 0 ° C to a stirred solution of 3.17 g of the compound thus prepared in 32 ml of anhydrous pyridine. The mixture was stirred at 0 C C for 6 hours and allowed to stand overnight at -4 C C without stirring. It is then poured into 200 ml of aqueous sodium chloride solution, acidified with 10 ml of 12N hydrochloric acid and suction filtered. The filter cake was dissolved in chloroform, and the solution was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off on a rotary evaporator. The residue was purified by flash chromatography on silica gel eluting with petroleum ether: ethyl acetate 1: 1. The combined fractions were evaporated to dryness in vacuo to give 3.04 g of pure title product, m.p. 123 to 124 ’C.

4- / 4- (2-Methoxyphenyl) -1-piperazinyl / butyraldehyde (intermediate XXXIX)

A solution of 5.4 g of 2- (3-chloropropyl) -dixolane and 15.9 g of 1- (2-methoxyphenyl) -piperazine in 60 ml of dimethylformamide was stirred at 80 ° C for 4 hours. After cooling to 20-25 ° C, the reaction mixture is poured into 500 ml of ice-cold 0.5N sodium hydroxide solution and extracted with dichloromethane. The organic phase is 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: ethanol 95: 5. It will be obtained

9.8 g of 2- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propyl} -dioxolane as an oil.

NMR CDC1 ₃ (S)

1.5 - 2.0 (4H, m, CH ₂ CH ₂ CH)

2.2 - 3.2 (10H, m, 5 x CH ₂ N)

3.7 - 4.0 (7H, m, OCH ₃ and 2 x OCH ₂ )

4.8 (1 H, t, OCHO)

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

A solution of 12.8 g of the compound thus prepared in 200 ml of tetrahydrofuran and 420 ml of 1N hydrochloric acid is kept at 20-25 ° C for 24 hours. Basify with 5N sodium hydroxide solution and immediately extract with dichloromethane. The organic layer 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 is obtained as an oil.

NMR cdci 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 and CH ₂ 2.9 - 3,2 (4H, m, 2 c CH ₂ NAr) 3.8 (3H, s, and ₃ ) 6.8 (4H, with aroma tonic protons) 9.3 (1 H, s, CHO).

8- (2,3-Epoxypropoxy) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (intermediate XL) ml of 2,3-epoxypropyl chloride was added dropwise at 20-25 ° C to a stirred mixture of 5 g 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 is poured onto 100 ml of water and the precipitate formed is suctioned off. After drying and purification by flash chromatography on silica gel (eluent petroleum ether: ethyl acetate 65:35), 4.45 g of the title compound is obtained, m.p. 128 DEG-129 DEG.

8- (N-Methyl-2- (4-methylphenylsulfonyloxy) -ethylsulfamoyl) -3-methyl-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 at 20-25 ° C for 2 hours, 100 ml of water and 100 ml of dichloromethane are added. 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 to give 4.5 g of 8- (N-methyl-2-hydroxyethylsulfamoyl) -3-methyl-4-oxo -2. 4-phenyl-4H-1-benzopyran, melting at 146-147 ° C after crystallization from ethanol.

The compound thus prepared is converted to the title compound by p-toluenesulfonylation according to the second step of the procedure described above for the preparation of intermediate XLII. The title compound was used without further purification.

8- / 2- (4-Methylphenylsulfonyloxy) -ethylsulfamoyl] -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (interm. XLII)

A solution of 5 g of intermediate VIII in 37 ml of tetrahydrofuran was added dropwise at 0 ° C to a mixture of 2.5 ml of ethanolamine and 2.5 ml of tetrahydrofuran. After stirring at 20-25 ° C, the reaction mixture is poured into 400 ml of water. A precipitate is formed which is suctioned off, washed with water and air-dried. 4.6 g of 8- (2-hydroxyethylsulfamoyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran are obtained, m.p. 186 DEG-187 DEG C. after crystallization from ethyl acetate.

2.1 g of p-toluenesulfonyl chloride are added portionwise at 0 ° C to a solution of 3.6 g of the compound thus prepared in 25 ml of pyridine. After 6 hours at 20-25 ° C, the reaction mixture is slowly poured onto crushed ice containing a slight excess of hydrochloric acid. The precipitate formed is collected by suction and washed with water. 4.9 g of the title compound, melting at (163) 166-169 ° C, after crystallization from ethyl acetate, is obtained.

8- (3-Aminopropylcarbamoyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride (intermediate XLIII)

A solution of 21.6 g of 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carbonyl chloride in 250 ml of anhydrous tetrahydrofuran was added dropwise at 0 ° C to a stirred solution of 17 g of 3- (2-methyl-2-propoxycarbamoyl). 1-propylamine (prepared as described in Saari WS et al., J. Med. Chem., 33, 97, 1990) and 13 ml of triethylamine. After stirring for 2 hours at ambient 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, m.p. 178 to 180 ’C.

96

A solution of 4.3 mL of trifluoroacetic acid in 15 mL of anhydrous dichloromethane was added dropwise at -5 ° C with stirring to a solution of 0.3 g of the compound thus prepared in 35 mL of anhydrous dichloromethane. After warming to ambient temperature, the mixture was stirred for 8 hours. Dichloromethane and excess trifluoroacetic acid were evaporated at 20-25 ° C using a rotary evaporator. The oily residue was dissolved in dichloromethane and 1N sodium hydroxide solution was added. The organic layer was washed with water, dried over anhydrous sodium sulfate and filtered. Excess ethanolic hydrogen chloride was added to the filtrate and the solvent was removed in vacuo. The residue was crystallized from ethanol to give 1.5 g of the title compound, m.p. 253 to 255 ° C

8- (2-Chloroethylureido) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (intermediate XLIV) ml of 2-chloroethyl isocyanate are added with stirring at ambient temperature to a solution of 3.9 g of 8-amino 3-methyl-4-oxo-2-phenyl-4H-1-benzopyrene in 52 mL of anhydrous dimethylformamide. Stirring was continued at 70 ° C for 5 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic phase is evaporated to dryness in vacuo. The residue is suspended in diethyl ether with stirring. The title product is then filtered off and recrystallized from methanol, yield 3.74 g, m.p. 213 to 214 ’C.

(Z, E) -8- 4- / 2 (1,3-dioxanyl) -1-butenyl-3-methyl-4-oxo-2-phenyl-4H-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)] - ethyltriphenylphosphonium bromide in 10 ml of anhydrous tetrahydrofuran. The mixture is stirred for 20 minutes

- 97 minutes at -20 C. C. A solution of 0.8 g of 8-formyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran in 11 ml of anhydrous tetrahydrofuran is added dropwise to the mixture, which is then warmed to 0 ° C for 90 minutes and then to ambient 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 to give the title compound as a mixture of diastereoisomers E and Z, m.p. (93) 98 to 100 ’C. The ratio of the two isomers was determined by NMR spectroscopy and made E: Z = 65:35.

NMR CDCl ₃ (δ)

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

7.2 - 7.8 (m, 7H, other aromatic CH groups of the benzopyran and phenyl ring)

6.9 (Dt, 1H, Fl-CH E-isomer) 6.8 (Dt, 1H , Fl-CH Z isomer) 6.4 (Dt, 1H , F1-CH = CH E isomer) 5.9 (Dt, 1H , F1-CH = CH Z isomer) 4,6 - 4.7 (M, 1H, CHO) 3.6 - 4.2 (M, 4H, OCH ₂ O dioxane ring) 2,4 - 2.7 (M, 2H, chch ₂ ch) 1,9 - 2.3 (M, 5H, CH 2 and CH ₂ in the 5-position 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 kg of 10% palladium on carbon catalyst and 1 g of intermediate XLV in 24 ml of methanol was hydrogenated in a Parr apparatus at ambient temperature under a hydrogen pressure of 1.5 atmospheres. After the theoretical consumption of hydrogen, the catalyst was filtered off and the solvent was removed by evaporation in vacuo. Crystallization of the residue from cyclohexane gave the title compound, m.p. 118 až

119.5 ’C.

The 8-carboxymethyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (intermediate XLVII) portions were taken with sodium sulfite and extracted

4.5 g of potassium permanganate are added in portions over a period of time

With stirring at 0-10 ° C to a mixture of 2.76 g of 8-allyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (P.Da Re, US 3350411), 17 g of Aliquat 336, 1.12 ml of acetic acid, 56 ml of dichloromethane, 3.2 ml of sulfuric acid (d = 1.84) and 60 ml of water. Stirring was continued at ambient temperature for 5 hours. After 0-5 ° C over 15 minutes, 3.4 g of the metabo-organic layer are separated, washed with water, with 60 ml of 1N aqueous sodium hydroxide solution.

The aqueous phase is acidified by the addition of dilute hydrochloric acid and extracted with ethyl acetate. The organic phase is washed with water, dried over anhydrous sodium sulphate and, after filtration, evaporated to dryness in vacuo. The residue was treated with carbon tetrachloride and the solid collected by suction filtration to give 1 g of the title compound, 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-isobutyryl chloride instead of acryloyl chloride. The solid obtained is filtered from water and dried, washed with hot diethyl ether and filtered off with suction to give the title compound. A sample crystallized from 50% aqueous ethanol and washed with diethyl ether, melts at (153) 162-164 ° C.

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

A solution of 0.5 g of intermediate XXIII in 1.5 ml of anhydrous dimethylformamide 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 dimethylformamide was added dropwise. Then the reaction mixture is stirred at 50 ° C for 1 hour, cooled to 20 ° C, poured into water, aspirated and dried at 60 ° C for 3 hours. 0.6 g of 8- (N-methyltrifluoroacetamido) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran is obtained.

NMR (CDC1 _3, δ)

8.15 (dd, 1H, benzopyran CH at position 5)

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

3.30 (s, 3H, CH ₃ -N)

2.10 (s, 3H, benzopyran CH ₃ c 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 dimethylsulfoxide was stirred at room temperature for 1 hour and then quenched with excess.

4N hydrochloric acid. After removal of the ethanol by evaporation in vacuo, the residue was rinsed with water, then with 3N sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The solid residue was crystallized from ethanol to give 0.22 g of the title compound, melting at 143-146 ° C.

8- (N-Methyl-acrylamido) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (interm. L)

This compound was prepared in the same manner as intermediate X, but using intermediate XLIX instead of 8-amino100

3-methyl-4-oxo-2-phenyl-4H-l-benzopyran. Instead of diluting with water, THF was removed by evaporation in vacuo 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 (eluting with ethyl acetate: petroleum ether 4: 6) and crystallized from cyclohexane melted at 136-137 ° C.

1- [2- (1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yloxy) -ethyl] -4- (2-methoxyphenyl) -piperazine (intermediate LI)

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

1- (2-aminoxyethyl) -4- (2-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. Ethanol was removed by evaporation in vacuo. The residue was washed with water and then with an excess of 37% hydrochloric acid and filtered. The acidic aqueous solution was basified with 5% sodium hydroxide and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness in vacuo to give 4.3 g of the title compound as an oil. The sample is converted to hy101 hydrochloride by salification with ethanolic hydrogen chloride in dichloromethane. The solvents were removed by evaporation in vacuo and the crude residue was crystallized from ethanol to give the title compound, m.p. 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 manner as Intermediate XXV but substituting 1-bromo-4-chlorobutane for 1-bromo-3-chloropropane, m.p. 81 DEG-84 DEG C. (ethanol).

8- (4-Chlorobutylsulfinyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (intermediate LIV)

The title compound was prepared in the same manner as intermediate XXVI, but using intermediate LIII instead of intermediate XXI. Sample after crystallization from cyclohexane: benzene 0.5: 1, melting at 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 is added dropwise, with stirring, at 20-25 ° C, to a solution of 22.5 g of 8-formyl-4-oxo-3-phenyl-4H-1-benzopyran (prepared as is described by G. Atassi et al., Eur. J. Med. Chem. - Chim. Ter., 20, 393 (1985)) in 150 ml of 85% ethanol and 450 ml of dimethylformamide. A solution of 32.67 g of 85% potassium hydroxide in 195 ml of water is then added dropwise with stirring at 15-20 ° C. After another

After stirring at room temperature overnight, the reaction mixture is filtered off with suction, the mother solution is acidified with 37% hydrochloric acid and diluted with 1.2 liters of water. Suction and washing with water to neutrality gave the title compound as a crude product. This product was suspended in 150 mL of ethyl acetate and stirred with 444 mL of 0.3 M sodium bicarbonate until clear layers were obtained. The aqueous layer was washed with 75 mL of ethyl acetate, then acidified with 37% hydrochloric acid, filtered and dried at 60-65 ° C to give 19.12 g of the title compound, melting at (215) 218 C. The sample after crystallization from ethanol had the same melting point.

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 in 75 ml of anhydrous toluene was stirred at 80-85 ° C for 4 hours. After removal of the solvent in vacuo, the residue was rinsed twice with 20 ml of toluene and evaporated to dryness in vacuo to give, after drying, 16 g of the title compound, melting at (126) 138-140 ° C, which was used without further purification. (130) 138-140 C (toluene).

8- (N-Acetylcarbamoyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (intermediate LVII)

A mixture of 3.5 g of 8-carbamoyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (described in JP 61-238783), 4.8 ml of acetic anhydride and 0.25 ml of sulfuric acid (d = 1.098) was stirred at 140 ° C for 3 minutes. The reaction was cooled to room temperature, diluted with water and suctioned off, after washing with water and desiccation, to give 3.88 g of the title compound.

103

NMR (CDC1 _3, δ) 10.50 (bs , 1H , imidic NH) 8.35 - 8.70 (M, 2H, CH in position 5 and 7 of benzopyran ring) 7.45 - 8.00 (M, 6H, other aromatic CH) 2.60 (with, 3H, ch ₃ co) 2.20 (with, 3H, CH ₃ in 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- (methylthi) -phenol, 13.7 g of anhydrous potassium carbonate and 3.13 g of tricaprylmethylammonium chloride in 140 ml of anhydrous dimethylformamide was stirred at 95 ° C for 38 hours. At the end of this time, the reaction mixture was cooled to ambient temperature, poured into 1 liter of water and extracted with diethyl ether. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The oily residue was purified by silica gel column chromatography eluting with petroleum ether: ethyl acetate 99: 1. Evaporation of the combined fractions gave 12.9 g of pure title compound. The sample after crystallization from n-hexane melts at 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 at 50 ° C for 2 hours. The organic solvent was then removed by evaporation in vacuo and the aqueous residue was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo to give 9.5 g of the title compound.

104 compound as a solid, which was used without further purification. A sample was crystallized from cyclohexane to give the pure title compound, m.p. 102 to 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. It crystallizes from diisopropyl ether and melts at 112-115 ° C.

8-Ethoxycarbonyl-4-oxo-4H-1-benzopyran (intermediate LXI)

4.35 g of sodium metal is added in pieces at ambient temperature to a solution of 9.85 g of ethyl 3-acetyl-2-hydroxybenzoate (synthesized with 3-acetyl-2-hydroxybenzoic acid (prepared as described in REFors, J.). Chem., 29, 538 (1986)), refluxing in 6N ethanolic hydrogen chloride for 1.5 hours, evaporating to dryness in vacuo and purifying the crude product by silica gel column chromatography (eluting with ethyl acetate-petroleum ether 8: 2) - mp 47 ° C (hexane)) in 98 ml of ethyl formate.

The reaction mixture was spontaneously refluxed for 20 minutes, then stirred at room temperature for 4 hours and the ethyl formate was removed by evaporation to dryness in vacuo. The crude solid obtained is rinsed with 120 ml of ethanol and 67 ml of 5.6M ethanolic hydrogen chloride. The mixture was stirred under reflux for 30 minutes, then allowed to cool to room temperature and evaporated to dryness in vacuo. The residue was purified by silica gel column chromatography eluting with ethyl acetate: petroleum ether 3: 7 to 6: 4 to give 8.31

105 g of the title compound. A sample crystallized from cyclohexane melts at 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 under reflux for 5 hours. The reaction mixture was cooled to ambient temperature and poured into 200 ml of water. After 12 hours at 0-5 ° C, the title compound is filtered off with suction. Washing with water and diethyl ether gives, after desiccation, 2.8 g of the title compound. A sample washed with boiling 25: 1, filtered and crystallized used without further acetonitrile: methanol from acetic acid, melting at 253-254 ° C.

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

A mixture of 1.5 g of 8-carboxy-6-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (prepared as described in JP 61-15880) and 28 ml of 57% hydroiodic acid in 47 ml of acid The acetic acid was stirred at reflux for 18 hours. The reaction mixture was cooled to ambient temperature and poured into water. 1 N sodium hydroxide is added to adjust the pH to 4-5. 2 g of sodium thiosulphate are added and stirring is continued for 15 minutes. The crude title compound was then filtered off with suction and dissolved in 0.5 M sodium 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 collected by suction filtration and dried. Yield: 1.12 g of the title compound used without further purification and melting at 279-281 ° C after crystallization from 50% ethanol.

106

2-Hydroxy-5-nitro-3-propionylbenzoic acid (intermediate LXIV)

97.1 g of 2-hydroxy-3-propionylbenzoic acid, prepared as described in Brit. pat. 1,343,119 (1974), is added over 5 minutes to 500 ml of sulfuric acid (d = lm84) with stirring at -25 ° C. A mixture of 40 ml of 65% nitric acid and 100 ml of sulfuric acid (d-1.84) is added over 40 minutes while maintaining the reaction mixture temperature between -20 and -13 ° C. The mixture was stirred at -18 ’C for an additional 30 minutes. After this time, the mixture was carefully poured into a mixture of 2.0 kg of crushed ice and 500 ml of water, stirred for 10 minutes and filtered to give the title compound, after washing with water and drying at 50 ° C for 6 hours. Crystallization of this solid from 50% ethanol gave 91.5 g of the title compound, melting at 186-189 ° C, which was used without further purification. The sample was recrystallized from 50% ethanol and melted at 189-191 ° C.

Ethyl 2-hydroxy-5-nitro-3-propionyl benzoate (intermediate LXV)

A solution of 93.3 g of intermediate LXIV and 25 ml of sulfuric acid (d = 1.84) in 490 ml of ethanol was refluxed for 17 hours. After cooling to room temperature, 47.7 g of sodium carbonate are added in portions and the ethanol is 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. To this suspension was added 37% hydrochloric acid to adjust the pH to 6. Filtration gave 85.4 g of the title compound used without further purification (m.p. 75-77 ° C). The sample is crystallized twice from ethanol and melts at 76-77 ° C.

107

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

A mixture of 48.1 g of intermediate LXV, 63 ml of benzoyl chloride and 85.6 g of sodium benzoate was stirred at 180 ° C (bath temperature) for 8 hours. The pasty mixture is cooled to 60-70 ° C. Add 700 ml of 50% ethanol and mix the resulting mixture again at 50 ° C for 30 minutes. At 5 CC, add 60 ml of 35% sodium hydroxide so that the temperature does not exceed 15 C. C. Aspirate and wash with 50% ethanol and water. The crude product was purified by double column chromatography on silica gel, eluting first with dichloromethane: petroleum ether increasing from 8: 2 to 9: 1, then with dichloromethane and finally with dichloromethane: ethyl acetate 95: 5. Evaporation in vacuo of the combined fractions gave the title compound, which was washed with 140 mL of ethanol. Yield 43 g, m.p. 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 intermediate LXVI and 48 ml of 1 N sodium hydroxide in 320 ml of ethanol is stirred under reflux for 30 minutes. The organic solvent was removed by evaporation 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 gave 11.1 g of the title compound, melting at (258) 286-292 ° C and used without further purification. After crystallization from dimethylformamide: water 6: 4, the title compound shows the same melting point.

108

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

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

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

216 ml of a 0.3 M solution of potassium permanganate in water are added dropwise over 40 minutes to a mixture of 7.94 g of 8-forrayl-7-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (prepared as described in Da). Re et al., J. Org. Chem., 25, 1097, 1960) and 54 ml of 5% sodium dihydrogen phosphate in 162 ml of tert. butanol, stirred at 75 ° C. After stirring for an additional 2.5 hours at this temperature, the reaction mixture was cooled to ambient temperature and 81 ml of 1M sodium dithionite was slowly added dropwise. The mixture was extracted with ethyl acetate. The organic layer was washed four times with 160 ml of 0.5 N sodium hydroxide, the combined aqueous alkaline layers were washed with diethyl ether and acidified with 37% hydrochloric acid. The title compound precipitated. Filter and wash with water, after drying, 3.3 g of a material suitable for the next reaction without further purification and melting at 180-181 ° C after crystallization from 95% ethanol.

109

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

A solution of 6.7 g of 4-trifluoromethylbenzoyl chloride (prepared from the corresponding acid and thionyl chloride in benzene at reflux and used without purification) in 50 ml of chloroform is added dropwise to a solution of 7.13 g of ethyl 2-hydroxy-3-propionyl benzoate and 9 ml triethylamine in 50 ml chloroform. The mixture was stirred at ambient temperature for 2 hours. The solvent was then evaporated in vacuo and the residue was purified by silica gel column chromatography using petroleum ether: ethyl acetate 85:15 as eluent. Evaporation of the combined fractions in vacuo afforded 7.4 g of the title compound as an oil.

NMR spectrum at 60 7.6 - 8,5 (m, 6H) 7.5 (t, 1 H, 4.2 (q, 2H) 2.9 (q, 2H) 1 - ’1,3 (2t, 6H)

MHz (CDC1 _3, S) CH aromatic) phenol ring, CH in 5) Cooch _{2) COCH2)}

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 tert. of potassium butoxide in 35 ml of pyridine was stirred at 100 ° C for 2 hours. After this time, the reaction mixture was cooled to ambient temperature, poured into a solution of 50 mL of acetic acid in 600 mL of water, and extracted with ethyl acetate. The organic layer 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. A solution of the compound so prepared and 2.2 ml of 37% hydrochloric acid in 35 ml of glacial acetic acid was stirred at RT

110

100 ’C 1.5 hours. After cooling to room temperature, the mixture was poured into 630 ml of 1 N sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The crude product was purified by silica gel column chromatography eluting with petroleum ether: ethyl acetate 85:15. Evaporation in vacuo to dryness afforded 2.95 g of the title compound, melting at 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 at ambient temperature for 1.5 hours. The mixture was poured into a solution of 30 ml of 1 N hydrochloric acid in 300 ml of water and suctioned off to give 2.47 g of the title compound which was used without further purification. A sample crystallized from 60% ethanol melted at 253-254 ° C.

8-Ethoxycarbonyl-2- (4-benzoyl-phenyl) -3-methyl-4-oxo-4H-1-benzopyran (intermediate LXXIII)

The title compound was synthesized according to the procedure for intermediate LXX and LXXI, but starting from 4-benzoyl chloride instead of 4-trifluoromethylbenzoyl chloride and this compound reacted in 1,2-dichloroethane instead of chloroform and in the presence of 4-dimethylaminopyridine instead of triethylamine. After the usual work-up, the residue was purified by column chromatography on silica gel, eluting with dichloromethane: ethyl acetate 9: 1. Evaporation of the combined fractions under vacuum to dryness afforded the title compound used without further purification. A sample crystallized from cyclohexyl xane has a melting point of 125-136 ° C (dec.).

8-Carboxy-2- (4-benzoyl-phenyl) -3-methyl-4-oxo-4H-1-benzopyran (intermediate LXXIV)

The title compound was prepared in the same manner as intermediate LXXII, but using intermediate LXXIII instead of intermediate LXXI. Purify by dissolving the crude product in 0.5 M sodium hydroxide, washing the aqueous layer with ethyl acetate, and precipitating the pure title compound by adding 37% hydrochloric acid. The sample was crystallized from acetic acid and melted at 260-262 ° C.

Ethyl 2- (4-phenoxybenzoyloxy) -3-propionyl benzoate (intermediate LXXV)

The title compound was prepared according to the procedure described for Intermediate LXX, but starting from 4-phenoxybenzoyl chloride instead of 4-trifluoromethylbenzoyl chloride. Evaporation of the solvent gave the pure title compound.

NMR spectrum at 200 MHz (CDC1 _3, S)

8.17 (dd, 3H, phenyl CH at ortho position to carboxylate groups)

7.92 (dd, 1H, phenyl CH at ortho to CO group)

7.38-7.48 (m, 3H, phenyl CH at meta position to carboxylate groups)

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

7.05, 7.10, (2d, 4H, other CH phenoxy ring)

4.25 (q, 2H, CH ₂ O)

2.90 (q, 2H, _CH2 CO)

1.05 to 1.20 (m, 6 H, 2 x CH ₃₎

112

8-Ethoxycarbonyl-3-methyl-4-oxo-2- (4-phenoxyphenyl) -4H-1-benzopyran (intermediate LXXVI)

The title compound was prepared in the same manner as Intermediate LXXI, but starting from Intermediate LXXV instead of Intermediate LXX. Purify by column chromatography on silica gel eluting with petroleum ether: ethyl acetate 6: 4. Evaporation in vacuo gave the pure title compound, m.p. 98 to 100 C.

8-Carboxy-3-methyl-4-oxo-2- (4-phenoxyphenyl) -4H-1-benzopyran (Intermediate LXXVII)

This compound is obtained in the same manner as intermediate LXXII, but starting from intermediate LXXVI instead of intermediate LXXI, m.p. 216-218 C. C.

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

2.4 g of this compound was dissolved in 4 ml of anhydrous pyridine, and 1 g of anhydrous tert. of potassium butoxide. The resulting ice mixture was heated at 100 ° C for 15 minutes, cooled to ambient temperature and poured into 50 g of ice water containing 8 ml of 10N 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 to give 2.1 g of crude ethyl 2-hydroxy-3- (2-pipvaloyl-propionyl) -benzoate, which is used without purification in the next step. 2 g of the compound thus prepared are heated at 100 DEG C. for 15 minutes after dissolution in a mixture containing 15 ml of acetic acid and 1.5 ml of 37% hydrochloric acid. After cooling to ambient temperature, the mixture is poured into 100 ml of water and extracted with diethyl ether. The organic phase is washed with 5% aqueous sodium bicarbonate, then with water, dried over anhydrous sodium sulphate and evaporated in vacuo. 1.6 g of crude 8-ethoxycarbonyl-2- (tert-butyl) -3-methyl-4-oxo-4H-1-benzopyran are obtained.

Dissolve 1.5 g of the above ester in 20 ml of methanol. 3 ml of 10N sodium hydroxide are added slowly while maintaining the temperature between 25 and 35 ° C. After 1.5 h at ambient temperature, the reaction mixture was diluted with 100 mL of water and extracted with ethyl acetate. The aqueous layer was acidified with 3N hydrochloric acid. The precipitate was filtered off with suction, washed with water and crystallized from ethanol to give 0.8 g of the title compound, melting at 225-228 ° C.

8-Carboxy-2-cyclohexyl-3-methyl-4-oxo-4H-1-benzopyran (intermediate LXXIX)

This compound was prepared according to the reaction sequence and methods described for intermediate LXXVIII, but starting from cyclohexylcarboxylic acid chloride instead of pivaloyl chloride with other minor variations. Ethyl 2-cyclohexylcarbonyloxy-3-propionyl benzoate is obtained after stirring for 8 hours in pyridine at room temperature and converted to ethyl114.

-2-hydroxy-3- (2-cyclohexylcarbonyl) propionyl) benzoate by heating with tert. butoxide for 1.5 hours at 100 ° C. Cyclization to 8-ethoxycarbonyl-2-cyclohexyl-3-methyl-4-oxo-4H-1-benzopyran was accomplished by heating in acetic acid / hydrochloric acid at 100 ° C for 1.5 hours and hydrolysis to the title compound was accomplished in 20 minutes at ambient temperature. The title compound melted at 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 tert. of potassium butoxide in 8 ml of anhydrous pyridine was stirred at 60 ° C for 15 minutes, cooled to ambient temperature and poured into 60 ml of ice water containing 15 ml of 10N hydrochloric acid. After extraction with ethyl acetate, the organic phase is washed with 5% aqueous sodium bicarbonate and water and dried over anhydrous sodium sulfate. Evaporation in vacuo gave 2.5 g of crude ethyl 3- (2-furoyl-propionyl) -2-hydroxy-benzoate.

2.5 g of the compound thus obtained are stirred at 100 DEG C. for 30 minutes with 10 ml of acetic acid and 0.7 ml of 37% hydrochloric acid. After cooling to room temperature, the mixture was poured into 180 ml of water. The title compound precipitated and was filtered off with suction, washed with water and crystallized from isopropanol. Yield 1.5 g,

mp 137 to 139 ’C.

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

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

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

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

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

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

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

A mixture of 1g of 8-methoxycarbonyl-4-oxo-2-phenyl-4H-1-benzothiopyran (Intermediate XCII), 2.2 ml of 12.5N sodium hydroxide, 15 ml of methanol and 5 ml of dioxane is stirred at ambient temperature for 2.5 hours. . After evaporation in vacuo, water is added until complete dissolution and the solution is extracted with chloroform. The separated aqueous phase was acidified with dilute hydrochloric acid until the crude material precipitated, which was filtered off and purified by crystallization from acetic acid. Yield 0.62 g, m.p. t. 302 ’C.

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

This compound was 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 was used in place of 2-furoyl chloride, and the obtained (E) -ethyl 2-hydroxy-3- (2-styryl-propionyl) -benzoate was used without purification in the second step. The title compound melts at 129-130 ° C after crystallization from isopropanol.

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

This compound was prepared according to the method described for Intermediate LXXXI, but using Intermediate LXXXV instead of Intermediate LXXX and maintaining the reaction at ambient temperature for 10 hours. The title compound melts at 284-286 ° C after crystallization from ethanol.

8-Carboxy-3-methyl-2- (4-methylphenyl) -4-oxo-4H-1-benzopyran (honey from LXXXVII)

A mixture of 1.9 g of 2-hydroxy-3-propionyl-benzoic acid

117 (prepared as described in British Pat. 1,343,119, 1974),

5.2 g of anhydrous sodium 4-methylbenzoate and 3.9 ml of 4-methylbenzoyl chloride are stirred at 185-195 ° C for 8.5 hours. 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 added until the pH of the aqueous phase was 8.9. The organic phase is extracted again with 3% carbonate and the aqueous phases are combined, re-extracted with diethyl ether and acidified with 10N hydrochloric acid. The precipitate was purified by flash chromatography on silica gel eluting with chloroform: methanol 100: 2 to 100: 20. The title compound,

The J obtained by evaporation in vacuo of the combined fractions containing it melts at 249-251 ° C after crystallization from ethanol.

8-Ethoxycarbonyl-2- (4-Fluorophenyl) -3-methyl-4-oxo-4H-1-benzopyran (intermediate LXXXVIII)

This compound was 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, 4-fluorobenzoyl chloride was used instead of 2-furoyl chloride and the reaction after 20 hours at ambient temperature gave ethyl 2- (4-fluorobenzoyloxy) -3-propionyl benzoate. This compound was used without purification for the second step. The title compound melts at 128-130 ° C after rinsing 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 ethyl acetate.

118 ml of water are kept at ambient temperature for 5 hours and then poured into 300 ml of 1N hydrochloric acid. The precipitate formed is collected by suction, washed with water and dried, yielding 2.3 g of the title compound, melting at 249-250 ° C after crystallization from 95% ethanol.

Ethyl 2- (2-furoyloxy) -3-propionyl benzoate (intermediate XC)

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

NMR spectrum at 60 MHz (CDC1 _3, δ)

8.2

8.0

7.7-7.8

7.43

7.45

6.6-6.8

4.3

2.9

0.95-1.35 (1H, dd, CH at position 4 of the benzene ring) (1H, dd, CH at position 6 of the benzene ring) (1H, dd, CH at position 5 of the furan ring) (1H, t, CH at position 5 of the benzene ring) (1H, s, CH at position 3 of the furan ring) (1H, m, CH at position 4 of the benzene ring) (2H, q, COOCH ₂ CH ₃ ) (2H, q, COCH ₂ CH ₃ ) ( 6H, m, 2 x CH _3).

- 119

Ethyl 3-propionyl 2- (2-thienylcarbonyloxy) 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 MHz (CDC1 _3, δ) 7.1 to 8.35 (6H, m, aromatic CH) 4.25 (2 H, q, cooch ₂ ch ₂ ) 2.9 (2 H, q, coch ₂ ch ₃ ) 0.95 to 1.3 (6H, m, 2xCH ₃ )

8-Methoxycarbonyl-4-oxo-2-phenyl-4H-1-benzothiopyran (Intermediate XCII)

A mixture of 16.8 ml methyl thiosalicylate, 25.6 ml ethylbenzoylacetate and 360 g polyphosphoric acid is stirred at 90 ° C for 3 hours. After cooling to room temperature, the mixture was poured onto crushed ice and the crude material was collected by filtration, washed with water and purified by crystallization from ethanol. MP: 170 to 171 ’C.

Elemental analysis for ^C 17 ^H 12 ° 3 ^N calculated 68.90 % C, H, 4.08; S, 10.82 found 68.59 % C, H, 4.13; S, 10.69 NMR Spectrum at 200 > MHz (cdci ₃ δ) 8.83 to 8.95 (Dd, 1Η. benzothiopyran CH v 5) 8.45 to 8.53 (Dd, 1Η. benzothiopyran CH v 7) 7.68-7.80 (M, 2Η. 2-phenyl CH in 2 and 6) 7.55-7.65 (T, 1H, benzothiopyran CH v 6) 7.45-7.55 (M, 3Η. 2-phenyl CH at 3,4 and 5) 7.24 (with, 1H, benzothiopyran CH v 3) 4.00 (with, 3H, cooch ₃ )

120

8-Ethoxycarbonyl-3-bromomethyl-4-oxo-2-phenyl-4H-1-benzopyran (intermediate XCIII)

A 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., J. Med. Pharm. Chem., 2 , 263, 1960), 6.4 g of N-bromosuccinimide and 0.04 g of benzoyl peroxide in 80 ml of anhydrous carbon tetrachloride are stirred under reflux for 1.5 hours. After cooling to ambient temperature, the succinimide formed is filtered off with suction and washed with cold carbon tetrachloride. The mother liquors were evaporated to dryness in vacuo and the residue was washed with diethyl ether and filtered off with suction. 9.2 g of the title compound melting at 133-134 ° C is obtained 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 is added dropwise at room temperature to a solution of 29 g of intermediate XCII in 300 ml of dimethylformamide. After stirring at 50 ° C for 1.5 hours, the reaction mixture was poured into 2 L of water and the precipitated title compound was filtered off with suction and crystallized from acetone to give 20 g (combined two yields), m.p. t. 151 to 152 ’C.

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

116 ml of 1N sodium hydroxide are added to a stirred suspension of 14.8 g of intermediate XCIV in 300 ml of 95% ethanol over 10 minutes. The reaction mixture is then heated at 60-65 ° C for 15 minutes to give a clear solution which is maintained at

- 121 around the next hour. After evaporation in vacuo, the residue is dissolved in 200 ml of water and the solution is acidified by the slow addition of 10 ml of hydrochloric acid (d = 1.18). After stirring at ambient temperature for 1 hour, the title compound is filtered off with suction, washed with water and crystallized from isopropanol to give 9.3 g, m.p. t. (225) 237-240 C. C.

Ethyl 2- (4-nitrobenzoyloxy) -3-propionyl benzoate (intermediate XCVI)

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

NMR spectrum at 60 MHz (cdci ₃ δ) 7.85-8.50 (M, 6H, aromatic CH) 7.50 (T, 1H, CH at position 5 of the phenol ring) 4.25 (Q, 2H, ch ₂ o) 3.95 (Q, 2H, ch ₂ ) 0.95-1.30 (M, 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 XCVI and 10.18 g of anhydrous tert. of potassium butoxide in 89 ml of anhydrous pyridine is stirred at 100 ° C for 13 hours. The reaction mixture was cooled to ambient temperature, poured into 400 mL of 4N hydrochloric acid, and extracted with dichloromethane. The organic layer was washed repeatedly with water, then 2.5% sodium bicarbonate, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The crude product was purified by silica gel column chromatography

122 eluting with 7: 3 hexane: ethyl acetate. Evaporation of the combined fractions in vacuo gave 7 g of the title compound, melting at (130) 145-148 ° C.

8-Carboxy-3-methyl-2- (4-nitrophenyl) -4-oxo-4H-1-benzopyran (intermediate XCVIII)

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

8-Ethoxycarbonyl-3-methyl-4-oxo-2-trifluoromethyl-4H-1-benzopyran (intermediate XCVIX)

3,15 ml of 1,8-diazabicyclo [5.4.0] undec-7-ene is added dropwise at 0 ° C by syringe to a stirred mixture of 3 g of ethyl 2-hydroxy-3-propionyl benzoate and 5.53 ml of trifluoroacetic anhydride . The reaction mixture is stirred at 60 ° C for 4 hours, then cooled to room temperature and diluted with ethyl acetate and water. The organic layer was washed with 1N sodium hydroxide and water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The residue was purified by silica gel column chromatography eluting with petroleum ether: ethyl acetate 95: 5 to give 0.8 g of the title compound.

NMR spectrum at 200 MHz (CDC1 _3, S)

8.41, 8.37 (2dd, 2H, CH at position 5 and 7 of the benzopyran ring)

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

123

4.46

2.22-2.27

1.39 (q, 2H, COOCH ₂ ) (m, 3H, J _{H- F} = 2.16Hz, CH ₃ at the 3-position of the benzopyran ring) (t, 3H, CH ₂ CH ₃ )

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

The title compound intermediate LXII but intermediate LXI and then instead of filtration was prepared by the same method as the limits of using intermediate XCIX instead of diluting with water, extracting with ethyl acetate. m.p. 175-178 ° C.

3- [4- (2-Methoxyphenyl) -1-piperazinyl] -N-methyl-propylamine (intermediate CI) ml of 35% aqueous methylamine is added to a solution of 8.2 g of 3- [4- (2-methoxyphenyl) -1 -piperazinyl] -propyl chloride in 48 ml of dimethylformamide. Heat the mixture at 60 ° C in a sealed vessel for 5 hours and then cool to 30 ° C. The solvent was evaporated in vacuo and the residue was stirred with 100 ml diethyl ether for 30 minutes. The solid obtained by suction is dissolved in 200 ml of chloroform: 5N methanolic ammonia 100: 3. After stirring at ambient temperature for 30 minutes, the solution is absorbed onto a chromatographic column which is eluted with chloroform: 5N methanolic ammonia increased from 100: 5 to 100: 15. Fractions containing the title compound were combined and evaporated in vacuo to give 3 g of intermediate CI as a thick oil.

NMR spectrum at 60 MHz (DMSO-d6, S)

124

6.80 (WITH, 4H, aromatic CH) 3.75 (WITH, 3H, och ₃ ) 3.20-2.75 (M, 4H, piperazine CH v pol. 3,5) 2.75-2.10 (M, 8H; piperazine CH v pol. 2,6 a 2.40 (with, 1H, NH) 2.30 (with, 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 CII)

A mixture of 11.1 g of ethyl 2-hydroxy-3-propionyl benzoate, 9.9 g of phenacyl bromide, 6.9 g of anhydrous potassium carbonate and 200 ml of acetone is stirred at reflux temperature for 7 hours. After cooling to room temperature, the inorganics were separated by filtration and the solution was evaporated in vacuo. The residue was purified by flash chromatography on silica gel eluting with toluene. The title compound, obtained by evaporating the combined fractions containing it under vacuum, is crystallized from 90% ethanol. 9.8 g, m.p. t. 64 to 66 ’C.

7-Carboxy-2-benzoyl-3-ethyl-benzo [b] furan (intermediate CIII)

A mixture of 7 g of intermediate CII, 275 ml of 0.95N sodium hydroxide and 400 ml of dioxane was stirred under reflux for 4 hours. After cooling to ambient temperature, the dioxane was evaporated in vacuo and replaced with an equal volume of water. After filtration with activated carbon, 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. t. 193-195 ’C.

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

125

This compound was 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, 4-methylbenzoyl chloride is used instead of 2-furoyl chloride and methyl 2-hydroxy-3-propionyl benzoate instead of ethyl 2-hydroxy-3-propionyl benzoate. The reaction is left at ambient temperature for 4 hours to give methyl 2- (4-methylbenzoyloxy) -3-propionyl benzoate. This compound was used without purification for the second step, which was carried out at 100 ° C for 1.5 hours. In the third step, 96% sulfuric acid was used instead of 37% hydrochloric acid. The title compound melts at 174-175 ° C after crystallization from ethanol.

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

This compound was prepared in three steps according to the methods described for the preparation of intermediate XC (first step) and intermediate CIV (second and third steps). In the first step, 4-phenylbenzoyl chloride was used instead of 2-furoyl chloride and the reaction was carried out for 20 hours at room temperature and 13 hours at reflux. Purification is accomplished by column chromatography on silica gel eluting with petroleum ether: ethyl acetate increasing from 100: 5 to 100: 10. Ethyl 2- (4-biphenylyl) -3-propionyl benzoate is obtained. The title compound melted at 165-167 ° C after washing with 95% ethanol.

8-Carboxy-2- (4-biphenylyl) -3-methyl-4-oxo-4H-1-benzopyran (intermediate CVI)

126

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 and refluxed for 16 hours. After cooling, the mixture was poured into 200 ml of water and extracted with ethyl acetate. The organic layer was separated and extracted with 20% aqueous sodium carbonate. The precipitate formed after acidification of the aqueous layer with dilute hydrochloric acid was collected by suction filtration, washed with water and dried to give 2.5 g of the title compound, melting at 242.5-244 ° C.

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-4-oxo-4H-1-benzopyran (prepared as described in JP 58-225083) and 60 ml of 48% hydrobromic acid in 80 ml of acid The acetic acid was stirred at reflux for 8 hours. After cooling, the mixture is poured into 500 ml of water and the precipitate is filtered off with suction and washed with water. The crude product is purified by flash chromatography eluting with chloroform: isopropanol increasing their ratio 9: 1 to 7: 3 and then eluting with methanol. 1 g of the title compound melting at 300 ° C is obtained.

4- [4- (2-Methoxyphenyl) -1-piperazinyl] -N-methyl-butylamine (intermediate CVIII)

A solution of 3.8 mL of trifluoroacetic anhydride in 25 mL of anhydrous dichloromethane was added dropwise with stirring at 0 ° C

127

NMR Spectrum 7.70-8.00 6.80-7.20 3.85

2.90 to 3.80

1.50-2.05 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 layer was dried over anhydrous sodium sulfate and evaporated in vacuo to give 3.3 g of pure 4- [4- (2-methoxyphenyl) -1-piperazinyl] -N-trifluoroacetylbutylamine.

at 69 MHz (CDCl ₃ , δ) (bs, 1H, NH) (m, 4H, aromatic CH) (s, 3H, CH ₃ O) (m, 12H, piperazine CH, CH ₂ N and CH ₂ NHCO) ( m, 4H, C-CH ₂ CH ₂ -C)

0.88 g of 50% sodium hydride was added portionwise with stirring at 0 ° C to a solution of 3.3 g of the above intermediate in 46 ml of anhydrous dimethylformamide. After stirring for one hour at the same temperature, 0.57 ml of methyl iodide is added. The reaction mixture was stirred at 0 ° C for an additional 1.5 hours. It is then poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to give 1.13 g of crude 4- [4- (2-methoxyphenyl) -1-piperazinyl] -N-trifluoroacetyl-N-methyl-butylamine which was used in to the next step without further purification. To a solution of 1.13 g of this intermediate in 30 ml of ethanol was added 0.18 g of sodium borohydride and the resulting mixture was stirred at 60 ° C for 1 hour. After cooling to room temperature, the reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated in vacuo to give 0.82 g of pure title compound.

NMR spectrum at 60 MHz (CDC1 _3, δ) 6.80-7.20 (M, 4H, aromatic CH) 3.85 (with, 3H, CH ₃ o) 2.90-3.20 (M, 4H, piperazine CH ₂ , positions 3 and 5) 2.30-2.80 (M, 8H; piperazine CH ₂ , positions 2 and 6, 2.50 (with, 3H, CH ₃ N)

- 128

1.80

1.40-1.80 (s, 1 H, NH) (m, 4H, _{C-CH2 -CH2} -C)

1- (3-Amino-2,2-dimethylpropyl) -4- (2-methoxyphenyl) -piperazine

The title compound can be prepared by treating 1- (2-methoxyphenyl) -piperazine with isobutyraldehyde, 37% formaldehyde in water and acetic acid at 90-150 ° C or the same in ethanolic hydrogen chloride (Mannich reaction) to give 1- (2). -formyl-2-methyl-propyl) -4- (2-methoxyphenyl) -piperazine, which is aminated by treatment with excess ammonia under reducing conditions. These may be hydrogen and a catalyst (e.g. palladium on carbon, Raney nickel or platinum oxide) in a solvent (e.g. ethanol, methanol, isopropanol, dichloromethane, chloroform or dimethylformamide) at temperatures between ambient temperature and 80 ° C or alternatively a metal hydride (e.g. sodium borohydride) , sodium or potassium cyanoborohydride or sodium triacetoxyborohydride) in a solvent (e.g. methanol, ethanol, chloroform, benzene or 1,2-dichloroethane) in the presence of an acid (e.g. hydrogen chloride or acetic acid).

It can be reacted with 8-chlorocarbonyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran in the same manner as described in Example 12 herein below to give 8- (2,2-dimethyl-3- [4- ( 2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl) -3-methyl-4-oxo-phenyl-4H-1-benzopyran.

8-trifluroacetamidomethyl-3-methyl-4-oxo-2-phenyl-4H-benzopyran

This compound can be prepared according to the procedure described 129 for intermediate XXIII, but using intermediate XXIV instead of 8-amino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran. It can be used as starting material instead of intermediate XXIII, in the reaction described in Example 32 to give 8- {2- [4- (2-methoxyphenyl) -1-piperazinyl] ethyl-aminomethyl} -3-methyl-4-oxo- 2-phenyl-4H-l-benzopyran.

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

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

8-Etenylsulfonylaminometyl-3-methyl-4-oxo-2-phenyl-4H-benzopyran

This compound can be prepared by reacting intermediate XXIV with 2-chloroethylsulfonyl chloride in a halogenated solvent such as dichloromethane in the presence of triethylamine at 0-40 ° C according to AA Goldberg, J. Chem. Soc., 464, 1945. It can be reacted with suitable HB compounds according to procedure (m) to give the corresponding final compounds. In the same manner as described above, but by starting from 8-amino-3-methyl-4-oxo-2-phenyl-4H-l-benzopyran the final compounds can be obtained by formula F1'-Y36- _{(CH2) 2} ~ B.

130

8-Chlórsulfonylmetyl-3-methyl-4-oxo-2-phenyl-4H-benzopyran

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

DETAILED DESCRIPTION OF THE INVENTION

Example 1

8- (2- [4- (2-Methoxyphenyl) -1-piperazinyl] -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 is added dropwise at 20-25 ° C to a stirred mixture containing 21.4 g of intermediate VI and 4.1 g of potassium carbonate in 120 ml of methanol. After stirring for 4 hours at the same temperature, the reaction mixture was stripped in vacuo. The residue was extracted with chloroform and the organic solution was washed with water, dried over anhydrous sodium sulfate / calcium chloride, filtered and stripped in vacuo. The crude product obtained was dissolved in acetone and a slight excess of ethanolic hydrogen chloride was added. After separation by suction and recrystallization from 95% ethanol, 16.3 g of the title compound are obtained, m.p. (189) 195-199 ° C.

Example 2

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

131

This compound was prepared according to Example 1 but using 1- (2-methylphenyl) -piperayzine instead of 1- (2-methoxyphenyl) -piperayzine and performing the reaction in dimethylformamide for 1 hour instead of in methanol for 4 hours, m.p. (194)

203-206 ° C (isopropanol).

Example 3

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

This compound was prepared according to Example 1 but using 1- (2-ethoxyphenyl) -piperazine instead of 1- (2-methoxyphenyl) -piperazine and the reaction was carried out in dimethylformamide for 2 hours instead of in methanol for 4 hours, m.p. 208-210 ° C (isopropanol).

Example 4

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

A solution of 10 ml of 37% formaldehyde in 15 ml of methanol is added dropwise over 3 minutes at 0 ° C to a solution of 5.75 g of 1- (2-methoxyphenyl) -piperazine in 10 ml of methanol. After 12 hours at 0 ° C, the mixture was stripped under vacuum and redissolved in 15 mL of methanol. At 0 ´C, distilled in 1,4-dioxane. A solution of 3.6 N hydrogen chloride in diethyl ether. In a vacuum, the residue was suspended in 15 ml of 8.3 g of intermediate V in 100 ml

1,4-dioxane is added with stirring at 20-25 ° C. After stirring at reflux for 8 hours, the reaction mixture was cooled to 30-40 ° C. Methanol (50 ml) was added and the mixture was refluxed for a further 2 hours. After cooling to 20-25 ° C, the resulting solution is diluted with 300 mL diethyl ether. Stirring was continued for another 3 hours at the same temperature. The title compound was collected by suction filtration and recrystallized from ethanol. Yield: 4 g. Mp 209-210 ° C.

Example 5

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

A mixture of 4.24 g of 8-carboxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran and 6.3 g of anhydrous potassium carbonate in 60 ml of DMF is stirred at 80 ° C for 30 minutes. Then 5.23 g of 1- (3-chloropropyl) -4- (2-methoxyphenyl) -piperazine are added and stirring is continued at 80 ° C for 3.5 hours. The reaction mixture was cooled to ambient temperature, poured into ice water and extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous sodium sulfate, and evaporated to dryness in vacuo. The residue was taken up in ethanol and excess ethanolic hydrogen chloride was added to the solution. Yield: 8.16 g of the title compound, m.p. 198 to 203 ’C.

Example 6

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

The procedure of Example 5 was followed but using 1- (2-chloroethyl) -4- (2-methoxyphenyl) -piperazine instead of 1- (3-chloropropyl) -4- (2-methoxyphenyl) -piperazine to give the title compound. , tt 200-203 'C of ethanol.

Example 7

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

A mixture of 2.8 g of 1- (2-chlorophenyl) -piperazine hydrochloride and 4.2 g of anhydrous potassium carbonate in 25 ml of dimethylformamide was stirred at ambient temperature for 15 minutes. 4.81 g of intermediate I was added and stirring was 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 then washed with aqueous sodium chloride solution, 0.1 N acetic acid, aqueous sodium chloride solution, aqueous 4% sodium carbonate solution and water, and then dried over anhydrous sodium sulfate. After evaporation to dryness in vacuo, the residue is dissolved in 160 ml of acetonitrile and excess hydrogen chloride in diethyl ether is added. The insoluble title compound was recrystallized from acetonitrile. Yield 3.6 g, m.p. 138-143 ° C.

Example 8

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

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

Example 9

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

Proceed as in Example 7, but using 1- (2-methoxyphenyl) -1-piperazine hydrochloride in place of 1- (2-chlorophenyl) -piperazine hydrochloride to give the title compound. This procedure is an alternative route to the product of Example 5 .

134

Example 10

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

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

Example 11

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

A mixture of 6.28 g of 1- (2-methoxyphenyl) -piperazine and 5.35 g of intermediate XXXVII 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. Fractions containing the title compound were combined. The solvents were removed in vacuo and the residue was dissolved in boiling ethanol. The solvent was filtered off, acidified with ethanolic hydrogen chloride and left overnight at 20-25 ° C. The crude product was collected by filtration and crystallized from ethanol to give 5 g of the title compound, m.p. (177) 182-186 ’C.

135

Example 12

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

A solution of 4.48 g of 8-chlorocarbonyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran in 40 ml of chloroform was added dropwise over 10 minutes at ambient temperature to a solution of 3.74 g of 3- [4- ( 2-methoxyphenyl) -1-piperazinyl] -propylamine, prepared as described in GB 2161807 and 1.97 g of triethylamine in 50 ml of chloroform. After stirring for 2 hours, the solution is washed first with 0.5 N hydrochloric acid, then with a saturated aqueous sodium bicarbonate solution and finally with water. The chloroform solution was dried over anhydrous sodium sulfate, and the solvent was evaporated in vacuo. The residue was worked up as described in Example 11 to give 6.67 g of the title compound, m.p. (177) 182-186 ° C. This procedure is an alternative to the preparation of the product of Example 11.

Thus, the following salts are also prepared:

monohydrochloride hydrate, m.p. 151-154 ° C, monomethanesulfonate, m.p. 162-164 ° C, (±) -hemalate hydrate, m.p. 110 to 112 ’C.

This example describes the condensation of an amine, 4- (2-methoxyphenyl) -1-piperazinyl] -propylamine, with carbonyl chloride, 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carbonyl chloride. It will be appreciated that the amine may be condensed with the corresponding free acid or the corresponding ethyl ester by heating equimolar amounts of these with or without a solvent. If a solvent is used, a high boiling hydrophilic or hydrophobic solvent is suitable. The amine can also be condensed at ambient temperature with an equimolar amount of the corresponding free acid in the presence of N, N'-dicyclohexylcarbodiimide and 4-dimethylaminopyridine in a solvent such as dichloromethane, chloroform, tetrahydrofuran or dimethylformamide.

136

Example 13

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

The title compound was prepared according to the method described in Example 16 but using intermediate XIV instead of intermediate XV and heating to 55-60 ° C for 32 hours. The processing is also changed as follows. After separation of the base by filtration, purification is carried out by flash chromatography on silica gel, eluting with chloroform: methanol 100: 0.5 and then 100: 1. The fractions containing the title compound were combined and the solvents removed in vacuo. The residue was crystallized from ethanol. After filtration, the solids are taken up in boiling water and dilute hydrochloric acid in an amount sufficient to be made into solution. The crystalline salt is precipitated by cooling and filtered off with suction. MP: 119 to 123 ’C.

Example 14

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

The procedure is as in Example 11, but using

2- (2-methoxyphenoxy) -ethylamine (prepared according to Austein, J. et al., J. Med. Chem., 8, 356, 1965) instead of 1- (2-methoxyphenyl) -piperazine, by heating for 2 hours instead of 5 hours and eluting with dichloromethane: methanol 100: 5 gave the title compound, m.p. 200-202 ° C (ethanol).

Example 15

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

137

The procedure is as in Example 11, but using 1-phenylpiperazine instead of 1- (2-methoxyphenyl) -piperazine, heating for 2 hours instead of 5 hours, and using dichloromethane: methanol 100: 4 as the eluent. The title compound is obtained, m.p. (251) 255-258 ° C for decomposition (87% ethanol).

Example 16

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

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

Example 17

8- {1-Hydroxy-2- (4- (2-methoxyphenyl) -1-piperazinyl] ethyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride.

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

9.5 g of the title compound, m.p. 248-249 ’C.

Example 18

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

This compound was prepared according to Example 17, but starting from the compound prepared in Example 2 rather than the one prepared in Example 1. M.p. 257-258 ° C (ethanol).

Example 19

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

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

Example 20

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

This compound was prepared according to Example 17 but starting from the compound prepared in Example 4 rather than the compound prepared in Example 1. The crude base was purified by flash chromatography (silica gel, eluent - ethyl acetate: chloroform 4: 1). Fractions containing pure base were combined, acidified with ethanolic HCl and distilled off in vacuo. The residue was crystallized from ethanol. MP: (126) 156-160 C. C.

Example 21

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

A solution of 3.04 g of intermediate XXXVIII and 2.45 g of 1- (2-methoxyphenyl) -piperazine in 21 ml of anhydrous dimethylformamide was stirred at ambient temperature for 5 hours. An additional 1.22 g of 1- (2-methoxyphenyl) -piperazine was added and the mixture was stirred for 4 hours, poured into 300 ml of water and extracted with ethyl acetate. The combined organic extracts 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 off on a rotary evaporator and the residue was dissolved in 0.81M ethanolic hydrogen chloride and distilled again in vacuo. The solid residue was crystallized from water: ethanol 9: 1 to give 2.43 g of the title compound, m.p. 144 to 146 ’C.

Example 22

8- {1-Ethoxy-2- [4- (2-methoxyphenyl) -1-piperazinyl] ethyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride ml of anhydrous dimethylsulfoxide is added to the 6.55 g of sodium hydride (50% in mineral oil, repeatedly washed with hexane) under nitrogen. A solution of 3 g of the compound prepared in Example 17 in 50 ml of anhydrous dimethylsulfoxide was added to the mixture at 20-25 ° C. After stirring at 20 ° C for 1 hour, 0.66 g of ethyl bromide is added. The reaction mixture was stirred for another 20 minutes at the same temperature and then poured into ice water. The crude product obtained after suction is purified by flash chromatography (silica gel, eluent - chloroform: ethyl acetate 8: 2). The fractions containing the pure title compound were combined, acidified with ethanol

140 with hydrogen chloride and distilled off under vacuum. The residue was crystallized from chloroform: diethyl ether and dried under vacuum at 140 ° C to give 1.6 g of the title compound, m.p. (155) 209 ’C.

Example 23

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

A mixture of 5.2 g of intermediate XXVII, 3.1 g of 1- (2-methoxyphenyl) -piperazine and 2.2 g of anhydrous potassium carbonate in 50 ml of dimethylformamide was stirred at 70 ° C for 7 hours. After cooling to 20-25 ° C, the reaction mixture is poured into 500 ml of water and extracted with dichloromethane. The organic phase is 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 98: 2. The title compound is obtained by forming a salt with ethanolic hydrogen chloride. MP: 217-219 ’C.

Example 24

8- (N-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- (2-methoxyphenyl) -piperazine in 75 ml of dimethylformamide was stirred at 95 ° C for 2 hours. After cooling to 20-25 ° C, the reaction mixture is poured into

200 ml of water, basified with potassium carbonate and extracted with ethyl acetate. The organic phase is washed with water and dried over anhydrous sodium sulfate. The solvent was removed in vacuo. The residue was purified by flash chromatography eluting with dichloromethane: methanol 100: 0.2.

base is made with ethanolic hydrogen chloride and recrystallization from methanol yields 4.4 g of the title compound, melting on silica gel,

141 (200) 227-228 ° C and containing one equivalent of methanol.

Example 25

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

A mixture of 3.42 g of intermediate XXXII, 2.74 g of 1- (2-methoxyphenyl) -piperazine and 0.71 g of anhydrous potassium carbonate in 34 ml of anhydrous dimethylformamide was stirred at 0 ° C for 2 hours. The reaction mixture was poured into water and suction filtered. The resulting solids were purified by flash chromatography on silica gel eluting with ethyl acetate: petroleum ether 6: 4. The combined fractions were evaporated to dryness in vacuo and the residue was crystallized from ethyl methyl ketone. The obtained base was treated in an ethanolic solution with a molar amount of aqueous 2.25N hydrochloric acid to give the title compound, m.p. 168 to 170 ’C.

Example 26

8- {N-Methyl-N- [4- (2-methoxyphenyl) -1-piperazinyl] acetamidomethyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran 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 at 20-25 ° C for 3 hours. The reaction mixture was then poured into water (500 mL) and extracted with dichloromethane. The organic phase is 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, melting at 144-145 ° C. The base was dissolved in ethanol and 8N hydrochloric acid and water were added. The title compound is obtained, m.p. 218-220 ° C after drying at 100 ° C under vacuum.

142

Example 27

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

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

Example 28

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

The procedure is as in Example 27, but using 2- (2-ethoxyphenoxy) -ethylamine instead of 1- (2-methoxyphenyl) -piperazine and a step of purification by flash chromatography on silica gel eluting with ethyl acetate: methanol 97: 3 is included. 4.25 g of the title compound is obtained, m.p. 191-193 C. C.

Example 29

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

2.5 g of potassium carbonate, 2.13 g of potassium iodide and 3.15 g of 1- (2-methoxyphenyl) -piperazine are added to a solution of 5 g of intermediate XXI in 50 ml of dimethylformamide. The mixture was stirred at 90 ° C for 4.5 hours. After cooling to ambient temperature, the reaction mixture was poured into 450 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. A solution of the residue in acetone was treated with a molar amount of 3.8N hydrogen chloride in diethyl ether, filtered off and crystallized from ethanol. 6.15 g of the title compound is obtained, m.p. (218) 223-224 ° C.

Example 30

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

The title compound was prepared by the method described in Example 29 using intermediate XXVI instead of intermediate XXI and stirring for 2.5 hours rather than 4.5 hours. After usual work-up, the residue was purified by flash chromatography on silica gel, eluting with ethyl acetate: methanol 97: 3. The combined fractions were acidified with excess ethanolic hydrogen chloride and evaporated to dryness in vacuo. The residue was crystallized from ethanol to give 5.2 g of the title compound, m.p. 170 DEG-172 DEG C. This compound contains 1 equivalent of ethanol.

Example 31

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

A mixture of 4.5 g of intermediate XXV, 2.36 g of 1- (2-methoxyphenyl) -piperazine and 0.84 g of potassium carbonate in 45 ml of anhydrous dimethylformamide was stirred at ambient temperature for 2.5 hours. The reaction mixture is poured into 300 ml of water and filtered off with suction, washed with water. The solid base is crystallized from ethanol and has a melting point of 143-146 ° C. The crystallizate was dissolved in 1,2-dichloroethane and acidified with ethanolic hydrogen chloride. 4.4 g of the title compound are obtained, m.p. 229-233 ° C, after recrystallization from methanol: water 1: 3.5.

144

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 is removed! and after 30 minutes at 20-25 ° C a solution of 4.1 g of 1- (2-chloroethyl) -4- (2-methoxyphenyl) -piperazine in 10 ml of dimethylformamide is added. The mixture was stirred at 90 ° C for 5 hours and then cooled to 20-25 ° C. Another addition 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 is stirred at 90 ° C for 8 hours and again cooled to 20-25 ° C. Water (200 ml) was carefully added and the mixture was extracted with ethyl acetate. The organic layer 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 3: 2 n-hexane: ethyl acetate. A mixture of the base of the title product 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 dimethylsulfoxide. To this solution was added 0.55 g of sodium borohydride in portions at 20-25 ° C. The mixture was stirred at this temperature for 3 hours 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 in vacuo. The residue was dissolved in dichloromethane. Add 2 equivalents of ethanolic hydrogen chloride to give the title compound, which is recrystallized from ethanol. Yield 3.8 g, mp.231-234 ° C,

Example 33

2.75 8-3- [4- (2-Methoxyenyl) -1-piperazinynyl] -propylamino} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride hydrate

145

Using 1- (3-chloropropyl) -4- (2-methoxyphenyl) -piperazine in place of 1- (2-chloroethyl) -4- (2-methoxyphenyl) -piperazine, but otherwise following the procedure of Example 32, the title compound was obtained, m.p. 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-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8.3 g of triacetoxyborohydride and 3.4 ml of acetic acid in 40 ml of 1. The 2-dichloroethane was stirred at 20-25 ° C for 6 hours. 15 ml of 5% aqueous sodium hydrogen carbonate solution are then 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 obtained base was dissolved in dichloromethane and 1 equivalent of ethanolic hydrogen chloride was added. After removal of the solvent in vacuo, the residue was crystallized from 50% ethanol to give 1.6 g of the title compound, m.p. (140) 151-153 ’C.

Example 35

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

A mixture of 4 g of the compound prepared in Example 33, as the base of the compound, 4.35 ml of 37% aqueous formaldenyde and 1.15 g of sodium cyanoborohydride in 25 ml of acetonitrile is stirred at 20-25 ° C while maintaining the pH within 5-6 by addition. acetic acid during the reaction. After 4 hours the solvent was evaporated in vacuo

146 vacuum. 80 ml of ethyl acetate and 200 ml of ice-cold 1N sodium hydroxide solution were added to the residue. The organic phase is washed with water, dried over anhydrous sodium sulphate 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 pure base thus obtained is dissolved in diethyl ether. 1 equivalent of ethanolic hydrogen chloride was added and the solvent was removed in vacuo. The residue was crystallized from water to give 2 g of the title compound, m.p. 186 to 187 ’C.

Example 36

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

A mixture of 4.8 g of the compound prepared in Example 33 as its base, 2.8 ml of acetic anhydride and 33 ml of pyridine is stirred at 80 ° C for 4 hours. After cooling to 20-25 ° C, the reaction mixture is poured into 200 g of ice water, acidified with 10N 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 pure base obtained is dissolved in dichloromethane, 1 equivalent of ethanolic hydrogen chloride is added and the solvent is removed in vacuo. The residue was crystallized from acetonitrile to give 3 g of the title compound containing 0.33 equivalents of acetonitrile, m.p. 208.5 to 210.5 ’C.

Example 37

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

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 at 60 ° C for 6 hours. The reaction mixture was then cooled to ambient 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 to give the base of the title compound, which was then dissolved in hot ethanol. To the solution was added 1 molar equivalent of 0.81M ethanolic hydrogen chloride. 4 g of the title compound are obtained, m.p. 255 DEG-257 DEG.

Example 38

8-2- [4- (2-Methoxyphenyl) -1-piperazinyl] ethylureido-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methanesulfonate

A mixture of 3.34 g of intermediate XVIV and 7.22 g of 1- (2-methoxyphenyl) -piperazine was stirred at 100 ° C for 5 hours. An additional 1.8 g of 1- (2-methoxyphenyl) -piperazine is then added and stirring is continued for another 2 hours at 100 ° C. After cooling to ambient temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The organic phase is washed with aqueous sodium hydroxide solution, dried over anhydrous sodium sulphate 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. The crude methanesulfonate obtained in vacuo was crystallized from ethyl acetate: ethanol 1: 1 to give 2.35 g of the title compound, melting at 191-193 ° C.

Example 39

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

A mixture of 6.61 g of intermediate XI, 8.34 g of 1- (2-methyl-4-xyl-phenyl) -piperazine and 1.26 g of sodium iodide in 70 ml of dimethylformamide was stirred at 80 ° C for 17 hours. After cooling to 20-25 ° C, the reaction mixture was poured into 600 mL of water, basified with 5% aqueous sodium bicarbonate, and extracted with dichloromethane. The organic extracts were washed with aqueous sodium chloride solution, 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 product were combined and the solvent removed in vacuo. The residue was dissolved in ethanol and ethanolic hydrogen chloride was added. The title compound crystallizes and is collected by suction filtration. Recrystallized from 95% ethanol to give 6.5 g, m.p. Mp 224-225 ° C.

Elemental analysis calculated 66.38% C, 6,34% H, 5.35% N, 6.76% C, 3.35% H ₂ 0 found 66.34% C, 6,14% H, 5.33% N, 6.75% C, 3.43% H ₂ 0 NMR spectrum at 60 MHZ (CDCl ₃ -CD ₃ OD) 7.8-7.1 (m, 8H) aromatic protons of the benzopyran ring) 7.1-6.6 (π, 4H, aromatic protons of 2-methoxyphenyl group 4.8-4.4 pins) (m, 2H) och ₂ ) 4.4-4.1 (m, 3H) H ₂ 0 and N ⁺ H) 3.9-3.0 (m, 10H) , 5 x CH ₂ N) 3.8 (S, 3H, och ₃ ) 2.1 (s, 3H, ch ₃ ) Example 40

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

This compound was prepared by the method described in the Example

149

39, but using intermediate IX instead of intermediate XI. Purification by flash chromatography was omitted in this case because it was not necessary. MP: Mp 226-227 ° C.

Example 41

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

A mixture of 7.75 g of intermediate XVI, 4.7 g of 1- (2-methoxyphenyl) -piperazine, 3.3 g of potassium iodide and 2.8 g of anhydrous potassium carbonate in 78 ml of dimethylformamide was stirred at 75 ° C for 2 hours. . After cooling to 20-25 ° C, the reaction mixture is poured into 600 ml of water and extracted with dichloromethane. The organic extracts were washed with water and dried over anhydrous sodium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate. The title compound thus obtained in the form of its base is transformed into its dihydrochloride by treatment with ethanolic hydrogen chloride. After crystallization from ethanol, it is obtained

6.5 g of the title compound, m.p. 217-219 ’C.

Example 42

8- {5- [4- (2-Methoxyphenyl) -1-piperazinyl] -pentyloxy} -3-methyl-4-oxo-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. MP: 173 DEG C. (ethanol). The corresponding base melts at 117-118 ° C (ethanol).

Example 43

8 - {- 3- [4- (2-methoxyphenyl) -1-piperazinyl] propoxy) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrate 1,75-hydrate

150

2.93 g of magnesium monoperoxyphthalate in 10 ml of water is added dropwise at -15 ° C to a solution of 4.34 g of the compound prepared in Example 40 and 0.1 g of benzyl (triethyl) ammonium chloride in 20 ml of dichloromethane and 20 ml of methanol. The mixture was stirred at 0 ° C for 2 hours and then warmed to ambient temperature. Pour into water and basify by addition of aqueous sodium hydroxide solution. Extraction with dichloromethane gave a solid after usual work-up which was purified by flash chromatography eluting with dichloromethane: methanol 9: 1. The combined fractions containing the pure compound were evaporated to dryness in vacuo and the residue was crystallized from acetonitrile to give 0.5 g of the title compound, m.p. 89 to 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., J. Med. Chem., 22, 1125, 1979) in 45 ml of benzene was added. Stir at 20-25 ° C for 18 hours and at reflux for 5 hours. The solvent was evaporated in vacuo and the residue was dissolved in 80 ml of anhydrous methanol. A 3 ° A molecular sieve is added. 0.61 g of sodium borohydride is then added at 0 ° C. The mixture is kept 1 hour at 0 ^{| C} and 1 hour at 20-25 DEG C. and 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 49: 1. The base obtained is treated with ethanolic hydrogen chloride. Crystallization from ethanol gave the title compound. Yield 40%,

mp 200 to 202 ’C.

151

Example 45

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

A solution of 3.7 g of intermediate XL and 4.64 g of 1- (2-methoxyphenyl) -piperazine in 40 ml of dimethylformamide was stirred at 80 ° C for 3 hours. After cooling to 20-24 ° C, the reaction mixture is poured into 400 ml of water and extracted with dichloromethane. The aqueous phase was basified with 1N sodium hydroxide and extracted with ethyl acetate. The combined organic extracts were washed with water and dried over anhydrous sodium sulfate. The solvents were removed in vacuo. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate. The fractions containing the title compound as its base are combined and distilled off under vacuum. The residue was dissolved in dichloromethane and one equivalent of ethanolic hydrogen chloride was added. The solvents were removed in vacuo and the residue was recrystallized from ethanol. 5 g of the title compound are obtained, containing one molar equivalent of ethanol. MP: (122) 126-128 ° C with decomposition.

Example 46

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

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

152

Example 47

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

A solution of 3.8 g of intermediate XXXV and 4 g of 1- (2-methoxyphenyl) -piperazine was heated at 60 ^° C for 7 hours. After cooling to 20-25 ° C, the reaction mixture is poured into 500 ml of water and extracted with dichloromethane. The organic extracts were washed with water and dried over anhydrous sodium sulfate, and the solvent was then 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 in this way. Dissolve in ethanol and add one equivalent of ethanolic hydrogen chloride. 4.5 g of the title compound are obtained, mp (215) 226-228 ° C.

Example 48

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

A solution of 4.5 g of intermediate XLII and 3.8 g of 1- (2-methoxy-phenyl) -piperazine in 40 ml of dimethylformamide was heated at 70 ° C for 7 hours. After cooling to 20-25 ° C, the reaction mixture is poured into 150 ml of water and extracted with dichloromethane. The organic solution 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, eluting with ethyl acetate: petroleum ether 3: 7 to give the title compound by salification with ethanolic hydrogen chloride. Yield 3.9 g, m.p. 236-238 C. C.

Example 49

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

153

The title compound was obtained by the method described in Example 48, but using intermediate XLI instead of intermediate XLII, m.p. 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 hemihydrate hemihydrate

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

Example 51

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

A solution of 1.33 ml of anhydrous dimethylsulfoxide 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. After stirring at -70 ° C for 15 minutes, a solution of 2.8 g of the compound of Example 21 (as base) in 14 mL of dichloromethane was added. After 15 minutes at this temperature, 4.7 ml of anhydrous triethylamine is added and the temperature is raised to -30 ° C over 30 minutes. Stirring is continued at -30 ’C for an additional 30 minutes. When the temperature is raised to 0 ° C, the mixture is diluted with 120

154 ml water and extracted with dichloromethane. The organic phase is washed with water, dried over anhydrous sodium sulphate and evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate: dichloromethane 9: 1. The fraction containing the title product as the base was evaporated to dryness in vacuo and, after dissolution in 30 ml of dichloromethane, one equivalent of methanesulfonic acid was added. The solvent was evaporated in vacuo and the residue was crystallized from ethanol to give 2.9 g of the title compound, m.p. 194-195 C.

Example 52

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

A mixture of 5.56 g of intermediate XLIII as base, 4.58 g of 2- (p-toluenesulfonyloxamethyl) -1,4-benzodioxane and 1.9 g of anhydrous potassium carbonate in 80 ml of anhydrous dimethylformamide was stirred at 110 ° C for 5 hours. The reaction mixture was cooled to room temperature, poured into water and extracted with dichloromethane. The organic phase is washed with water, dried over anhydrous sodium sulphate, filtered and evaporated to dryness in vacuo. The residue was purified by flash chromatography using a silica gel column eluting with ethyl acetate: methanol 95: 5. The fraction containing the title compound as a base was evaporated to dryness in vacuo. The residue was dissolved in ethanol and one equivalent of methanesulfonic acid dissolved in ethyl acetate was added. The crystallized product is filtered off and recrystallized from ethanol. 2.4 g of the title compound are obtained, m.p. 172 to 174 ’C.

Example 53

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

A solution of 2.8 g of intermediate XLVI and 0.13 g of acid

155 p-toluenesulfone in 150 ml 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 3 hours. After filtration, the reaction mixture was evaporated to dryness in vacuo to give 2.5 g of 8- (4,4-dimethoxybutyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran.

NMR (CDC1 _3, δ) 1.6-1.9 (4H, m. chch ₂ ch ₂ ch 2.2 (3H, with, flavon CH ₃ ) 2.9 (2H, t, fi-ch ₂ ) 3.3 (6H, with, 2 x OCH ₃ ) 4.4 (1 H, t, ch ( ₃ ) ₂ ) 7.3 (1 H, dd , flavon CH in 6) 7.5-7.8 (6H, m. flavon CH at 7 and 5 8.1 (1 H, dd , flavon CH in 5) solution 2.5 g thus prepared

and 30 ml of acetic acid is heated at 50 ° C for 2.5 hours. The reaction mixture was cooled to ambient temperature, diluted with ice water, basified with aqueous sodium carbonate and extracted with chloroform. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to dryness in vacuo. The residue was purified by flash chromatography on silica gel, eluting with petroleum ether: ethyl acetate 3: 1. 2.1 g of 8- (4-oxobutyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran are obtained (> 75% yield) and used in the next step without further purification.

NMR (CDC1 _3, S)

1,9-2,1 2,2

2.5 2.9 7.3

7,5-7,7 8,1

9.7

δ) (2H, dd ch ₂ ch ₂ ch _? cho) (3H, with, flavon CH ₃ ) (2H, t, ch ₂ cho) (2H, t, fi-ch ₂ ) (1 H, dd , flavon CH in 6) (6H, m. flavon CH at 7 and 5 x (1 H, dd , flavon CH in 5) (1 H, with, CHO)

2.3 ml of hydrochloric acid in ethanol, solution 2.1

156 g of the compound thus obtained in 40 ml of methanol and 0.45 g of sodium cyanoborohydride are added successively to a solution of 8 g of 1- (2-methoxyphenyl) -piperazine in 30 ml of methanol. After stirring the reaction mixture at ambient temperature for 24 hours, it was poured into 500 ml of ice water and extracted with dichloromethane. The organic phase is washed with water, dried over anhydrous sodium sulphate and evaporated to dryness in vacuo to give a residue which is purified by flash chromatography using a silica gel column, eluting with ethyl acetate: petroleum ether 9: 1. The fraction containing the title product as a base was evaporated to dryness in vacuo. The residue was dissolved in 30 mL of dichloromethane and one equivalent of methanesulfonic acid was added. The solvent was evaporated in vacuo and the residue was crystallized from acetone to give 2.35 g of the title compound (mp 141-143 ° C).

Example 54

8- [3- (4-Phenyl-1-piperidinyl) -propylcarbamoyl] -3-methyl-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. Purification was performed by flash chromatography using a silica gel column eluting with dichloromethane / ethanol 100: 5. MP: 157-159 ’C (ethyl acetate) .The base melts at (127) 147-149 C C (ethanol).

Example 55

8- [3- (4,4-Diphenyl-1-piperidinyl) -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

157 hours. MP: 221-223 ° C (ethyl acetate).

Example 56

8- {3- [4- (4-Fluoro-benzoyl) -1-piperidinyl] -propylcarbomoyl} -3-methyl-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 performed for 30 minutes instead of 5 hours. Purification was accomplished by flash chromatography using a silica gel column eluting with dichloromethane: 5N methanolic ammonia increasing from 100: 1 to 100: 20. MP: 181-183 ’C (ethanol).

Example 57

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

This compound was prepared by the method described in Example 11 using 4- (2-oxo-1- (2-oxo-1-benzimidazolinyl) -piperidine instead of 1- (2-methoxyphenyl) -piperazine. Purification was by flash chromatography using Silica gel column eluting with chloroform: 5N methanolic ammonia 100: 3, mp 238-241 ° C (ethanol).

Example 58

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

The title compound was prepared according to 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. The product was purified by flash chromatography using a silica gel column eluting with 100: 3 chloroform: methanol. The desired fractions were dissolved in dichloromethane and one equivalent of methanesulfonic acid was added. After evaporation of the solvent in vacuo, the residue was boiled with ethyl acetate for 1 hour and then filtered off. MP: Mp 209-210 ° C. The product contains 0.2 equivalents of ethyl acetate and 0.1 equivalents of water. The corresponding base melts at 178-180 ° C (ethanol).

Example 59

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

Follow the procedure of Example 11 but using 1- (2-hydroxyphenyl) -piperazine instead of 1- (2-methoxyphenyl) -piperazine, heating for 1.5 hours instead of 5 hours and using dichloromethane: methanol 100: 3 to 100: 10 as the eluent for column chromatography to give the title compound, mp Mp 118-120 ° C (ethanol 95%).

Example 60

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

This compound was prepared by the method used in Example 12 but using 4- [4- (2-methoxyphenyl) -1-piperazinyl] -butylamine instead of 3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylamine. The reaction mixture is stirred at room temperature for 22 hours, diluted with water and filtered off with suction, and the insoluble solids are washed with water. The crude residue was dried and purified by column chromatography on silica gel eluting with ethyl acetate: methanol 9: 1. The fractions containing the pure product as the base were combined, evaporated to dryness in vacuo and dissolved in dichloromethane. Methanesulfonic acid was added to the solution, and the salt precipitated by the addition of 2 volumes of ethyl acetate, filtered and recrystallized from ethanol. The title compound is obtained, m.p. 230-232 ° C.

159

This product contains 0.3 molar equivalents of ethanol.

Example 61

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

This compound was prepared according to the procedure of Example 12 but using Intermediate VIII instead of 8-chlorocarbonyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran with stirring for 24 hours instead of 2.5 hours. The crude product was purified by silica gel column chromatography, eluting with ethyl acetate: methanol 98.5: 1.5. Combined fractions containing pure product as base were evaporated to dryness in vacuo and dissolved in dichloromethane. Methanesulfonic acid was added to the solution and the solvent was evaporated 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-methoxy-phenoxy) -ethyl-amino] -propylcarbamoyl} -3-methyl-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 prepared in Example 14 in 55 ml of acetonitrile and 20 ml of water. After stirring for 15 minutes at room temperature, 2.70 g of 95% sodium cyanoborohydride was added to the red solution, and 1.38 ml of acetic acid was added for 15 minutes under the same conditions. After stirring for 3 hours, the solvents were removed in vacuo and the residue was washed with 250 mL of water and 250 mL of chloroform. After addition of 3N sodium hydroxide, the organic phase is separated and the aqueous phase is extracted twice with chloroform. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel eluting with chloroform: 5.2N methanolic ammonia 100: 0.5 to 100: 2. Pooled fractions containing the pure title compound as a base

160 was evaporated to dryness in vacuo and the residue was dissolved in hot ethanol. The solution was acidified with ethanolic hydrogen chloride and, after evaporation of the solvent in vacuo, the residue was washed with diethyl ether and stirred at room temperature. The crude product was collected by filtration and crystallized from acetonitrile. 3.1 g of the title compound, m.p. 146-148 ° C.

Example 63

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

The procedure was as in Example 37, but using intermediate L instead of intermediate X and stirring at 90 ° C for 4 hours instead of at 60 ° C for 6 hours. The title compound is obtained as a crude base. After purification by column chromatography, silica gel eluting with ethyl acetate: methanol 95: 5 gave the crude methanesulfate as described in Example 61 and crystallized from acetone to give the title compound, m.p. 200 - 202 ’C.

Example 64

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

The title compound was prepared as described in Example 12 but using intermediate LVI instead of 8-chlorocarbonyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran and stirred for 24 hours instead of 2.5 hours. The crude product was purified by column chromatography eluting with ethyl acetate: metynol 92: 8 and the pure base obtained by evaporation in vacuo of the combined fractions was dissolved in dichloromethane. Two equivalents of metynsulfonic acid are added. The crude dimethyl sulfonate obtained after evaporation of the solvent is recrystallized from acetone, m.p. 153 to 156 'C (200).

161

Example 65

8- {3 - [(3,4-Dihydro-1-oxo-2H-naphthyl) -methyl-amino] -propylcarvamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methanesulfonate

A mixture of 6 g of intermediate XLIII, 2.4 g of 2-methylene-α-tetralone (prepared as described in Org. Synth., 60, 88 1981) and 3.14 ml of triethylamine in 48 ml of anhydrous dimethylformamide is stirred at room temperature. hours and then at 50 ° C for 1 hour. The reaction mixture was diluted with water and extracted with dichloromethane. The organic layers were washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The crude residue was purified twice by column chromatography eluting first with dichloromethane: methanol 95: 5 and then dichloromethane: methanol: 5.8N methanolic ammonia 98: 2: 0.2 to give 1.74 g of the title compound as a base. The base was converted to the methanesulfonate by the procedure described in Example 61. The salt was recrystallized first from acetone and then from acetonitrile to give the title compound, m.p. (69) 157-159 ’C.

Example 66

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

The title compound was prepared according to 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, mp 193-196 ’C of ethyl alcohol: diethyl ether.

Example 67

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

The title compound is prepared as described in the Example

162

61, but using 4- [4- (2-methoxyphenyl) -1-piperazinyl] -propylamine instead of 3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylamine. The crude dimethanesulfonate is crystallized first from acetonitrile and then from ethanol, m.p. M.p. 172-174 ° C.

Example 68

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

A solution of 3.6 g of 1- (3-chloropropyl) -4- (2-methoxyphenyl) -piperazine in 30 ml of anhydrous dimethylformamide was added dropwise with stirring at 0 ° C to a mixture of 3.92 g of O- (2-tetrahydropyranyl) -hydroxy. Lamin nu (prepared as described by RN Watrener et al., Angewandte Chem. Int. Ed., 5, 511, 1966). Stirring was continued at 0 ° C for 2 hours and then at 110 ° C for 12 hours. The reaction mixture was cooled to room temperature and dimethylformamide was removed by distillation in vacuo. The residue was washed with water and extracted with ethyl acetate. The combined organic layers were washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo to give 4.39 g of 1- [3- (2-tetrahydropyranyloxyamino) -propyl] -4- (2-methoxyphenyl) -piperazine.

¹ H / NMR (CDCl ₃ , δ)

6.50-6.75

5.20

4.60

3.30- 4.00 2.80-3.20 2.20-2.80

1.30-2.00 (m, 4H, aromatic protons) (bs, 1H, NH) (m, 1H, O-CH-O) (m, 5H, OCH ₂ and tetrahydropyran CH ₂ O) (m, 6H, piperazine 2 x CH ₂ , alkyl chain CH ₂ N) (m, 6H, piperazine 2 x CH ₂ , alkyl chain CH ₂ N) (m, 8H, tetrahydropyran 3 x CH ₂ , alkyl chain C-CH ₂ -C)

A solution of 2.79 g of 8-chlorocarbonyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran in 47 ml of chloroform is added dropwise at a temperature

163 rooms to a mixture of 3.26 g of the compound thus prepared and 1.42 g of potassium carbonate in 47 ml of chloroform. The reaction mixture is stirred for 3 hours and then diluted with 75 ml of chloroform and washed three times with 1M sodium hydride. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The crude residue was purified by silica gel column chromatography eluting with ethyl acetate: methanol 98: 2. The combined fractions were evaporated to dryness in vacuo to give 2.99 g of the title compound as a base. The base was dissolved in dichloromethane and methanesulfonic acid was added to this solution. The solvent was removed by evaporation in vacuo and the crude salt was crystallized from ethyl acetate to give the title compound, m.p. Mp 159-160 ° C.

Example 69

8- {4- [4- (2-Methoxyphenyl) -1-piperazinyl] butyramido} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hemihydrate 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. ° C instead of 7 hours at 100 ’C. After the usual work-up, the crude residue was purified by silica gel column chromatography eluting with ethyl acetate: methanol 95: 5. 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 one equivalent of methanesulfonic acid was added. After evaporation of the solvent to dryness, the crude acetone salt crystallizes in vacuo, m.p. 175 to 176 'C.

Example 70

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

164

A solution of 5.4 g of 8-formyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran and 5.13 g of intermediate LIII in 10 ml of chloroform containing a 3Å molecular sieve is stirred under reflux for 6 hours. The molecular sieve was removed by filtration and the solution was evaporated to dryness in vacuo. The crude product was purified by column chromatography on silica gel eluting with ethyl acetate: petroleum ether 7: 3. The two fractions were separated and evaporated to dryness in vacuo. The first eluted group of fractions (less polar) contains mostly pure title compound; second group (polar-

highest) is mixture of 1: 1 E and Z diastereomers as determined by NMR. ¹ H-NMR (CDCl 3)? 3, δ) 8.75 (dd, 0.5H, benzopyran CH at 7, Z) 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 'and 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 _CH2, E + Z) 2.70-2.90 (m, 6H, piperazine 2 x CH ₂ and 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) The E diastereomer was crystallized from ethanol: water 2: 1 to give

2.5 g of pure title compound, m.p. Mp 107-109 ° C.

Example 71

0.25 H ₂ O 8- (N-hydroxy-3- [4- (2-methoxy-phenyl) -1-piperazinyl] -propylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-1 methanesulfonate benzopyran

165

A solution of 2.04 g of the compound of Example 68 as a base in 104 ml of 1.6N ethanolic hydrogen chloride was stirred at ambient temperature for 12 hours. Ethanol was removed by evaporation in vacuo and the residue was washed with 1N sodium hydroxide and dichloromethane. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. One molar equivalent of methanesulfonic acid was added to the residue solution. The solvent was removed and the crude methanesulfonate was crystallized from acetone to give 1.02 g of the title compound, m.p. Mp 211-213 ° C. The product contains 0.25 mol of water.

Example 72

1,2-H ₂ O methanesulfonate E-8- <2- {2- [4- (2-methoxyphenyl) -1-piperazinyl] -ethylcarbamoyl} -ethenyl> -3-methyl-4-oxo-2-phenyl-4H -l-benzopyran

The title compound was obtained by the ametode described in Example 61, but using intermediate IV instead of intermediate VIII and 2- [4- (2-methoxyphenyl) -1-piperazinyl] -ethylamine instead of corresponding to propylamine, in 1,1,2,2-tetrachlorethylene as a solvent. At the end, the reaction mixture was diluted with water and chloroform and washed with 1N aqueous sodium hydroxide, then water. To the organic layer, after drying over anhydrous sodium sulfate, methanesulfonic acid was added and the solvent was evaporated in vacuo. The crude product was crystallized twice from isopropanol to give the title compound containing 1.2 molar equivalents of water. MP: Mp 124-127 ° C.

Example 73

8- {4- [4- (2-Methoxyphenyl) -1-piperazinyl] -butylsulfinyl} -3-methyl-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, stirring at 70 ° C for 3 hours again at 90 ° C for 3 hours after addition of a potassium iodide amount (0.01 equivalents) of potassium iodide. . Purification by column chromatography on silica gel, eluting with ethyl acetate: methanol 9: 1, afforded the title compound as a base. One molar equivalent of methanesulfonic acid was added to the crude base dissolved in dichloromethane. After removal of the solvent by evaporation in vacuo, the resulting salt was crystallized from acetone to give the title compound, m.p. 183 to 184 ’C.

Example 74

8- {3- [3- (2-Methoxy-phenoxy) -propylamino] -propylcarbamoyl} -3-methyl-4-oxo-phenyl-4H-1-benzopyran hemihydrate hemihydrate

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

Example 75

8- {3- [2- (2-Methyl-thiophenoxy) -ethylamino] -propylcarbamoyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methanesulfonate

1.85 g of 95% sodium borohydride is added to a solution of 7 g of intermediate LIX in 70 ml of methanol, stirred at 0 ° C. After stirring for 1 hour at the same temperature, the solvent was removed by distillation in vacuo. The residue was diluted with water and 2N hydrochloric acid and extracted with ethyl acetate. organic

167

The J layer 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 prepared in 35 ml of pyridine, stirred at 0 ° C. After stirring at ambient temperature for 14 hours, the reaction mixture was poured into cold 2N hydrochloric acid and extracted with dichloromethane. The organic layer was washed twice with water, dried over anhydrous sodium sulfate and evaporated in vacuo to give 7.8 g of a 3: 1 mixture of 2- (2-methylthiophenoxy) ethyl p-toluenesulfonate and 2- (2-methylthiophenoxy) ethyl chloride. (by NMR) 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 is kept in an oil bath at 140 ° C for 20 minutes. After this time, the molten mass is cooled to ambient temperature and solidified. The solid residue was washed with dichloromethane and 4N sodium hydroxide. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo.

The crude product was purified by column chromatography on silica gel eluting with dichloromethane: methanol 9: 1 to give 2.07 g of the title compound as a base. This is converted to the crude methanesulfonate by a conventional procedure, which is first crystallized from acetone and then from acetonitrile. MP: 143 to 146 ’C.

Example 76

8- {3- [2- (2,6-Dimethoxyphenoxy) -ethylamino] -propylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride

A homogeneous mixture of 3.3 g of 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 Heat in an oil bath at 150 ° C for 10 minutes. The molten mass is cooled to room temperature and solidified. The solid residue was washed with ethyl acetate and 2N sodium hydroxide. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The oily residue was purified twice by silica gel column chromatography, eluting first with ethyl acetate: methanol: 5N methanolic ammonia 97: 3: 0.3 and then with dichlorometalonol: methanol: triethylamine 90: 10: 0.3. 3.3 g of pure title compound are obtained as a base, which is crystallized from acetone and then from acetonitrile, m.p. Mp 179-181 ° C.

Example 77

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

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

Example 78 (E) -8- {4- [4- (2-methoxy-phenyl) -1-piperazinyl-1-butenyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran

33.4 ml of a 1 molar solution of lithium bis (trimethylsilyl) amide in anhydrous tetrahydrofuran was added dropwise over 15 minutes to a suspension of 6.4 g of 3-hydroxypropyltriphenylphosphonium bromide in 60 ml of anhydrous tetrahydrofuran cooled to -15 ° C. A solution of 4 g of 8-formyl-3-methyl-4-oxo-2-2-phenyl-4H-1-benzopyran in 40 ml of tetrahydrofuran is then added dropwise. The reaction mixture was stirred at 0 ° C for 30 minutes, then at room temperature for 1.5 hours.

169

Quench with methanol then evaporate to dryness in vacuo to give a residue which was purified by column chromatography on silica gel eluting with ethyl acetate: petroleum ether 6: 4. The combined fractions were evaporated in vacuo to give 4.17 g of 8- (4-hydroxy-1-butenyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran as a mixture of EZ diastereoisomers having a ratio of 3, 5: 1 by NMR.

¹ H NMR, 200MHz (CDCl ₃ , δ) 8.10-8.20 (d, 1H, benzopyran CH at 5, E + Z) 7.30-7.80 (m, 7H, other aromatic, E + Z) 6.80 -7.00 (2d, 1 H, aryl-CH =, E + Z) 6.41 (dt, 0.78H, _CH-CH2, E) 5.90 (dt, 0.22H, _CH-CH2, Z) 3.60-3.80 (m, 2H, CH ₂ O, E + Z) 2.45-2.60 (m, 2H, _CH-CH2, E + Z) 2.18 (s, 3H, benzopyran CH ₃ in 3, E + Z) 1.60-1.90 (sa, 1 H, OH, E + Z)

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

A solution of 2.85 g of the above p-toluenesulfonic acid ester and 2.98 g of 1- (2-methoxyphenyl) -piperazine in anhydrous dimethylformamide was stirred at ambient temperature for 48 hours. After this time, the mixture was poured into 250 ml of water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The residue was purified by column chromatography on silica gel eluting with ethyl acetate: petroleum ether 6: 4. The combined fractions were evaporated to dryness in vacuo from 170 and the crude product was crystallized from 70% ethanol to give 1.48 g of the title compound, melting at 119-121 ° C.

¹ H. NMR, 200 MHz (CDCl ₃ , δ)

8.14 (dd, 1H, benzopyran CH at position 5)

7.85 (dd, 1H, benzopyran CH at 7)

7.41-7.70 (m, 5H, phenyl CH)

7.34 (dd, 1H, benzopyran CH at position 6)

6.70-7.10 (m, 5H, aryl-CH = and methoxyphenyl CHs) 6.30-6.50 (dt, 1H, J _trans = 16.5 Hz, _CH-CH2) 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)

2.18 (s, 3H, benzopyran CH ₃ in 3)

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

The title compound was prepared according to Example 6, but using intermediate III instead of 8-carboxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran. After usual work-up, the residue was crystallized twice from ethanol to give a solid which was purified by silica gel column chromatography eluting with chloroform: ethyl acetate 8: 2 to give a pure base which was dissolved in chloroform: methanol 1: 1. Methanesulfonic acid was added to the solution and the solvents were removed in vacuo. The crude salt was crystallized from isopropanol to give the title compound, melting at 193-195 ° C. This compound contains 0.33 equivalents of isopropanol and 0.25 equivalents of water.

Example 80

8- {2- [4- (2-Methoxyphenyl) -1-piperazinyl] ethylcarbamoylmethyl} -4-oxo-2-phenyl-4H-1-benzopyran hydrate methanesulfonate

A mixture of 2.8 g of intermediate XLVII and 1.28 g of 1-hydroxybenzo171 triazole in 20 ml of anhydrous dimethylformamide was stirred at 0-5 ° C for 15 minutes. A solution of 1.96 g of dicyclohexylcarbodiimide in 20 ml of anhydrous dimethylformamide is added dropwise over about 40 minutes. After stirring at ambient temperature for 8 hours, a solution of 2.24 g of 1- (2-aminoethyl) -4- (2-methoxyphenyl) -piperazine in 15 ml of anhydrous dimethylformamide is added. After stirring for 5 hours and standing overnight at the same temperature, the insoluble material was filtered off and the filtrate was poured into about 300 ml of water and basified with 1N sodium hydroxide. The mixture was extracted with dichloromethane and the organic layer was separated, dried over anhydrous sodium sulfate and evaporated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with chloroform: methanol 95: 5. One molar equivalent of methanesulfonic acid was added to a solution of the crude base in ethanol. Diethyl ether is added until the salt crystallizes. The salt was then filtered and recrystallized from ethanol: diethyl ether 1: 2 to give 1.15 g of the title compound, m.p. 160 to 162 C.

Example 81

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

A solution of 3.86 of intermediate LVII, 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 at 90 ° C for 7 hours. After cooling to room temperature, the reaction mixture was poured into 500 ml of water and extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The residue was purified by silica gel column chromatography eluting with ethyl acetate: petroleum ether 7: 3 to give 1.89 g of the title compound, melting at (55) 62-63 ° C.

172

Example 82

8- {2- [4- (2-Methoxyphenyl) -1-piperazinyl] ethylsulfonylamino) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methanesulfonate

1.05 ml of 2-chloroethanesulfonyl chloride is 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 at 0 ° C. The reaction mixture was stirred at ambient temperature for 2 days. After filtering off the solid precipitate, the solution was evaporated to dryness in vacuo to give a crude residue containing 8- (ethenylsulfonylamino) -3-methyl-4-oo-2-phenyl-4H-1-benzopyran, which could be used without further purification. A mixture of 7.54 g of potassium carbonate in 100 ml of dimethylformamide was stirred at ambient temperature for 4 hours, poured into 600 ml of water and extracted with ethyl acetate. The organic layer was evaporated to dryness in vacuo and the residue was purified by silica gel column chromatography eluting with petroleum ether: acetone 8: 2. The combined fractions were evaporated to dryness in vacuo and crystallized from 70% ethanol to give 0.75 g of the title compound as a base. This solid was dissolved in dichloromethane and one equivalent of methanesulfonic acid was added. The crude methanesulfonate, obtained by evaporation in vacuo, is crystallized from acetone to give 0.6 g of the title compound, melting at 202-203 ° C.

Example 83

8- {3- [4- (2-Methoxyphenyl) -1-piperatinyl] -propylthiocarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methanesulfonate

A stirred 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 of pyridine was refluxed for 6 hours. After evaporation of the solvent in vacuo, the residue was purified by flash chromatography on silica gel, eluting with chloroform. The title compound (as base) was obtained, which was dissolved in dichloromethane and one equivalent of methanesulfonic acid was added. The title compound is obtained by evaporation in vacuo and crystallization of the residue from acetonitrile. Yield 0.7 g, m.p. 189 to 190 C.

Example 84

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

The title compound was prepared according to Example 73 but using intermediate LX instead of intermediate LIV. Purification is performed by column chromatography on silica gel eluting with ethyl acetate: petroleum ether 7: 3. To a solution of the crude base in dichloromethane was added one molar equivalent of methanesulfonic acid. After removal of the solvent in vacuo, the resulting salt was crystallized from acetone to give the title compound, m.p. 212 to 214 ’C.

Example 85

0,4 Ethanol 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3-hydroxymethyl-4-oxo-2-phenyl-4H-1-benzopyran

A mixture of 3.6 g of intermediate XCV and 1.65 g of 1-hydroxybenzotriazole in 35 ml of anhydrous dimethylformamide was stirred at 0-5 ° C for 15 minutes. A solution of 2.5 g of dicyclohexylcarbodiimide in 35 ml of anhydrous dimethylformamide was added dropwise to this mixture. After stirring for 1 hour at the same temperature, a solution of 1- (3-aminopropyl) -4- (2-methoxyphenyl) -piperazine is added. After stirring at this temperature for 2 hours and standing overnight at room temperature, the reaction mixture was evaporated to dryness in vacuo. The residue was purified by flash chromatography eluting with dichloromethane: methanol 100: 3, followed by crystallization from ethanol. 2.5 g of the title compound are obtained, m.p. 152 to 154 ’C.

174

Example 86

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

3.6 ml of diethyl cyanophosphonate is added dropwise at 0-5 ° C to a stirred solution of 4 g of 8-carboxy-4-oxo-2-phenyl-4H-1-benzopyran (prepared as described in Da Re et al., Ber., 99, 1962, 1966) and 3.75 g of 1- (3-aminopropyl) -4- (2-methoxyphenyl) -piperazine in 35 ml of anhydrous dimethylformamide. 2.5 ml of triethylamine are immediately added dropwise at the same temperature. After stirring at 0-5 ° C for 30 minutes and at ambient temperature for 1 hour, the reaction mixture was poured into 350 mL of 2.5% aqueous sodium carbonate. The precipitate formed is stirred for 1 hour at ambient temperature, collected by suction filtration and crystallized from ethanol. The base of the title compound so obtained is dissolved in dichloromethane and one equivalent of methanesulfonic acid is added. Evaporation in vacuo gave a glassy solid which was partitioned and refluxed for 1 hour in acetone. 5 g of the title compound, melting at 191 DEG-194 DEG C., is obtained.

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 2.9 g of 8-carboxy-2,3-dihydro-4-oxo-4H-1-benzopyran (prepared by Lichtenberger et al., Bull. Chem. Soc.Fr., 275, 1963) and 1.75 ml of triethylamine in 17 ml of dichloromethane are stirred at this temperature. Stirring was continued for 1.5 hours at the same temperature, after which time the reaction mixture was evaporated to dryness in vacuo to give crude 8-chlorocarbonyl-2,3-dihydro-4-oxo-4H-1-benzopyran. This was used in the method of Example 10 instead of 8-chlorocarbonyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran and the base of the title compound was prepared, which was purified by column chromatography 175 eluting with ethyl acetate: methanol 85: 15th Yield 1.91 g of pure base. After dissolution in dichloromethane, acidification with methanesulfonic acid and evaporation to dryness in vacuo, the resulting crude salt was crystallized from acetonitrile to give 1.57 g of the title compound, melting at 175-177 ° C.

Example 88

1,25 H ₂ 0. 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -4-oxo-4H-1-benzopyran methanesulfonate

The title compound was prepared according to 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. 155-157 C. C.

Example 89

8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -6-bromo-3-methyl-4-oxo-2-phenyl-4H-l-benzopyran

This compound was prepared according to Example 86 but using 8-carboxy-6-bromo-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (prepared as described in EP 107804) instead of 8-carboxy-4. oxo-2-phenyl-4H-l-benzopyran. Purify as a base by flash chromatography on silica gel eluting with dichloromethane: methane 100: 3 and crystallize from 95% ethanol. MP: (150) 154 to

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 diethyl cyanophosphonate and 0.85 ml triethylamine were added

176 adds to the solution 1.7 g of 8-carboxy-6-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (prepared as described in JP 61-15880) and 1.51 g 1 - (2-methoxyphenyl) -4- (3-amino-propyl) -piperazine in 20 ml of anhydrous dimethylformamide with stirring at 0 ° C. After stirring for 1 hour at 0 ° C at 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, is filtered off and washed with water. After drying, it is converted to the methanesulfonate in a conventional manner, which is crystallized from acetonitrile. Yield 1.7 g, m.p. 185 to 186 ’C.

Example 91

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

0.8 g of the compound prepared in Example 114 and 5.8 ml of 1N sodium hydroxide in 10 ml of methanol were stirred at ambient temperature for 4 hours. After standing overnight, 15 ml of 1N sodium hydroxide and 15 ml of methanol are added and the mixture is stirred at ambient temperature for 1 hour. The methanol was evaporated in vacuo and water was added to the residue. The suspension is filtered off with suction to give 0.48 g of the base of the title compound. This is converted to its methanesulfonate salt in the usual manner, recrystallized from acetone. MP: 200 to 202 ’C.

Example 92

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

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., Pharm. Pharm. 296, 714 (1963) instead of 8-carboxy-6-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran. The crude methanesulfonate is crystallized from acetonitrile and melts at 196-197 ° C.

177

Example 93

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

This product was obtained by the procedure of Example 12 but using intermediate LXVIII instead of 8-chlorocarbonyl-3-methyl-4-oxo-2-phenyl-4H-1-bynzopyran and 1,1,2-trichloroethane instead of chloroform. After the usual work-up, the crude product is purified by column chromatography eluting with dichloromethane: methanol 98: 2. Evaporation in vacuo of the dry fractions and crystallization from ethanol gave the title compound, m.p. 159.5 to 161 C.

Example 94

8- (3- (4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -6-amino-3-methyl-4-oxo-2-phenyl-4H-l-benzopyran

A mixture of 33 g of the compound prepared in Example 93, 109 ml of 1N hydrochloric acid, 105 ml of water and 8.78 g of Raney-nickel in 950 ml of ethanol is hydrogenated in a Parr apparatus under 2 atmospheric hydrogen pressure with stirring at 40 ° C for 12 hours. After this time, the catalyst was filtered off and washed with 80% ethanol. The mother liquors were evaporated in vacuo to a volume of 80 ml and filtered. The crude product is washed with water and suspended in water. To adjust the pH to 1, 37% hydrochloric acid was added. The insoluble material is filtered off with suction and the filtrate is basified by addition of 35% sodium hydroxide. The title compound precipitated. Obtained by filtration and washed with water. Drying gave 26 g of the compound melting at (108) 215-217.5 ° C for use in Example 95 without further purification. For characterization, 4.7 g of the product was crystallized first from ethanol and then from 85% ethanol to give 3 g of the title compound, m.p. 218-219 "C.

178

Example 95

8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -6-acetamido-3-methyl-4-oxo-2-phenyl-4H-l-benzopyran

The title compound is obtained by the procedure of Example 36 but using the compound prepared in Example 94 instead of the compound prepared in Example 33. The reaction mixture is diluted with water and suction filtered, washing the solid with water. After drying at 80 ° C, this solid was purified by column chromatography on silica gel eluting with 95: 5 chloroform / methanol. Evaporation in vacuo of the combined fractions and crystallization from 95% ethanol yielded a residue of the title compound, m.p. Mp 218-220 ° C.

Example 96

8-3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl-6-ethylamino-3-methyl-4-oxo-2-phenyl-4H-l-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 ethanolic hydrogen chloride in 73 ml of methanol is stirred at ambient temperature for 5 days. After this time, the reaction mixture was poured into cold 1.5N sodium hydroxide. The suspension is diluted with water and aspirated. After drying, the residue was purified by column chromatography on silica gel eluting with chloroform: methanol 100: 3. Evaporation of the combined fractions in vacuo gave 6 g of the compound of Example 94 and 2.67 g of the title compound, which melted at 198-201 ° C after recrystallization from ethanol.

Example 97

8- {3- [4- (2-methoxyphenyl) piperazinyl] -propylcarbamoyl} -6-dimethylamino-3-methyl-4-oxo-2-phenyl-4H-benzopyran

The title compound prepared according to Example 35 but using the compound prepared in Example 94 instead of the compound

179 of Example 35, reaction of 10 molar equivalents of 40% formaldehyde instead of 7 molar equivalents and 3 moles of sodium cyanoborohydride instead of 2 moles and with stirring at ambient temperature for 18 hours instead of 4.5 hours. After usual work-up and purification by silica gel column chromatography, eluting with chloroform: methanol 97: 3, evaporating the combined fractions in vacuo and crystallizing the residue from ethanol, the title compound melts at 183-186 ° C.

Example 98

8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -7-methoxy-3-mety1-4-oxo-2-phenyl-4H-benzopyran

The title compound was prepared according to the procedure for EXAMPLE 87 but substituting LXIX instead of 8-carboxy-2,3-dihydro-4-oxo-4H-1-benzopyran. After the usual work-up, the solid residue was purified by column chromatography on silica gel, eluting with ethyl acetate: methanol 8: 2. The combined fractions were evaporated to dryness in vacuo and the residue was crystallized from acetonitrile to give the title compound, melting at 151-152 ° C.

Example 99

Ί

8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3-methyl-4-oxo-2- (4-trifluoromethylphenyl) -4H-1-benzopyran methanesulfonate sesquihydrate

The title compound was prepared according to the procedure for EXAMPLE 90 but using intermediate LXXII as starting material instead of 8-carboxy-6-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran. The methanesulfonate melts at (85) 90-120 ° C (dec.) After crystallization from acetonitrile.

180

Example 100

8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] propylcarbamoyl) -2- (4-benzoylphenyl) -3-methyl-4-oxo-4H-1-benzopyran hemihydrate hemihydrate

The title compound was prepared according to the procedure for EXAMPLE 90 but starting from intermediate LXXXIV instead of 8-carboxy-6-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran. The crude methanesulfonate crystallizes from aletonitrile, m.p. 208-210 ’C.

Example 101

0.25 H ₂ 0.metánsulfonátu 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3-methyl-4-oxo-2- (4-phenoxyphenyl) -4H-1 benzopyran

The title compound was prepared by the sub-procedure of Example 90 but starting from intermediate LXXVII instead of 8-carboxy-6-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran. The crude methanesulfonate crystallized from acetonitrile melts at 200-202 ° C.

Example 102

8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl) -2,3-dimethyl-4-oxo-4H-benzopyran

This compound was prepared according to the procedure of Example 86 but using 8-carboxy-2,3-dimethyl-4-oxo-4H-1-benzopyran (prepared according to Da Re, Farmaco Ed. Sci., 11, 678, 1956) instead. 8-Carboxy-4-oxo-2-phenyl-4H-1-benzopyran and reactions were carried out at ambient temperature for 5 hours. Purify by flash chromatography on silica gel eluting with chloroform: methanol 98: 2 and crystallize from acetone. MP: 155-158.5 C. C.

Example 103

8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -2- (tert-butyl) -3-methyl-4-oxo-4H-1-benzopyran dihydrochloride dihydrate

181

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 eluting with chloroform: methanol 49: 1 and converted to the dihydrochloride in methanol: diethyl ether. This melts at 226-229.5 ° C after recrystallization from methanol: diethyl ether 1: 1.

Example 104

8- (3- (4- (2-Methoxyphenyl) -1-piperazinyl] propylcarbamoyl) -2-cyclohexyl-3-methyl-4-oxo-4H-1-benzopyran

This compound was prepared according to Example 86 but using intermediate LXXIX instead of 8-carboxy-4-oxo-2-phenyl-4H-1-benzopyran and the reaction was carried out for 5 hours at ambient temperature. Purify by flash chromatography on silica gel eluting with chloroform: methanol 49: 1 and crystallize from acetonitrile (m.p. 155-157 ° C).

Example 105

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

This compound was prepared according to Example 86 but using intermediate LXXXI instead of 8-carboxy-4-oxo-2-phenyl-4H-1-benzopyran and the reaction was carried out at ambient temperature for 5 hours. After interruption, the title compound was isolated by extraction with chloroform and purification by flash chromatography on silica gel eluting with chloroform: methanol 49: 1, and then crystallized by lysis from acetonitrile, m.p. 151 to 153 ’C.

Example 106

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

This compound was prepared according to Example 86 but using intermediate LXXXIII instead of 8-carboxy-4-oxo-2-phenyl-4H-1-benzopyran. Purify by stirring in water (to remove dimethylformamide) and then column chromatography on silica gel eluting with chloroform: methanol 49: 1, and crystallize from acetonitrile, m.p. Mp 174-175 ° C.

Example 107

8- {3- [4- (2-Methoxy-phenyl) -1-piperazinyl) -propylcarbamoyl} -4-oxo-2-phenyl-4H-1-benzothiopyran

A mixture of 2.8 g of intermediate LXXXIV and 3.4 g of 1,1'-carbonyldiimidazole in 60 ml of anhydrous dimethylformamide is stirred under nitrogen at ambient temperature for 1.5 hours. Then 2.7 g of 1- (3-aminopropyl) -4- (2-methoxyphenyl) -piperazine are added. Stir for an additional 2 hours at ambient temperature, pour the reaction mixture into water (300 mL) and extract with chloroform. The organic layer 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 to give 2 g of the title compound, melting at 144-146 ° C.

Example 108 (E) -8-3- [4- (2-Methoxy-phenyl) -1-piperazinyl] -propylcarbamoyl-3-methyl-4-oxo-2- (2-styryl) -4H-1-benzopyran

183

This compound was prepared according to Example 86 but using intermediate LXXXVI instead of 8-carboxy-4-oxo-2-phenyl-4H-1-benzopyran. Purified by crystallization from acetonitrile, m.p. 191 to 194 ’C.

Example 109

8-3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl-3-mety1-2- (metylfeny1) -4-oxo-4H-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 carried out at ambient temperature for 4 hours. After interruption, the title compound is isolated by extraction with ethyl acetate, drying over anhydrous sodium sulfate and evaporation in vacuo, followed by washing with diethyl ether and crystallization from acetonitrile. MP: 161 to 163 ’C.

Example 110

8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -2- (4-methoxyphenyl) -3-methyl-4-oxo-4H-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- Of 4-oxo-2-phenyl-4H-1-benzopyran and the reaction is carried out at ambient temperature for 3.5 hours. Purify by flash chromatography on silica gel eluting with chloroform / methanol 49: 1 followed by crystallization from acetonitrile. MP: 158 to 161 ’C.

Example 111

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

184

This compound was prepared according to Example 86 but using intermediate LXXXIX instead of 8-carboxy-4-oxo-2-phenyl-4H-1-benzopyran. Purify by flash chromatography on silica gel eluting with chloroform: methanol 100: 2 to 100: 6 and crystallize from 95% ethanol, m.p. Mp 166-168 ° C.

Example 112

8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -6-methanesulfonylamino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride stirring at -20 ° C 3 , 5 hours.

0.032 ml of methanesulfonyl chloride in 1 ml of dimethylformamine was 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 under C. Stirring was continued at the same time. and the suspension is filtered by suction. 0.1 g of the title compound is obtained, which is recrystallized from 80% ethanol, m.p. 272-275 C. C.

Example 113

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

The title compound was prepared according to the procedure described in Example 90, but starting from intermediate XCVIII instead of 8-carboxy-6-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran. After stirring at ambient temperature for 1 hour, the reaction mixture was poured into cold 2% sodium carbonate solution and the precipitated solid was collected by suction filtration. After drying and crystallization from ethanol, the title compound melts at (60) 185-187 ° C.

185

Example 114

8- {3- [4- (2-methoxyphenyl) -1-piperazinyl) -propylcarbamoyl) -6-dietoxyfosfonyloxy mety1-4-3-oxo-2-phenyl-4H-benzopyran

The title compound was prepared according to the procedure described in Example 90, but starting from intermediate LCIII instead of 8-carboxy-6-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran and using 2 equivalents of diethyl cyanophosphate instead of 1. , 1 equivalents. Filtration from water gave the title compound, melting at 48-50 ° C. The title compound can be evaluated as the prodrug of 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -6-hydroxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran .

Example 115

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

The procedure of Example 90 was followed, but starting from intermediate C instead of 8-carboxy-6-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran to give the crude base of the title compound. After the usual work-up by extraction with diethyl acetate, the residue is purified by column chromatography on silica gel, eluting with ethyl acetate: methanol 9: 1. It is converted to its methanesulfonate by conventional means and recrystallized from ethyl acetate, m.p. 145 to 148 ’C.

Example 116

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

This compound was prepared according to Example 12 but using intermediate CI instead of 3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylamine. The crude base was purified by flash chromatography on silica gel eluting with chloroform: 5N methanolic186 while ammonia 100: 1 and converted to the hydrochloride in the usual manner, m.p. 195-198 ° C after crystallization from acetone.

Example 117

7- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -2-benzoyl-3-ethyl-benzo [b] furan

This compound was prepared according to Example 86 but starting from intermediate CIII instead of 8-carboxy-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic acid, operating at ambient temperature for 4 hours. Purified by crystallization from ethanol, m.p. 165 to 166 ’C.

Example 118

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

The title compound was prepared according to Example 86 but starting from intermediate CVI instead of 8-carboxy-4-oxo-2-phenyl-4H-1-benzopyran. The reaction was left at room temperature for 20 hours. The base was purified by crystallization from ethanol (m.p. 164-166 ° C).

Example 119

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

A mixture of 6.2 g of methyl 3-propionyl salicylase and 5.8 g of nicotinoyl chloride hydrochloride in 18 ml of anhydrous pyridine is stirred, and heated at 100 ° C for 2 hours under nitrogen. 16 ml of triethylamine are then added and heating is continued for 1 hour at the same temperature. The reaction mixture was cooled to room temperature and poured into 600 mL of water. The precipitate is filtered off with suction

187 and washed with water to give 5.4 g of methyl 2-hydrosy 3- (2-nicotinoylpropionyl) benzoate which is used without purification in the next step. 3.4 g of the compound thus prepared is heated to 100 DEG C. for 1.5 hours 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 bicarbonate and then with water, dried over 1.3 g of crude 8-methoxycarbonyl-3-methyl-4-oxo-2- (3-pyridyl) -4H-1-benzopyran.

g of this ester is dissolved in 9 ml of methanol and 15 ml

1,4-dioxyne and slowly add 1.7 mL of 10M sodium hydroxide, maintaining the temperature between 20 and 25 C. C. After 1 hour at 50 ° C, the reaction mixture is poured into 150 ml of water and extracted with ethyl acetate. The aqueous layer was acidified with 1N hydrochloric acid. The precipitate was filtered off with suction to give 0.6 g of 8-carboxy-3-methyl-4-ΟΧΟ-2- (3-pyridyl) -4H-1-benzopyran which was used without purification in the next step.

The title compound was prepared as in Example 86, but using the acid thus prepared instead of 8-carboxy-4-oxo-2-phenyl-4H-1-benzopyran, and reactions were carried out for 2 hours at room temperature. The base was purified by flash chromatography on silica gel eluting with chloroform: methanol 98: 2, followed by crystallization from acetone. Yield: 0.15 g, m.p. 134.5 to 137 C. C.

Example 120

8- {3- [4- (2-Acetoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3-methyl-4-oxo-2- (3-pyridyl) -4H-1-benzopyran g of Example 59 and 0 32 g of 4-dimethylaminopyridine are dissolved in 10 ml of dichloromethane. Add 0.15 ml of acetyl chloride slowly, maintaining the temperature between 8 and 10 ° C. Mon 2

188 hours at room temperature, the reaction mixture is poured into 70 ml of water and extracted with dichloromethane. The organic layer was washed with 5% aqueous sodium sulfate and evaporated to dryness in vacuo. The crude base was purified by flash chromatography on silica gel eluting with ethyl acetate: methanol 9: 1, followed by crystallization from acetone. Yield: 0.74 g of the title compound, m.p. Mp 120-123 ° C.

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 50 and 1.8 g of methyl isocyanate are added Dissolve in 30 ml of dry dimethylformamide and stir at room temperature for 24 hours. The mixture was diluted with water, stirred for 2 hours and then filtered off with suction. The crude base was purified by flash chromatography on silica gel eluting with chloroform: 5N methanolic ammonia 100: 3. The title compound melted at 132-135 ° C after crystallization from ethanol.

Example 122

8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -6-acetoxy-3-methyl-4-oxo-2-phenyl-4H-benzopyran

0.17 ml of acetyl chloride was added dropwise over 5 minutes while stirring at 0 ° C to a solution of 1 g of the 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 layer was separated, washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. Crystallization of the residue from acetonitrile gave 0.8 g of the title compound, melting at 148-149 ° C.

189

Example 123

(R, S) -8- {3- [4- (2-Methoxy-phenyl) -1-piperazinyl] -propylcarbamoyl} -2,3-dihydro-4-hydroxy-4H-1-benzopyran methanesulfonate

The title compound was prepared as described in Example 17, but starting from the compound of Example 87 instead of the compound of Example 1. The reaction mixture was diluted with water and stirred for 15 minutes. Extract with ethyl acetate. Conventional work-up yields a crude product which is purified by flash chromatography on silica gel eluting with dichloromethane: methanol 95: 5. Evaporation of the combined fractions in vacuo gave a pure base which was converted to the methanesulfonate and crystallized from acetonitrile, m.p. 172 to 175 ° C.

Example 124

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

2.22 g of the compound of Example 113 and 0.56 g of Raney-nickel in 96 ml of atanol and 4.8 ml of acetic acid are hydrogenated in a Parr apparatus (hydrogen pressure = 1 atm) at room temperature. After shaking for 6 hours, the catalyst is filtered off. The filtrate was basified with 3N sodium hydroxide and diluted with water. After 2 days of standing, the precipitated compound is filtered off with suction, washed with water, dried and recrystallized not later than from ethyl acetate and then from ethanol, yield 1.5 g, m.p. 192-194 C. C.

Example 125

8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl) -2- (4-acetylamino-phenyl) -3-methyl-4H-benzopyran

The title compound was prepared according to the method described in Example 36, but starting from the compound prepared in Example 124 instead of the compound prepared in Example 33. Purification was carried out by crystallization in 95% ethanol, m.p. 207 to 209 ’C.

Example 126

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

The title compound was prepared according to the method described in Example 86, but using intermediate CVII instead of 8-carboxy-4-oxo-2-phenyl-4H-1-benzopyran, reacting for 14 hours at ambient temperature using hyxamethylene phosphoramide as co-solvent . The isolated diethylphosphonyl ester of the title compound is hydrolyzed by alkaline treatment followed by neutralization with dilute hydrochloric acid. The crude base was extracted with chloroform. The organic layer was washed with water and evaporated in vacuo. The salt is prepared by adding ethanolic hydrogen chloride to an acetone base solution, evaporating to dryness and washing with acetone, m.p. 193 to 205 ’C.

Example 127

The monohydrate of 8- {3- [4- (2-methoxyphenyl) -1-piperidin] -propylcarbamoyl} -2-phenyl-4, Ν ^3, N ⁴ -trioxo-4H-benzopyran

0.32 ml of 30% hydrogen peroxide was 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. 0.48 ml of 30% hydrogen peroxide was added to the mixture in three portions. After cooling, the mixture was poured into 240 ml of water, neutralized (pH 7) with 5% aqueous sodium bicarbonate and extracted with chloroform. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated in vacuo to give 0.18 g of the title compound, melting at 172-175 ° C after crystallization from acetonitrile.

191

Example 128

7- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -2-phenyl-benzo [b] furan

The title compound was prepared according to the method described in Example 86 but using 7-carboxy-2-phenyl-benzo [b] furan (prepared as described in EP 0306226) instead of 8-carboxy-4-oxo-2-phenyl-4H- of 1-benzopyran and the reaction is carried out at ambient temperature for 1.5 hours. Purified by crystallization from carbon tetrachloride, m.p. 132-136 ° C.

Example 129

8- (N-Methyl-3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylsulfamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methanesulfonate

2.29 g of intermediate VII were added portionwise with stirring at 0 ° C to a solution of 1.5 g of intermediate CI and 0.95 of triethylamine in 30 ml of chloroform. After stirring at ambient temperature for 2 hours, the reaction mixture was diluted with dichloromethane, water, and 0.5N sodium hydroxide. The organic layer 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 combined fractions in vacuo gave the pure title compound as a base. It was converted to its methanesulfonate salt by a conventional procedure, which was crystallized from ethyl acetate to give 2.75 g, melting at 135-141 ° C (dec.).

Example 130

8- (N-Methyl-4- [4- (2-methoxyphenyl) -1-piperazinyl] -butylsulfamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methanesulfonate

The title compound was obtained according to the method described in Example 129, but starting from intermediate CVIII instead of intermediate Cl2. Crystallized from acetonitrile, m.p. Mp 173-175 ° C.

Pharmacological data

methodics

Male Sprague Dawley rats (Crl: CD'BR) weighing 200-300 g, female Albino Swiss mice (Crl: CD-I (ICR) BR) weighing 20-30 g, and male beagle dogs (10-12 kg body weight) ) were obtained from Charles River, Italy and Nossan (Correzzana, Milan, Italy). The animals were kept with free access to food and water and maintained until the day of the experiment in an intensified light-dark cycle at 22-24 ° C.

Acute toxicity

The acute toxicity of the synthesized compounds was evaluated in female Albino Swiss mice after intraperitoneal and oral administration. Four log graded doses of the compounds were dissolved or suspended in 0.5% Methocel and administered in a volume of 10 ml / kg to groups of 4 mice / dose. Mortality was recorded 7 days after administration. Analysis values: LD ₅₀ values and their predicted limits were calculated according to the Weil method (Biometrics, 8, 249, 1952).

Receptor-Binding Studies:

ľ ³ Hlprazosine binding (and ^ ^ receptors)

Rat cerebral cortex was homogenized in 50 volumes of original wet weight in ice-cold 50 mM Tris-HCl buffer pH 7.4. The homogenates were centrifuged at 48,000 x g for 10 minutes and the pallets were resuspended in an equal volume of ice-cold buffer, centrifuged and resuspended two more times. The resulting final pellets were resuspended in an equal volume of buffer and incubated under the conditions shown in the table below.

Said receptor binding studies as well as experimentally

193 values in the dogs listed below, evaluate the compounds of the invention as α-β-blockers, i. in a class of substances widely used as antihypertensives and anti-BPH agents. See. e.g. Frishman W. H. et al., Medical Clinics of N. America, 72, 427, 1988 and references cited therein.

-Γ ³ H18-OH-DPAT binding (5ΗΤ _1Λ receptors)

Hippocampi rats were homogenized in 50 volumes of original wet weight in ice-cold 50 mM Tris-HCl buffer pH 7.4. The homogenates were centrifuged after 10 minutes and the pallets were resuspended in an equal volume of ice-cold buffer, incubated for 10 minutes at 37 ° C, centrifuged and resuspended twice. The final obtained pellets were resuspended in an equal volume of buffer and incubated under the conditions shown in the table below.

These receptor binding studies serve to evaluate the compounds of the present invention as ligands for the 5HT _1A receptor. As indicated above, the compounds which are 5-HT ligands _1Ä exhibit anxiolytic and antidepressant effects in animals and humans (Hamon, M. et al., Ann. NY Acad. Sci., 114, 1990; Traber J. et al., TIPS, 8 437 (1987).

194

Receptor binding studies

1 5-HTi _Nr Receptor / ligand adrenergic serotonergic conditions [ ³ H] prazosin [ ³ H] 8-OH-DPAT [nM] ligand 0.35 1.0 preparation (c.m.p.) 1 ml 1 ml 10 mg / ml 10 mg / ml incubation buffer * * Tris-HCl Tris-HCl 50 mM 50 mM pH 7.4 pH 7.4 nonspecific binding prazosin 5-HT 2 μΜ 10 μΜ incubation Deň: 18 ° C 25 ’C 30 min 30 min

c.m.p. = crude membrane preparation * = containing 1% ascorbic acid and 10 μline pargyline

Incubations were terminated after a suitable time (see table) by rapid filtration through Whatman GF / B filters using a Brandel cell harvester. The filters are washed twice with 15 ml ice-cold buffer (see table). The radioactivity retained on the filters is determined by liquid scintillation counting. Non-specific binding (which generally amounts to 10 to 30% was evaluated by adding high concentrations of specific displacement (see table). All compounds at the start of testing at 1 x 10 ^-6 M and in the presence of significant displacement activity generated completely competitive curves (decrease). concentration to ^10-11 M) All samples were evaluated in triplicate.

Competitive curves were always analyzed (to evaluate IC _5Q values) using non linear curve fitting logistic

195 equations according to the method described by De Lean et al. (Am. J. Physiol., 235, E97, 1978), using the ALLFIT program (available from the National Institutes of Health (N.I.) Bethesda, Maryland, USA) for IBM PC.

K ⁺ -induced rat bladder strips:

The entire rat bladder was removed and immediately placed in

Krebs solution heated to 37 ° C. Strips of muscle detrusor (20 to 30 mm long, 1 to 2 mm wide) were cut from the bladder arch. Each strip was placed in a 10 ml organ bath and attached, under a constant load of 1 g, to an isometric voltage gauge (DY-1, Basel, Comerio, Varese, Italy). Boba contraction recorded using Basile 7070 polygraphs. After 60 minutes of equilibration, the strips were exposed to 80 mM KCl (final concentration). This produces a rapid phase contraction followed by a slow and sustained tonic component. When the tonic concentration was stable, the strips were washed and 30 minutes later a new contraction was induced. After recording two or more reproduced responses, one concentration of test drugs was added to the bath and a new concentration was induced 30 minutes later. Test groups consisting of at least two preparations taken from different animals for each concentration of test drug. IC ₅₀ values of inhibition of agonist-induced contractions were evaluated by linear regression analysis.

Effects on urethral contraction and blood pressure in dogs

The experiments were carried out according to the method described by Imagawa et al. (J. Pharmacol. Methods, 22, 103-111, 1989), with substantial modifications as follows: adult male beagle dogs weighing 8-10 kg were anesthetized with sodium pentobarbital (30 mg / kg iv and 2 mg / kg / h iv), intubated and spontaneously ventilated from room air. To monitor systemic blood pressure (BP), a PE catheter was inserted into the aortic bend through the right common carotid artery.

196

The left femoral vein collateral was cannulated for infusion of the anesthetic and the right femoral vein was cannulated for drug administration. For intra-arterial (ia) injection of norepinephrine (NA), a PE catheter was inserted into the lower abdominal aorta through the predominant external iliac artery. By this procedure, NA was selectively distributed to the lower urinary tract. Bladder and proximal urethra were exposed by moderate laparotomy. To prevent bladder failure, two ureters were cannulated and urine was removed. To record the prostatic urethral pressure, a Micro-tip catheter (6F) was inserted into the bladder through the external urethral orifice and removed when the pressure transducer was placed in the prostatic urethra. The ligature was placed between the bladder and urethra throat to isolate this and eliminate any interaction with the bladder. Another ligature was guided around the Micro-tip catheter at the external urethral orifice to provide a separate catheter. The stabilization period was followed by a surgical procedure (30 min.) In which the arterial and prosatatic urethral pressure were continuously monitored as basal values, and the administration of NA was performed at 10 min intervals. The NA dose was selected to produce at least a 100% increase in urethral pressure. Test compounds were administered iv in a cumulative manner at intervals of 15 to 20 minutes between administrations. NA injections were repeated approximately 5 min. after each dosing of the test compound. Dose response curves were constructed by calculating the percentage inhibition to increase in urethral pressure (induced by NA), and the percentage decrease in blood pressure produced by the test compound. ED ₂₅ for diastolic blood pressure (dose inducing 25% decrease) and ID ₅₀ (dose inducing 50% inhibition of NA-induced increase in urethral pressure) were calculated by regression analysis.

The results

The compounds prepared in the examples were tested by the above methods and the results are shown below

197 in the table, together with comparative results for the reference standards used. Compounds with receptor affinity (IC ₅₀ values) of less than about 500 nM are generally considered to have good affinity. Compounds with IC ₅₀ values less than 100 nM are generally preferred.

198

TABLE 1

compound Sample no. Receptor binding. IC ₅₀ Acute toxicity in a mouse K + stimulation of rat bladder IC ₅₀ (μΜ) Contractions ^LD 50 ip (Mg / kg) p. about. ^and l = “ ^H1 la phases. not that. 4 550 55 346 1732 5 20 19 621 > 3000 6 107 1000 233 7 86 155 384 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 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 20 169 85 297 594 2.7 2.5 21 17 33 297 566 22 117 . 48 > 500 > 2,000 24 690 212 > 1000 > 3000 26 270 > 1000 > 500 > 2,000 27 23 124 399 > 3000 1.0 0.8 28 120 96 203 1127 29 86 45 730 > 3000 10.0 10.0 32 119 46 301 > 2,000 10.0 > 10 33 17 38 399 > 2,000 10.0 10.0 34 30 34 > 500 2.8 3.6 35 15 8 329 959 36 18 54 > 500 > 2,000 37 32 77 > 500 > 2,000 38 20 344 > 500 > 2,000 39 90 170 > 1000 > 3000 40 75 83 140 349 0.5 0.9 41 43 53 399 2241 0.7 1.4 42 111 39 459 2163 10.0 10.0 43 166 > 1000 44 685 201 84 399 0.6 0.5 45 15 106 329 1727 46 86 23 47 36 23 330 1047 2.7 5.2 48 104 5 500 1914 49 152 g 432 > 2,000 50 39 300 211 299 51 22 84 > 500 > 2,000 52 89 2 127 224 53 7 4 1 127 1020 54 35 143 106 421 55 291 > 1000 128 > 2,000 56 25 748 > 500

199

TABLE 1 CONTINUED

compound Sample no. IC ₅₀ receptor binding (nM) Acute toxicity in a mouse K + rat bladder IC ₅₀ (μΜ) Phase contraction. not that. ^ld 50 ip (Mg / kg) after. "1 ^b_Hi la 57 69 > 1000 500 > 2,000 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 64 40 11 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 > 2,000 73 6 89 202 462 74 178 482 75 147 15 78 18 116 79 77 141 > 500 > 2,000 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 18 104 9 15 107 37 16 110 26 15 Flavoxate >> 1000 >> 1000 385 808 13 13

200

TABLE II

Effects on urethral contractility and blood pressure in dogs

compound Sample no. Uretra ED ₅₀ µg / kg) DBP ED ₂₅ (^ g / kg) DBP / urethra 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 W _ W 3.1 40 11.0 125 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 -

Uretra: active dose in inhibition of 50% noradrenaline-induced urethral contraction

DBP: active dose in reducing diastolic blood pressure by 25%

DBP / urethra: ratio between active doses (selectivity index) * non-selective: substantial influence on both urethra and DBP

Effective amount

The following provides guidance for effective oral, parenteral or intravenous dosage ranges, expressed in ml / kg body weight, for the following uses:

(a) In obstructive disorders of the lower urinary tract in general 0,001 20

201 preferred 0.05 - 1 • flp most preferred 0.3

(b) As antihypertensive agents:

generally 0.01-20 preferred 0.1-5 µk most preferably 1

C) As anxiolytics-antidepressants generally preferred * * most preferred

d) As bladder spasmolytics generally preferred > J? P most preferred

0.01 - 20 0.05 - 5 0.5

0.01 - 20

0.02 - 10

The most preferred values relate to oral dosing. Intravenous doses should be 10 to 100 times lower.

Patients in the treatment with the present compounds also include people who have one or more symptoms of depression (as defined in Harrison's Principles of Internal Medicine, XII ed., McGraw-Hill, Inc., p. 2124) or people with anxiety symptoms ( Harrison's supra, pp. 2131-2134).

Selective use dosages, i.e. dosages that are active in the lower urinary tract without a substantial effect on blood pressure, depend upon the particular compound employed, but generally can be given four times the _ED50 of a selective compound without substantially affecting the blood pressure. Further refinement and dose optimization can be accomplished by routine experimental procedures.

202

The active compounds of the invention may be administered orally, for example, with an inert diluent or an edible carrier, or enclosed in gelatin capsules, or compressed into tablets. For the purpose of oral therapeutic administration, the active compounds of the invention may be incorporated into excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like. Such formulations should contain at least 0.5% of the active compounds, the amount of active ingredient may vary depending on the form and may usually be between 5% and about 70% by weight of the unit. The amount of active compound in such formulations is such that a suitable dosage will be obtained, although the desired dosage may be obtained by administering multiple dosage forms. Preferred compositions and compositions of the invention are prepared so that the oral dosage unit form contains between 1.0 to 300 milligrams of active compound.

Tablets, pills, capsules, troches and the like may also contain, for example, the following ingredients: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an additive such as starch or lactose, a disintegrant such as alginic acid, Primogel, corn starch, and the like; a lubricant such as magnesium stearate or Sterotex; a glidant such as colloidal silica; a sweetening agent such as sucrose or saccharin may be added as well as a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil. Other dosage unit forms may contain other various materials which modify the physical form of the dosage unit, for example, as coatings. The tablets or pills may be coated with sugar, shellac, or other enteric coating agents. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes, coloring and flavoring agents. The materials used in the preparation of these various compositions should be

203 pure and non-toxic in the amounts used.

For the purpose of parenteral therapeutic administration, the active compounds of the invention may be incorporated into a solution or suspension. These preparations should contain at least 0.1% of active compound, but this amount may vary between 0.5 and about 30% of their weight. The amount of active compound in such cases is such that a suitable dosage will be obtained. Preferred compositions and preparations of the present invention are prepared so that the parenteral dosage unit contains between 0.2 and 100 milligrams of active compound. The solutions or suspensions may also contain the following components: a sterile diluent such as water for injection, saline, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium sulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. Parenteral multiple dose vials may be glass or plastic.

Claims (17)

A compound of formula I R. (I) where - - - represents a single or double bond, X represents an oxygen or sulfur atom or an imino, alkylimino group, W represents a valence bond or a carbonyl, thiocarbonyl, methylene or hydroxymethylene group, R 2 represents a hydrogen atom or an alkyl, trifluoromethyl, phenethyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, carbocyclyl, substituted carbocyclyl, 2-furyl, 2-thienyl, 3-pyridyl or aroyl group wherein the substituents of the above groups are one or more halogen atoms and / or one or more alkyl, cyano, hydroxy, alkoxy, phenyl, phenoxy, trifluoromethyl, nitro, amino, alkylamino, dialkylamino, acylamino, alkylsulfonylamino or benzoyl groups, R 1 is hydrogen or alkyl, hydroxyalkyl, alkoxyalkyl, aralkoxyalkyl, phenyl, hydroxy, alkoxy, or aralkoxy, 205 R ₆ represents a hydrogen or halogen atom or a nitro, amino, alkylamino, dialkylamino, acylamino, alkylsulfonylamino, cyano, hydroxy, alkoxy or alkyl group, R y represents a hydrogen atom or an alkoxy group, Y represents one of the following groups, each of which is shown to be attached to a heterobicyclic ring from its left end and to its Z end from its right end: (YI) -WHAT-, (Y2) COO, (Y3) -CONH-, (Y4) CON _(CH3) -, (Y5) -CON (OH) -, (Y6) -CH (OH) -, (Y7) CH (O-alkyl) -, (Y8) -CH = CH-, (Y9) -CH = CH-COO-, (Y10) -CH = CH-CONH-, (Y11) -CH = NO-, (Y12) -ch ₂ -, (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- (Y 21) -ch ₂ nh-conh- (Y22) CH ₂ NHSO ₂ -, (Y23) -ch ₂ o-. (Y24) -ch ₂ s-, (Y25) -ch ₂ so-, (Y26) -ch ₂ Sat ₂ -, (Y27) -ch ₂ with ₂ nh-, 206 (Y28) -ch ₂ with ₂ n (ch. (Y29) NH, (Y30) -N _(CH3) -, (Y31) -n (coch ₃ ) -, (Y32) -n (conh ₂ ) -, (Y33) -NHCO- (Y34) -N _(CH3) -CO-, (Y35) NH-CONH-, (Y36) -nhso ₂ -, (Y37) -about-, (Y38) -with-, (Y39) -SO-, (Y40) ^-s0 2 ~ ' (Y41) -so ₂ nh-, (Y42) _-SO2 N _(CH3) - (Y43) -con (coch ₂ ) (Y44) -CSNH-. (Y45) -en (ch ₃ ) -, / 0 (Y46) -CON (O- < (Y47) Y -NHCOO-, and (Y48) -COS-. Z represents a straight or branched alkylene group having 1 to 6 carbon atoms and optionally having one hydroxy substituent; and B represents one of the following groups (Bi: wherein Q represents a methylene or ethylene group and A represents one of the following groups: (A1) phenyl substituted by one or more halogen atoms and / or one or more alkyl, alkoxy or hydroxy groups, phenyl, (A2) 2-pyrimidinyl (A3) a group of general formula (B2) wherein - - - is as defined above and E represents an oxygen atom or a valence bond, wherein each L ₃ and L ₂ independently represents a hydrogen atom, phenyl, 4-fluorobenzoyl or 2 oxo-1-benzimidazolinyl or a group of the general formula (CH ₂ J _n -OA, where n is 0 , 1 or 2a A is as defined above, with the proviso that and L _{2 is} not both hydrogen, (B3) R wherein each R and R ₃₁ independently represents 208 H or alkoxy or alkylthio, R ₁₂ is H or C akupinu n is 2 or 3, (B4) wherein R ^{_12, m} and are as defined above and R ₁₃ is H or C, and wherein R ₁₂ is as defined in the or a prodrug, enantiomer, diastereoisomer, N-oxide or a pharmaceutically acceptable salt of such a compound. Compounds according to claim 1, wherein - - - is a double bond, X is an oxygen atom, W is carbonyl, R ₂ is phenyl, R 2 represents a methyl group, 209 R ₆ represents a hydrogen atom and R ₇ represents a hydrogen atom. A compound according to claim 1 or 2, wherein Y is one of Y 2, Y 3, Y 37, Y 40 or Y 41. A compound according to any one of the preceding claims wherein Z is a trimethylene or tetramethylene group. A compound according to any one of the preceding claims, wherein B is one of group B1 or B3. A compound according to any one of the preceding claims wherein B represents a 4- (2-methoxyphenyl) -1-piperazinyl group. A compound according to any one of the preceding claims wherein Y, Z and B together form a 3- [4- (2-methoxyphenyl) -1-piperazinyl] propylcarbamoyl group. 8. 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran or its prodrug, enantiomer, diastereoisomer, or The N-oxide, or its dihydrochloride hemihydrate, monohydrochloride hydrate, monomethanesulfonate or (±) -hemimalate hydrate, or other pharmaceutically acceptable salt thereof. 9. Any of the following compounds: 8- {2- [4- (2-methoxyphenyl) -1-piperazinyl] -1-oxoethyl} -3-methyl-4-oxo-2-phenyl-4H-benzopyran, 8- {2- [4- (2-methylphenyl) -1-piperazinyl] -1-oxoethyl} -3-methyl-4-oxo-2-phenyl-4H-benzopyran, 8- {2- [4- (2-ethoxyphenyl) -1-piperazinyl] -1-oxoethyl} -3-mety1-4-οχο-2-phenyl-4H-benzopyran, 210 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -1-oxopropyl} -3-methyl-4-oxo-2-phenyl-4H-benzopyran, 8 - <3- [4- (2-methoxyphenyl) -1-piperazinyl] propoxycarbonyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {2- [4- (2-Methoxyphenyl) -1-piperazinyl] -ethoxycarbonyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {3- [4- (2-Chloro-phenyl) -1-piperazinyl] -propoxycarbonyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, ¹ 8- [3- (4-phenyl-l-piperazinyl) -propoxykarbonyl] -3-methyl-4-oxo-2-phenyl-4H-benzopyran, 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propoxycarbonyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -2-methyl-2-propoxycarbonyl} -3-methyl-4-oxo-2-phenyl-4H-benzopyran, 8- {2- [4- (2-methoxyphenyl) -1-piperazinyl] ethylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-benzopyran, 8- {3- [2- (2-Methoxy-phenoxy) -ethylamino] -propylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- [3- (4-phenyl-l-piperazinyl) -propylcarbamoyl] -3-methyl-4-oxo-2-phenyl-4H-benzopyran, 8- {N-methyl-2- [4- (2-methoxyphenyl) -1-piperazinyl] ethylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {1-hydroxy-2- [4- (2-methoxyphenyl) -1-piperazinyl] ethyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {l-hydroxy-2- [4- (2-methylphenyl) -1-piperazinyl] ethyl} -3-methyl-4-oxo-2-phenyl-4H-benzopyran, 8- {1-hydroxy-2- [4- (2-ethoxyphenyl) -1-piperazinyl] ethyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {1-hydroxy-3- [4- (2-methoxyphenyl) -1-piperazinyl] -propyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {l-hydroxy-4- [4- (2-methoxyphenyl) -1-piperazinyl] -butyl} -3-methyl-4-oxo-2-phenyl-4H-benzopyran, 8- {l-ethoxy-2- [4- (2-methoxyphenyl) -1-piperazinyl] ethyl} -3-methyl-4-oxo-2-phenyl-4H-benzopyran, 8- {N-methyl-2- [4- (2-methoxyphenyl) -1-piperazinyl] -ethylaminomethyl} -3-methyl-4-oxo-2-phenyl-4H-benzopyran, 211 8- {N-acetyl-2- [4- (2-methoxyphenyl) -1-piperazinyl] -ethylaminomethyl} -3-methyl-4-oxo-2-phenyl-4H-benzopyran, 8- [4- (2-methoxyphenyl) -1-piperazinylacetamidometyl] -3-methyl-4-oxo-2-phenyl-4H-benzopyran, 8- {N-methyl-N- [4- (2-methoxyphenyl) -1-piperazinyl] acetamidomethyl} -3-methyl-4-oxo-2-phenyl-4H-benzopyran, 8- {2- [4- (2-methoxyphenyl) -1-piperazinyl] ethoxymethyl} -3-methyl-4-οχο-2-phenyl-4H-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] -etyltiometyl} -3-methyl-4-oxo-2-phenyl-4H-benzopyran, 8- {2- [4- (2-methoxyphenyl) -1-piperazinyl] -etylsulfinyImety1) -3-methyl-4-oxo-2-phenyl-4H-benzopyran, 8- {2- [4- (2-methoxyphenyl) -1-piperazinyl] -etylsulfonylmetyl} -3-methyl-4-oxo-2-phenyl-4H-benzopyran, 8- {2- [4- (2-methoxyphenyl) -1-piperazinyl] -ethyl-amino} -3-methyl-4-οχο-2-phenyl-4H-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propyl} -3-methyl-4-oxo-2-phenyl-4H-benzopyran, 8- {4- [4- (2-methoxyphenyl) -1-piperazinyl] -butylamino} -3-methyl-4-oxo-2-phenyl-4H-benzopyran, 8- {N-methyl-3- [4- (2-methoxyphenyl) -1-piperazinyl] -propyl} -3-methyl-4-oxo-2-phenyl-4H-benzopyran, 8- {N-acetyl-3- [4- (2-methoxyphenyl) -1-piperazinyl] -propyl} -3-methyl-4 -? - oxo-2-phenyl-4H-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propionamido} -3-methyl-4-oxo-2-phenyl-4H-benzopyran, 8- {2- [4- (2-methoxyphenyl) -1-piperazinyl] -ethylureido} -3-methyl-4-oxo-2-phenyl-4H-benzopyran, 8- {2- [4- (2-methoxyphenyl) -1-piperazinyl] -ethoxy} -3-methyl-4-oxo-2-phenyl-4H-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] propoxy} -3-mety1-4-oxo-2-phenyl-4H-benzopyran, 8- {4- [4- (2-methoxyphenyl) -1-piperazinyl] -butoxy} -3-methyl-4-oxo-2-phenyl-4H-benzopyran, 212 8- {5- [4- (2-methoxyphenyl) -1-piperazinyl] pentyloxy} -3-methyl-4 -οχο-2-phenyl-4H-benzopyran, 8- {3- [4- (2-Methoxy-phenyl) -1-oxo-1-piperazinyl] -propoxy} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {2- [2- (2,6-dimethoxy-phenoxy) ethylamino] -ethoxy} -3-methyl-4-οχο-2-phenyl-4H-benzopyran, 8- {2-hydroxy-3- [4- (2-methoxyphenyl) -1-piperazinyl] -propoxy} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] propylthio} -3-methyl-4-oxo-2-phenyl-4H-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] propylsulphonyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- (2- [4- (2-methoxyphenyl) -1-piperazinyl] -ethylsulphamoyl) -3-methyl-4-oxo-2-phenyl-4H-benzopyran, 8- {N-methyl-2- [4- (2-methoxyphenyl) -1-piperazinyl] -ethylsulphamoyl} -3-methyl-4-oxo-2-phenyl-4H-benzopyran, 8- {N-carbamoyl-3- [4- (2-methoxyphenyl) -1-piperazinyl] -propyl} -3-methyl-4-oxo-2-phenyl-4H-benzopyran, 8- {4- [4- (2-Methoxyphenyl) -1-piperazinyl] -1-oxobutyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {3-2- [1,4-benzodioxolanyl) methylamino] propylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-benzopyran, 8- {4- [4- (2-Methoxyphenyl) -1-piperazinyl] butyl} -3-methyl-4-oxo-2-phenyl-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) -propylcarbamoyl] -3-methyl-4-iso-2-phenyl-4H-1-benzopyran, 8- {3- [4- (4-Fluorobenzoyl) -1-piperidinyl] -propylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {3- [4- (2-Oxo-benzimidazolinyl) -1-piperidinyl] -propylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {3- [4- (2-pyrimidinyl) -1-piperazinyl] -propylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-benzopyran, 8- {3- [4- (2-hydroxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-benzopyran, 213 8- {4- [4- (2-Methoxyphenyl) -1-piperazinyl] -butylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -3--propylsulfamoy1} met.yl-4-oxo-2-phenyl-4H-benzopyran, 8- {3- [N-methyl-2- (2-methoxyphenoxy) ethylamino] -propylcarbamoyl} 3-methyl-4-oxo-2-phenyl-4H-benzopyran, 8- {N-Methyl-3- [4- (2-methoxy-phenyl) -1-piperazinyl] -propionamido} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran> 8- {3- [4- (2-Methoxy-phenyl) -1-piperazinyl] -propylcarbamoyl} -3-phenyl-4-oxo-4H-1-benzopyran 8- {3- [4- (3,4-Dihydro-1-oxo-2H-naphthyl) -methyl-amino] -propylcarbamoyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {2- [4- (2-methoxyphenyl) -1-piperazinyl] -ethoxycarbonyl-methyl} -3-methyl-4-oxo-2-phenyl-4H-benzopyran, 8- {4- [4- (2-methoxyphenyl) piperazinyl]} -butylsulfamoyl-3-methyl-4-oxo-2-phenyl-4H-benzopyran, 8- {N- (2-tetrahydropyranyloxy) -3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-benzopyran, 8- {4- [4- (2-Methoxyphenyl) -1-piperazinyl] -butyramido} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, E-8- {2- [4- (2-methoxyphenyl) -1-piperazinyl] -ethoxyiminomethyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {N-hydroxy-3- [4- (2-methoxyphenyl) -1-piperazinyl] propylcarbamoyl} -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-benzopyran, 8- {4- [4- (2-Methoxyphenyl) -1-piperazinyl] butylsulphinyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {3- [3- (2-Methoxy-phenoxy) -propylamino] -propylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {3- [2- (2-methylthiophenoxy) -ethylamino] -propylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-benzopyran, 8- {3- [2- (2,6-dimethoxy-phenoxy) ethylamino] -propylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-benzopyran, 8- {3- [4- (5-Chloro-2-methoxy-phenyl) -1-piperazinyl] -propylcarb214-moyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, (E) -8 - {4- [4- (2-Methoxyphenyl) -1-piperazinyl] -1-butenyl} -3-methyl-4-oxo-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] ethylcarbamoyl-methyl} -4-oxo-2-phenyl-4H-benzopyran, 8- {N-acetyl-3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {2- [4- (2-Methoxyphenyl) -1-piperazinyl] ethylsulfonylamino} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] propylthiocarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {4- [4- (2-methoxyphenyl) -1-piperazinyl] -3-butylsulfonyl} mety1-4-oxo-2-phenyl-4H-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl} -propylcarbamoyl-3-hydroxymethyl-4-oxo-2-phenyl-4H-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -4-οχο-2-phenyl-4H-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -2,3-dihydro-4-oxo-4H-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -4-oxo-4H-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -6-bromo-3-methyl-4-oxo-2-phenyl-4H-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -6-methoxy-3-mety1-4-oxo-2-phenyl-4H-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -6-hydroxy-3-mety1-4-oxo-2-phenyl-4H-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3,6-dimethyl-4-oxo-2-phenyl-4H-benzopyran, {8-3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3-methyl-6-nitro-4-oxo-2-phenyl-4H-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -6-amino-3-mety1-4-oxo-2-phenyl-4H-benzopyran, 215 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -6-acetamido-3-methyl-4-oxo-2-phenyl-4H-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -6-ethylamino-3-methyl-4-oxo-2-phenyl-4H-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -6-dimethylamino-3-methyl-4-oxo-2-phenyl-4H-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -7-methoxy-3-mety1-4-oxo-2-phenyl-4H-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl) -3-methyl-4-oxo-2- (4-trifluoromethylphenyl) -4H-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -2- (4-benzoylphenyl) -3-methyl-4-oxo-4H-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3-methyl-4-oxo-2- (4-phenoxyphenyl) -4H-benzopyran, 8- {3- [4- (2-Methoxy-phenyl) -1-piperazinyl] -propylcarbamoyl} -2,3-dimethyl-4-oxo-4H-1-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -2- (t-butyl) -3-methyl-4-oxo-4H-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -2-cyclohexyl-3-methyl-4-oxo-4H-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -2- (2-furyl) -3-methyl-4-oxo-4H-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3-methyl-4-oxo-2-thienyl-4H-benzopyran, 8- {3- [4- (2-Methoxy-phenyl) -1-piperazinyl] -propylcarbamoyl) -4-oxo-2-phenyl-4H-1-benzothiopyran, (E) -8- {3- [4- (2) -methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3-methyl-4-oxo-2- (2-styryl) -4H-1-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3-methyl-2- (4-methylphenyl) -4-oxo-4H-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -2- (4-methoxyphenyl) -3-methyl-4-oxo-4H-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -2- (4-fluorophenyl) -3-methyl-4-oxo-4H-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -6-methanesulfonylamino-3-methyl-4-oxo-2-phenyl-4H-benzopyran, 216 8- {3- [4- (2-Methoxy-phenyl) -1-piperazinyl] -propylcarbamoyl} -3-methyl-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-Methoxy-phenyl) -1-piperazinyl] -propylcarbamoyl} -3-methyl-4-oxo-2-trifluoromethyl-4H-1-benzopyran, 8- {N-methyl-3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 7- {3- [4- (2-methoxy-phenyl) -1-piperazinyl] -propylcarbamoyl} -2-benzoyl-3-ethyl-benzo [b] furan, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -2- (4-biphenylyl) -3-methyl-4-oxo-4H-1-benzopyran, 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] propylcarbamoyl) -2- (4-biphenylyl) -3-methyl-4-oxo-4H-1-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3-methyl-4-oxo-2- (3-pyridyl) 4H-benzopyran, 8- {3- [4- (2-Acetoxy-phenyl) -1-piperazinyl] -propylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {3- [4- (2-metylaminokarbonyloxyfenyl) -1-piperazinyl] -propylcarbamoyl) -3-methyl-4-oxo-2-phenyl-4H-benzopyran, 8- {4- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -6-acetoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, (R, S) - 8- {3- [4- (2-Methoxy-phenyl) -1-piperazinyl] -propylcarbamoyl} -2,3-dihydro-4-hydroxy-4H-1-benzopyran, 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl) -2- (4-aminophenyl) -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] -propylcarbamoyl) -2- (4-hydroxyphenyl) -3-methyl-4H-1-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -2-phenyl) -4, N ¹ , N ⁴ -trioxo-4H-1-benzothiopyran, 7- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -2-phenyl) -benzo [b] furan and 8- {N-methyl-4- [4- (2-methoxyphenyl) -1-piperazinyl] butylsulfamoyl} -3-methyl-4-oxo-2-phenyl) -4H-1-benzopyran, 217 or a prodrug, anantiomer, diastereoisomer, N-oxide or a pharmaceutically acceptable salt of such a compound. A pharmaceutical composition comprising a compound according to any one of the preceding claims, or a prodrug, anantiomer, diastereoisomer, N-oxide or a pharmaceutically acceptable salt of such a compound in admixture with a pharmaceutically acceptable diluent or carrier. A process for the preparation of a compound of formula F1-YZB, wherein Y, Z and B are as defined in claim 1 and F1 forms a group of the formula wherein - -. X, W, R ₂ , R ₃ , R 8 and R 8 are as defined in claim 1, characterized in that it comprises condensing a compound of the general formula Fl-YZL. wherein L is a halogen atom or a leaving group, with a compound of formula HB. A process for the preparation of a compound of formula Fl-Y-Z-B, according to claim 11, comprising condensing a compound of formula Fl-Y-H with a compound of formula L-Z-B, wherein L is as defined in claim 11. A process for the preparation of a compound of formula Fl-YZB wherein Z and B are as defined in claim 10 and Y is one of Y 3, Y 4, Y 5, ΥΙΟ, Y 14, Y 27, Y 28, Y 41, Y 42 or Y 44 as defined in Claim 1, characterized in that it comprises the condensation of a compound of the general formula Fl-XQ-Cl, wherein X is a valence bond or a moiety. And Q represents a carbonyl or a sulfonyl group, with a compound of formula A-NH-Z-B wherein A is hydrogen, an alkyl group OPr, wherein Pr is a protecting group. A process according to any one of claims 10 to 13, characterized in that it is carried out in a polar solvent in the presence of a base at a temperature of 20 to 140 ° C. The process of claim 14, wherein the base is potassium carbonate or triethylamine. The process of claim 14 or 15, wherein the solvent is dimethylformamide, chloroform, dichloromethane or methanol. 17. A process for preparing a compound of formula YZB to in claim 11, characterized in that it comprises reacting a compound of formula X-Fl-COOH, Fl-CHO-X, X-F1-COC1, _F1-X-NH2 and Fl -X-OH, wherein X is as defined in claim 12, with a suitable compound such as HZB, LZB, HS-ZB, HO-ZB, H ₂ NO-ZB, A-NH-ZB or HCO-ZB, wherein L and A are as defined in claims 11 to 13.