LT3038B - Heterobicyclic 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

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

Flavoxate, 8- (2-piperidinoethoxycafinyl) 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran of formula

is used as a pharmaceutical urinary tract disorder agent having smooth muscle relaxant activity attributable to its calcium antagonist activity. This activity manages the smooth muscles of the bladder dome or may be related to the urinary center in the central nervous system.

An essential feature of the compounds of the invention described below is that the piperidine group is replaced by other amino-containing structural members. In addition, the ethoxycarbonyl group that connects the amino base to the benzopyran ring can be substituted by other groups. Alternative substitutions are possible 2, -3, -6- and · 7

- positioning of the benzopyran ring, substitution of the heteroatom of the ring with a sulfur atom or sulfinyl, sulfonyl or amino group, and / or 2,3hydrogenation of the benzopyran ring.With these structural modifications, new compounds acquire the ability to interact with different biological systems based on affinity 5HT _1A -Serotonergic

compounds of general formula I

where / 1Ό // 1ίΧΐ5 / 1 --7 -. + 7:, ...

- - - - corresponds to single or double.connector;

x represents an oxygen or sulfur atom, or an imine, alkylimino, sulfinyl or sulfonyl group;

·

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

R ₂ represents a hydrogen atom or an alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, carbocyclyl overpack! - a hundred carbocyclyl, heterocyclyl, substituted heterocyclyl or aroyl group; previously pa25 / the strange groups substitutes for one or more k & Logen atoms and / or one or more alkyl, cyano, hydroxy, phenyl, phenoxy, trifluoromethyl, nitro, amino, alkylamino, dialkylamino, acylamino, alkyl30 'sulfonylamino or benzoyl groups;

_ ^R 3 ^j: / represents a hydrogen atom or an alkyl, hydroxyalkyl, alkoxyalkyl, aralkoxyalkyl, phenyl, hydroxy, alkoxy or aralkoxy; a group; /.

R ₆ represents a hydrogen or halogen atom or

R ₇

Y n is a amino, alkylamino, dialylamino, acylamino, alkylsulfonylamino, cyano, hydroxy, alkoxy or alkyl group;

represents a hydrogen atom or an alkoxy group;

corresponds to one of the following groups, each of which is shown with its left end attached to a heterobicyclic ring and its right end attached to group Z:

20 ·

(Yl) -CO-, (¥ 2) -COO-, (¥ 3) -CONH-, (Y4) -CON (CH ₃ ) -, (Y5) -CON (OH) -, (¥ 6) -CH (OH) -, (¥ 7) -CH (OAlkyl) (¥ 8); -CH = CH-, <Y9) -CH-CH-COO-, (¥ 10) -CH = CH-CONH ~, (¥ 11) -CH = NO-, (Y12) / (Y13) -ch ₂ coo-, (¥ 14) (¥ 15) ' -CH ₂ CONH-, -CH ₂ NH-, (¥ 16) -CH ₂ N (CH ₃ ) -, (¥ 17) -CH ₂ N (COCH ₃ ) -, _ρπ ΚΙ / ΓΤίΚίΡ V_ ' Estonia; (¥ 19) 7 7 -ch ₂ nhco-, (¥ 20) -CH ₂ N (CH ₃ ) CO-, (¥ 21) (Y22) (Y23) -CH ₂ NH-CONH-, -CH ₂ nhso ₂ -,; ; -ch ₂ o-, (Y24) -CH ₂ S-, V; -7 ' ^? (¥ 25) -CH ₂ SO-, 7 7

(Y26) -CH ₂ SO ₂ ) -, (Y27) -ch ₂ so ₂ nh-, (Y28) -CH ₂ SO ₂ N (CH ₃ ) - (Y29) -NH-, (Y30) -N (CH ₃ ) -, (Y31) -N (COCH ₃ ) -, (Y32) -N (CONH ₂ ) -, (Y33) —NHCO—, (Y34) -N (CH ₃ ) CO-, (Y35) -NH-CONH-, (Y36) -nhso ₂ -, (Y37) -0-, (Y38). -S-, (Y39> -SO-, (Y4G) -so ₂ -. (Y41) -SO ₂ NH-, _t (Y42) -so ₂ n (ch ₃ ) (Y43) -CONHO-, (Y44). -CON (COCH _3. ) -, (Y45) -CSNH-, (Y46) -CSN (CH ₃ ) -, (Y47) -CON (0J j ' (Y48) -NHCOO-, and (Y4.9) -COS-, linear and branched

) -, an alkylene chain having 1 to 6 carbon atoms or optionally substituted with one hydroxy.

represents one of the following groups:.

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

(Al) phenyl substituted with one or more substituents

r. ,, ..; _; -r ·. r. r y. · r. R; .. ·.; ·· _; r. ar, -r) to '. ) R.? · _: R AR-) c R ..- 'to.' ) 'ARa _: ΛΛ -) 73 □ a halogen atom and / or one or more alkyl, alkoxy or hydroxy groups (A2) 2-pyrimidinyl group and (A3) group of general formula

wherein E is an oxygen atom or a valence bond, (B2) (B3) wherein each of L _x and L ₂ independently represents a hydrogen atom, a phenyl, a 4-fluorobenzoate or a 2-oxo-1-benzimidazolinyl group, or a (CH ₂ ) _n -OA group of the general formula wherein n is 0,1 or 2 and A is as above provided that L _x and L ₂ together do not represent hydrogen atoms,

-N- (CH _{= O)} -O iin

wherein each of R ₁₀ and R _n independently represents a hydrogen atom or an alkoxy or alkylthio group, R ₁₂ : '6' // 'represents a hydrogen atom or an alkyl group, on is 2 or 3,' 1. . f; / '*.'

j When 5 '; -i corresponds to a double bond, W corresponds to. a carbonyl group and x represents an imine group, the ring may be tautomerized to give a 4-hydroxyquinoline structure;

such tautomeric compounds are within the scope of the invention.

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

The term prodrugs, as used herein, refers to a derivative of a compound of general formula I wherein the reactive group is an amino, an imine or a hydroxy group (particularly, as in W, R ₂ , R ₃ , R ₆ , Z, JV and B2) or an acidic amino groups (e.g., Y3, ΥΙΟ, Y19, Y27,

Υ36, and Y41) masked; a derivative which retains the compound in the living body and thus exhibits the same pharmacological efficacy in the body as the compound itself. Misses can be 'prepared' so that e

alter the pharmacokinetic properties of the compound, for example, delayed and non-sustained release of the compound may be prepared. form, or otherwise modified metabolism, adsorption, distribution or plasma half-life of the compound.

Examples of prodrugs include compounds derived 114 and 12015

Here is abbreviated 'Fl. The following are preferred Fl group substitutions:

- - - -: double connector, -.

X: oxygen atom,

W: carbonyl group,

R ₂ : phenyl group,

R ₃ : methyl group,

R ₆ : hydrogen atom, and

T ₇ : hydrogen atom

All of these first-order substituents are substituted by the 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-yl group.

The most suitable groups which may correspond to Z are trimethylene and tetramethylene. Y in the first order corresponds to one of. Y2, Y3, Y37, Y40, Y41 or Y42. B in the first row corresponds to one of the JV and B3 groups, in particular the 1- (2-methoxyphenyl) piperazinyl group.

^8th

Other abbreviations used herein include Me methyl, Et instead of ethyl, Ac instead of acetyl, Alk instead of alkyl, THF instead of tetrahydrofuran, DMF dimethylfermamide, and DMSO instead of dimethylsulfoxide.

The adrenergic antagonist αJ of the compounds of the invention is suitable for application to agents acting on body tissues, particularly those rich in L _x -adrenergic receptors (such as blood vessels, prostate and urethra). antiadrenergic compounds within the scope of the invention, by virtue of their binding characteristics, may be useful agents, e.g. hypertension and urinary problems associated with destructive lower urinary tract / urinary tract disorders, including, but not limited to, treatment of those with non-malignant pro s tatical hypertrophy.

receptor therapeutic

The serotonergic activity of the compounds of the invention is suitable, in particular, for targeting them to receptors acting as tissue-acting agents in the central nervous system. _: ·· k ^: is ^r . it is believed.

where ^; functions 5HT that the 5HT regimen regulates the action and release of serotonin as well as the release of other neurotransmitters and is found both upstream and downstream.

Compounds of the Invention By Blocking Communication Between Specific. 1 ligand of the invention: compounds that are biologically active, the following receptors and their various (e.g., serotinine) ^: compounds which interact::; with the 5HT _1A receptor:: (deprived at remi on is; -; bind to, their receptor characteristic) may be useful. agents for the treatment of anxiety and depression.

Compounds of the Invention. affinity for both Iltie, who ams and is characterized by a 5Λ 1įž _return ///// 7-1 7 /, / · / './ /7.1/ <ι' .. _: . / ...

selectivity for the lower urinary tract of mammals, i.e. y. they are essentially more active in resisting urethral contractions than in lowering blood pressure.

.5 In contrast, known L _x -antagonists such as prazosin, 1- {4-amino-6,7-di-methoxy-2-quinazolinyl) -4 (2-furoyl) -pperperazine (GB 1156973), do not exhibit high levels of activity. selectivity (which actually lowers blood pressure, which is the most common side effect), while flavone derivatives structurally similar to flavoxate, such as terflavoxate, which is 8 {1,1-dimethyl-2-priperidine-ethoxycarbonyl ) -3-Methyl-4-oxo-2-phenyl-4H-benzenesulfonate hydrochloride (EP

0072620) is not effective for urethral contractions.

| 5 | / ιΐ: ΐ | 7ΐ; ΐ | ι1 / +

Of course, those compounds of the invention that are not selective for the lower urinary tract are useful as antihypertensive agents. agents, but even selective compounds are frequently used to be iipertonic agents due to their low toxicity.

The compounds of the invention exhibit good antagonist efficacy in potassium chloride contraction in rat bladder cancer. This effect can be attributed to calcium antagonistic activity and is suitable for the application of novel compounds to lower urinary tract spasmolytic (i.e., suitable for the treatment of urinary incontinence, need syndrome, etc.). ·

Most of the compound of the invention is characterized by low toxicity. Because of this advantage, they can be used in bulk, which often compensates for more than the relatively low level of activity some of these compounds possess. Of course, compounds that are ρΒ§χ2'γπώ. <73 ^ Ρ. '<ίΐάβ3ηιυ ··:. activity and lower toxicity.

The invention further provides a pharmaceutical composition comprising. a salt of a compound of the invention or a pharmaceutically acceptable salt of an enantiomer, diastereoisomer, N-oxide or pharmaceutically acceptable salt thereof; diluent .and carrier.

SYNTHESIS OF THE INVENTION COMPOUNDS

The compounds of the invention may be obtained (unless the substituents R ₆ and R ₂ are OH, NH ₂ or aminoalkyl and Y = .Y 15 'at Y 29) are as follows;

Path a:

· By condensing 'Fl-Y-Z-L compounds, where. L ·. Corresponds to a halogen atom or a fusing group, such as a tosyloxy group, with H-B. Condensation is desirable but not necessary and is carried out at temperatures between 20 and 1.40 ° C in a polar solvent such as dimethylformamide or methanol, often in the presence of a base, potassium carbonate. .These condensations. illustrate 1-3, 7-9, '11, 13-16, 21,

23-31, 38-42, 46-49, 54-59 ,. 69, 73,. 77, 78 and 84 below. See also Gibson chapter in Patai, The Chemistry of the Amino Group,

45 et seq., Wiley Intersience, New York, 1968.

V f / 'Ulle / t'; - <'/··-ūVų'/Ū-įj;.';·'/' /·/.·· 'j · <// <' / • / in ·. . · S: // - · '-' · t. '

An alternative process for the preparation of the compounds of the invention (under the same conditions as described in the preceding paragraph) is the condensation of the Fl-Y-H compound with the E-Z-B compound - wherein E is as noted above. This condensation is illustrated in Figures 5, 6, 66, 79 and 81

In the examples. This path can also give compounds where Y = Y15 or Y29 (see Gibson ^T chapter in Pat. Above).

Formula (I) compounds containing NH ₂ groups corresponding to R _6, or R ₂ as substituent may be prepared ¹¹ receive the corresponding formula (I) compounds wherein R ₆ or R ₂ substituent is NO ₂ group reduction,. Such reduction may be effected:

- Reney Ni catalyst in an acidic solvent selected from methanol, ethanol, isopropanol, water and mixtures thereof; or -SnCl ₂ ,, H ₂ 0, optionally in the presence of hydrochloric acid or in an acidic solvent such as methanol, ethanol, isopropanol, water in acetic acid and mixtures thereof, or in an aprotic solvent, in ethyl acetate; or ·

-Fe and aqueous hydrochloric acid in an acidic solvent in methanol, ethanol, isopropanol and mixtures thereof.

Temperatures for the reactions described above are selected from 20 ° C to 100 ° C (J.March, Advanced Organic Chemistry, III Ed., Page 1103, Wiley Interscience, 1985). '·

This reduction is shown in Examples 94 and 124.

(I). The compounds of formula I which are substituted with the NHAlk group R ₆ can be obtained by the corresponding starting (I).

monoalkylation of compounds of formula 'wherein R ₆ is NH ₂ .

For example, by reacting an amine compound (I) with an excess of trifluoroacetic anhydride, the resulting trifluoroacetyl derivative is reacted with an alkyl-L reagent and finally the resulting trifluoroacetyl is deprotected.

- an alkylated derivative by treatment with potassium carbonate · methanol or sodium borohydride in methanol or dimethylsulfoxide. These are the reactions described in Examples 32 and 33 where they are performed for Y groups.

Alternatively, compounds of formula (I): with NHAlk or

N (Alk) ₂ groups as a R ₆ substituent or as a R ₂ phenyl substituent can be obtained by alkylation of the corresponding starting compounds of formula (I) wherein R ₆ =

ΝΗ ₂ , with the corresponding alkanals in the presence of a reducing agent, sodium cyanoborohydride. These reactions are described below in Examples 96 and 97. Compounds bearing an OH group in place of R ₆ or R ₂ may be obtained from the corresponding alkoxy-substituted (I) starting materials. compounds' in the above positions. The parent compounds can be treated, for example, with BBr _{3 in} dichloromethane at 0-40 ° C (TW Greene, Protective

Groups in Organic Synthesis, page 87, Wiley Interscience, 1981) or other methods described in the same instructions.

Compounds of general formula I in which - - - - represents a single bond may be obtained either by the selective hydrogenation of the corresponding compounds in which - - - - double bond or by conversion of the corresponding starting materials already saturated at 2,3 the materials are obtained by Reaction Schemes 4, 6 to 9,11,12 and 14 described below. The latter route is illustrated in Example 87 below, and is particularly suitable for a compound having a nitro group, since the hydrogenation can be converted to an amino group during hydrogenation. Alternative hydrogenations are carried out alternatively using:

hydrogen in the presence of a metal or metal oxide catalyst (e.g. palladium on charcoal or platinum oxide) in an acidic solvent at 20-120 ° C (EHRodd, Chemistry of Carbon Compounds, Vol. IVB, page 903, Elsevier, 1959); or / ^; .

- di (isobutyl) aluminum hydride in an aprotic solvent (e.g. tetrahydrofuran and / or dichloromethane) at -70 to 0 ° C (H. Sarges et al.,

J.Med. Chem., 33, 1859 (1990). '

Compounds in which W represents a 3,3-hydroxymethylene group and a 2,3-bond is saturated can be obtained / Λ ·. · ^'13 Λ /' - · / ...

reduction of the corresponding compounds wherein W represents a carbonyl group and the 2,3-bond is saturated with sodium borohydride as described below in Example -123.

In some cases, the compounds of the general formula I may be obtained by conversion of other starting compounds of the invention »

Such conversions include:

Road b; Fl-CO-Z-B -> Fl-CH (OH) -Z-B / - and reduction as illustrated in Examples 17-20 below, /. ? · - *; · '

Path c :. Fl-CH (OH) -Z-B Fl-CH (OAlkyl) -Z-B

- -erification as illustrated below, · '··' ./ 22 In the example, _ / - '///' /

Path d: Fl- (CH ₂₎ -NH-ZB -> Fl- (CH _{2) n} -N (CH ₃₎ -ZB wherein n = 0 or 1, N-methylation as illustrated in Example 35 below, /. <

The E 'Fl- (CH ₂₎ -NH-ZB> Fl- (CH ₂₎ -N (COCH ₃₎ -ZB • <n = 0 or 1, N-acetylation as illustrated in Example 36 below , ./

Path f: Fl- (CH ₂₎ -NH-ZB Fl- (CH _{2) n} ~ N (CONH ₂₎ -ZB wherein n = 0; or 1, reaction with / potassium isocyanate as illustrated below 50 // y / · In the example,

Path g: Oxidation of Fl-CH (OH) -ZB Fl-CO-ZB, - / · _: · as illustrated in Example 51 below,

Route h: Oxidation of Fl-Y-Z-B ^ Fl-Y-Z-B (N-oxide) as illustrated below 43 and /, '122 In the Examples,

Path i: // 2Η ₂ Ν-Ε'1'-Υ-Σ-Β CH ^ CONH-F1-YZB: '_; (wherein H ₂ N-F 1 corresponds to the F 1 group wherein R ₅ is an amino group or R ₂ has an amino group) using the N-acylation method 36 and .95 described in Examples.

Path j: Identification of Fl (R ₆ = NH ₂ ) -YZB. Amidification of Fl (R ₆ = CH ₃ SO ₂ NH) -YZB using the method described in Example 112 /.

ΊΟ

Path k:

CJD-YZ-NH- (C. ₂₎ n-0 (> ^ fl-YZN (AIC} -N-0

Flr-Y * Z-KH-C £ f ₂

Q.

F »3

fili

'Fl-YZN (Alk) -CH ₂ - Ji

to U Lt.

F ^ TY-Z-NH-CBj-r

N-alkylation using the methods described in Examples 35 and 62

When, the compounds can be obtained by coupling reactions. For example, those in which Z has a hydroxy substituent can be obtained by attaching the epoxy group "· \, Λ · 4"

Path 1: .Fl-Y-CH ₂ -CH-CH ₂ + HB Fl-Y-Cl ^ -CH (OH) - C% -B as illustrated in Example · 45. Also j. possible connection via double connector ^ eg: 'be <<<,.

Path m: << / Fl-Y-CH CH, + HB 4 Fl - Y-CH _O -CH, -B 'j as illustrated below 37, 63 and 82

In the Examples, another synthesis scheme i involves the formation of a <Y, Z, or B reaction

'.' Ν · year, for example: '

Path n: Fl- (X) - (Q) -C1 + A-HN-ZB: ^: | Ί- · <Χ) Λθ'-ΊίίΑ) _: τΖ-Β ^; <

'(where X - = bond, C H ₂ or CH-CH, Q = CO ar.

,, SO ₂ while A = H, alkyl or 'OP _r where' P _r 'is present. ; . protecting group) as illustrated in 12

61, 64, 67, 68, 72, 87, 88, 93, 98,116, i 120 and 130 in Examples. They. the compounds themselves may also be obtained by other routes, which include:

F1- (X) -COOH + A-NH-Z-B in the presence of a coupling agent (e.g., dicyclohexylcarbodi35 imide, N, N'-carbonyldiimidazole or diethyl cyanophosphonate), optionally in the presence of an accelerating agent (e.g.

γΐ ', 1, 4-dimethylamine pyropyridine or N-hydroxybenzotriazole) in an aprotoninic or chlorine 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. / · NęwerO; M '/ - Org. Chem. ± 5, 61,: 1968; Ishihara, Chem. <

o> 1991) / illustrated

80, 86, 89.90, // 92, / 9

119 and 128 in Examples. .Fl * - (X) -COOH + ANH-Z-B without solvent at 150-220 ° C (Mitchell et al., J. Am. Chem. Soc.

1879, 1931) or in high-boiling ethereal solvents (e.g., diglyme);

Fl- (X) -COO-Al'k + A-NH-ZB optionally in the presence of a coupling agent (e.g. trimethyltinyl) in the presence of an '' i '' - in a chlorinated solvent and / or a chlorinated solvent (e.g. / 80 ° C, or ^: without solvents at 80-180 ° C (S, M, Weinreb et al., Tetrahedron: 417 (1977)); 74 .F / Lipton et al., 0rg.Synth. 5 - 9 ₍ 1979); /; - / / 'Fl- (X) -COOH + alkyl chloroformate in the presence of tertiary amine (e.g., triethylamine), //:'/; 0 \ -'--- ^; ./?/ ''' ⁰ after /:' to - '//' adds: - / ': A-ijH-ZB // added · - 0-80 ° C;

accelerating agent, // paslrlrrk-tins, (e.g., / 1-hydroxypiperidine) may be added prior to the addition of the amine (Albertson, Org. React., 12, 157, 1962).

Path o: F1-COC1 + HS-Z-B -> F1-Y49-Z-B /

Path p: FL-COC1 + HS-ZB F1-Y2-ZB. _; ^; as illustrated below in Example 10.

Path g: - FlCHO + HNO-Z-B -> Fl-Yll-Z-B • As illustrated below in Example 70.

High R: Fl-CHO + A-HN-Z-B -> Fl-CS-N (A) -ZB

Road s

Path t:

Path ur Path v:

Path w:

Path x:

(where A = H or CH ₃ ) in the presence of sulfur in an aprotic solvent, e.g. DMF with. pyridine at 60-120 ° C (M. Carmac et al., Org. Reaction., 83, 1947; R. Benenas et al., Org. Magn. Res., 15, 25, 1981), as illustrated below, 83 In the example.

FL-NH ₂ + HCO-ZB F1-Y29-ZB: d as illustrated below in Example 34.

Fi "Y" 0H ₃ + ho-ch ₂ -b -> fi-yc: ₂ -ch ₂ -b as illustrated below in Example 4. .

Fl-CH = CH-COONH ₂ + HOCH ₂ -B -> Fl-Y ₁₀ -CH ₂ -B. Rio.

Fl-YZN ₃ -4 HCO-CH ₂ -0 - / H). Fl-YZ-8 under reducing conditions as illustrated in Example 44 below.

^R l £>

. F1-NH-YZ _2+. L ~ (CH ₂ ) n-0- ΖΛ.? '. ::; / in. & Tt '. _: how i1ius is handled below.

FI-YZ-NH ₉ + L-CH

k Fl-Y-Z-S as illustrated below 52 Example e.

F1-YZ-HN ₂ 4- ^Cw 2

-> Fl-Y-Z-8

Path y:

as shown below in Example 65 Example Fl-YZ-CHO + HB -> Fl-YZB '.. ¹¹ as illustrated · in Example 53 below. 127 In the example this path. the resulting N, N> dioxide. '' d-dy Route z: Oxidation of Fl (X = S) -YZB Fl (X = SO or SO ₂ ) -YZB d 1 with hydrogen peroxide in acetic acid or 'other oxidizing agents in the presence of acids.

One skilled in the art will appreciate that: all of the above pathways b) -y) may be simplified provided that the reactive intermediate does not have additional groups sensitive to the same reactants (for example:

CO, NH ₂ , NHAlk or OH groups) compounds of Formula I with such reactive groups may be obtained by the routes b) -y) ', provided that the reactive groups present in the starting materials are protected in advance and the protecting groups removed after the reaction, as illustrated in Example 71. Separate guards and guards. Examples of removal for various reactive groups can be found in TWGreen, Protective Groups in Organic Synthesis, Wiley Interscience, 1981 (Edition 1991).

Alternatively, non-reactive groups (eg NO ₂ ) may be left in the first reaction and converted to reactive (eg NH ₂ ) in the final step. For example, watch the path a). The choice of the synthesis route depends on the compound to be synthesized, but the pathway is most suitable for the compounds that may be obtained. Additional Synthesis; the techniques will be clear to the practitioner. ydddj; - · -: ·.

d for d:

The paths described above are used ';

The starting materials (Fl-YZL and Fl-YH and; others) can be obtained from simple compounds, Fl-COOH, Fl-COCl, · FlNH ₂ and converting Fl-OH known to those skilled in the art. d

Such conversions are described in detail below. Many of these simple compounds (F1-C00H, Fl-chu, C0C1-F1, F1-NH _second

and Fl-OH) are commercially available or their synthesis is described in the literature. Those who are inaccessible can.

be synthesized by one or more of the 1-16 Reactions. . schemes.

The reaction scheme yields compounds wherein W represents a carbonyl group and X represents an oxygen atom.

'

Tier 1-ar

Preparation of the intermediate phenyl ester without isolation:

- R ₃ CH ₂ COCl 1 'or R ₃ CH ₂ CO ₂ O and Lewis acid (eg AlCl ₃ or ZnCl ₂ ) without solvent or in an aprotic solvent (eg nitrobenzene or chlorinated solvent) at. 20-180 ° C.

Method for the preparation of the phenyl ester of the intermediate, with isolation:

• '- R ₃ CH ₂ CC1 or (R ₃ CH ₂ CO) ₂ 0 is heated with the starting material, or - _{s by} other esterification methods such as Schotten-Bauman. The isolated ester is then heated in nitrobenzene or other non-acidic solvent (e.g., chlorinated solvent) or without any solvent at 20180 ° C in the presence of Lewis acid, A1C1 ₃ ? or ZnCl ₂ (AMBlatt, Org. React. 1, 342, 1942).

^; i '35

SCEMA 1

</ j · // / J / · / '' '' - 5

A = CO ₂ CH ₃ , COgGaHsrNOa / CH ^ CHGHg, / B ^ GOgH / NHa ^Λ

Tier 1b

- R ₂ COC 1 or (R ₈ CO ₂ O and R ₂ COONa or in a high boiling non-acidic solvent (such as o-dichloro-loroberizole) at 150-220 ° C; this reaction allows the direct conversion of (2) into compounds (6) ' (2) in compounds A = COOH;

-RzC (GAlk} ₃ in the presence of HClO _{4 at} 20-40 ° C or pyridine in the presence of piperidine at 6 ° C-80 ° C;

- R _z COCl or (R ₂ CQ) ₂ G in chlorinated solvent 10120 ° £ r at base 1,8-diazabicycloundecene (DBU).

Tier 1c

- R ₂ COC 1. pyridine at 20-100 ° C or in an acidic solvent at 0-80 ^Q C _f optionally in the presence of NEt ₃ base or 4-dimethylaminopyridine,

Tier 1d, ¹

.. 20 '' 'Y' '-

- K ₂ CO _{3 in} acetone or methyl ethyl catechol 20-80 ° C;

NaH in DMSO or THF at 0-40 ° C

- KOH or potassium t-butoxide with pyridine at 20-100 ° C <

Step down

- HCl or H ₂ SO _{4 in} AcOH at reflux or in alcohol (MeOH, 'EtOH, isopropanol) at a boiling point of 20 ° C;

- CF ₃ COOH in dichloromethane at 20 to 40 ° C;

Refluxing p-toluenesulfonic acid in benzene or toluene.

³⁵

.21

- R ₂ COCl and K ₂ CO / ± KOH in water or in a heterogeneous catalyst boiled in benzene or toluene

- / womb reversible refrigerator; '' // ',' - / 'j, - <' Ϊ

- R ₂ COOAlk and lithium bis (trimethylsilyl) amide ar? lithium / diisopropylpropylamide in THF at -78-0 ° C.

.-13 .:. + // + '' +. // // '+' When A is COOCH ₃ ar, COOC ₂ H ₅ Group: ·

- NaOH in aqueous EtOH at 0-75 ° C;

- LiOH in aqueous DMF, MeqHar THF or a mixture thereof at 10-100 ° C;

HCl in an aprotic solvent such as dioxane at

6O-120 ° chi ++ <// ^ '-' \ + / + _ + '/' / J '^;'

When A is NO ₂ :

- Reduction with ReneeUsNi catalyst in an acidic solvent (eg isopropanol) or acidic /.

/ Mixing of 23 solvents at 23-100 ^° C;

Reduction with hydrogen and catalyst (e.g. Renee in Ni or Pd / C in acidic solvent .-: 7 ..,.: /. -, //.:; .-. '7 //./- 7- ./ .. :. ^; //.7 ^! R '. //// ... 7 -.,: 7.' / O (e.g., MeOH, EtOH, in isopropanol or a mixture thereof) at 2 ° C to 10 ° C; / 7 /.//+// 7 ./.- Reduction with SnCl ₂ in the presence of aqueous HCl / acidic solvent ⁵ / (e.g. AcOH) pfie + '20 -100 ^Q C;

'/ -7 / - Reduction + in the presence of Fe 7 and aqueous HCl in acidic solvent at 20-100 ° C.

. + /. // When A is' CH = CHCl ₃ group: / / -, Oxidation with Na ₂ Cr ₂ 07 or other oxidizing agents; as KMn0 _{4 in} acetone / H ₂ S0 ₄ at 0-100 ° C. , / ++ 7

Reaction Scheme 2 gives compounds where + x / represents a sulfur atom or / sulfinyl or sulfonyl group and W represents a carbonyl group. The starting o-mercaptobenzoates (1) are commercially available or can be obtained by known methods, for example, by the conversion of the corresponding diazone salts of o-alkoxycarbonyl-bisphenol 22 with potassium ethylxanthate (MSCohen et al., J. Org. Chem., 18, 1394, 1953). ,,

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

R 8 in C-COOAlk and Al ₂ 0 _{3 in an} aprotic solvent (e.g., Et ₂ O) at 0-40 ° C;

- R ₂ C = C-COOAlk and base in an aprotic solvent (such as THE or DMF).

The latter two cases are treated with polyphosphoric acid 10 at 50-120 ° C.

Step 2b

- NaOH in aqueous EtOH at 40-75 ° C;

- LiOH in aqueous DMF at 40-10 ° C.

Tier 2c

- Stoichiometric 30% H ₂ O _{2 in} AcOH at 25-60 ° C;

- m-chloroperbenzoic acid in chloroform at 030 ° C.

Tier 2d

- 30% H ₂ O _{2 in} AcOH at 50-80 ° C.

The reaction scheme yields compounds wherein R ₇ represents a methoxy group, W represents a carbonyl group, and, X represents an oxygen or sulfur atom. (1) The compounds can be obtained from the corresponding phenols or thiophenols (unchanged at position 2 or 6 • COOAlk or NO ₂ ) by Reaction Schemes 1 and 2.

35 'Frame,)' R / '

. y /

SCHEME 3y

fcis ^; /\.yy; ': y2 <

O

·• Tier 3a

- HCHO and gaseous HCl AcOH-e containing aqueous. HCl (d = 1.18) at 50-10G (P. Da Re et al., Ann.

- Chim., 46, 904, 1956).

This method may be used when R ₃ is other than H or CH ₂ 0H.

The resulting 'intermediates 2 can be converted, by known methods, to the starting materials suitable for the desired invention. for the preparation of compounds. (See LXIX Intermediate).

Simple 2,3-dihydro intermediates (- - - - - single bond) may be obtained by reaction of other protected reactive groups (e.g. NH ₂ , OH) as described above. The compounds (4) thus obtained can be converted into the corresponding derivatives having A = COOH .. or NH ₂

Step by step lg method.

Step 4a

R ₂ -CHO, aqueous NaOH in EtOH or y in another acidic solvent; -? // · '?

5y - 'R ₂ ~ CHO, NaH or potassium t-butoxide in THF. (or other dipolar aprotic solvent) at 0-150 ° C.

Step 4b

- Millerary acid (eg HCl or H ₂ SO ₄ ) in water or other acidic solvent (eg EtOH, AcOH) at 0-100 ° C.

. · Tier 4c J y? Y? // jyyyy /// y / i / y'y /? Yy '// ^;: ?' / ^{;:; <} Yjyyy / '/ · yi'y ^{; i} /'> ? - / i ·.

- R ₂ ~ CHO, Ο, ΙΝ - 1N aqueous NaOH or a suitable base in an acidic solvent;

- R ₂ -CHO, pyrrolidine in an acidic (e.g. MeOH) or polar protic solvent at 0-100 ° C (HJKabbe, Synthesis, 1978, p. 886).

Step 4d · - Lithium diisopropylamide in THF at 0-20 ° C; followed by dimethylsilyl chloride and an organic base (e.g., NEt ₃ ) (SEKelly et al., J. Org. Chem., 56, 1325,

1991).

Step4e

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

-Lithium diisopropylamide in THF at -78 ° C followed by R ₂ -CHO (A.Banerij et al., Tetrahedron Letter, 197 9,

5. 3685) ...

Tier 4g

- R ₂ -CH = CR ₃ COCl, Lewis acid (e.g. AlCl ₃ ) in suitable

10 'in solvent (eg nitrobenzene) or solvent free at

20-180 ° C.

Tier 4h.

- R ₂ -CH = CR ₃ COOAlk, triethylbenzylammonium hydroxide, in an aprotic solvent (e.g. benzene) or solvent-free at 50-150 ° C; followed by aqueous NaOH in MeOH at 20-50 ° C or LiOH in aqueous DMF. (In this case, compounds wherein A = COOCH ₃ or COOC ₂ H ₅ are also hydrolyzed to compounds wherein A = COOH).

Step 4i

- Concentrated with H ₂ SO ₄ or P ₂ 0 ₅ or polyphosphorus or

Lewis acid in nitrobenzene or toluene with or without solvent at 0-180 ° C. (Hydrolysis of A = COOAlk to A = COOH also occurs in this case).

, Simple - starting materials in which R ₃ = OH or OR _S , where

R ₀ is alkyl or aralkyl, can be obtained by reaction of 5 with A having the same meaning as' and 1

Reactions In the Scheme. Compounds (1) and (2) · (the same as (2) and (4) in Reaction Scheme 4, but R ₃ = H) can be obtained from Reaction Phenols or Thiophenols, respectively. R ₃ = H. (4) Compounds used in 5

Reactions in the Scheme may be prepared by known methods and by the use of appropriate salicylates or thiosalicylates (see J.March, '28.

Advanced Organic Chemistry, 486, John Wiley and Sons, New York, 1985; Rene et al., Eur. J.Med. Chem. Chim. Ter., 4, 385, 1977 and directions cited therein).

As noted in Reaction Scheme 1, '5 Reaction Schemes',. · '(3) and. (6) The substitution A of the compounds can be converted to the substituent B by the steps of lg.

5a

- Aqueous NaOH in a c.c. solvent (e.g.

MeOH or EtOH) followed by (N.D. Meyer et al., Directions cited herein by J.Med.).

30- '

H ₂ O ₂ at ~ 10-78 ° C.

Chem., 34, 736, 1991, and '(Even when A is. CH = CH-CH ₃ ; when A = COOR, it is immediately converted to GOOH)'.

Step 5b

When ~ ~ ~ ~ = single connection:

Amyl nitrite or other alkyl nitrite without solvent or in a suitable solvent (e.g., EtOH or benzene) in the presence of a catalyst, 37%, CH1 (Org. React. 7, 327, 1953 and references cited therein); followed by aqueous H ₂ SO _{4 in} acidic solvent (e.g., AcOH) at .10-100 ° C (Acheson RM, An Introduction to Chemistry of Heterocyclic Compounds, 3'47, John Wiley and Sons, New York, 1976).

When - - - - = double connector: ·

- lithium diisopropylamide in the dry state. THF at -78 ° C; followed by AcOH _; , and 30% H ₂ 0 ₂ (BDM Cunningham et al., Anti-Cancer Drug Design, 7, 365, 1992)

Step 5c

- R ₂ -CH = CH-NO ₂ (1 to 1.5 equivalents) in a suitable solvent (e.g. diisobutyl ether, DMSO or DMF), in the presence of a base (e.g. KOH or NaOH) in the catalyst or in stoichiometric amount at 20150 ° C: ( see Rene, supra, and T. Sakakibara et al., Bull.Chem. Soc. Jpn., 51, 3095, i!

: LT 3038 B

-i ·>'/ bki 7/7? ³¹ / L'a \ '' / j / ^Λ ·? · ::

.. Tier 5d

- 15% H ₂ O ₂ , NaOH or other base (eg NEt ₃ ) in an acidic solvent such as MeOH at 20-100 ° C

5. (S.R.Deshpande 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-charged-16 ether at 20100 ° C (Rao. TS, 'Heterocycles, 26,2117). 1987). (No. when A is CH = CH-CH ₃ , when A = COOR it is converted directly into COOH). .

Step 5e

- a group of R ₈ L where L corresponds to the departing one (e.g.

alkyl sulfate, halogen, tosyl) and a base (e.g. K ₂ CO ₃ , NaH, KOH, NaOH or LiOH) in a suitable solvent (e.g. THF, DMSO, DMF, benzene) in the presence or absence of a heterogeneous catalyst (e.g. benzyltriethyl20 for ammonium bromide) at 0-180 ° C.

Step 5f

- lb Tier Methods.

> 6 Reaction Scheme in which A has the same meaning as in Scheme 1 gives · compounds wherein W represents a thiocarbonyl group. Reactions Scheme compounds (1) and (2) can be obtained by Reaction Schemes 1, 2, 4 and 5. 6th

The substitution of the compound of Reaction Scheme (4) in Step A lg may be substituted by a B substituent as defined in Reaction Scheme 1.

'

SCHEME 6

L.T3038B

P ₂ S ₅ pyridine at 50-100 ° C (Stavaux et al., Bull. Sochi Chim. Fr., 2082, 1967).

5 * '·'

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, 2963; RK Razdan et al., J. Med. Chem. 21, 643, 1978; K. Clausen et al., Tetrahedron, 37, 3635, 1991).

Step 6c

- COC1 ₂ without solvent or with with an inert solvent (A.Chonberg et al., 20th (e.g. benzene) Chem. Ber., 101, at 40-90 ° C 701, 1968). 5 Tier 6d Tioacto with thiobenzoic acid, or potassium

diethylxanthogenate in a suitable solvent (e.g.

benzene) under reflux (A.Schonberg, supra). .

Reaction Scheme wherein A represents the same as Reaction Scheme 1 / gives compounds wherein W is a corresponding methylene or hydroxymethylene group. 7th

Reaction Scheme Compounds (1) ', (2) and (4) can be obtained in Reaction Schemes 1, 2, 5 and 6. 7- The substituent A in the reaction scheme in the compounds A (7) can be converted to the substituent B in the Ig step as defined. 1 In the reaction scheme.

SCHEME 7. . 35 '

Tier '7a' ·;

- 1,2-ethanodithionyl · or 1,3-propanodithiol in an aprotic solvent (e.g. .

Tier 7b, 101 ./'// j / j / ii ² , '. -; c; '; ./-// · -.//// 7. f. '''._; / / ..

R ₂ COCH ₂ R _{3 in a} suitable solvent mixture (e.g., EtOAc or dichloromethane J. EtOH or MeOH) saturated with gaseous HCl at 0-40 ° C; followed by aqueous. HClO _{4 in} AcOH at 20-100 ° C (L. Jurd,

Tetrahedron, 28, 493, 1972).

Step 7c

- LiAlH _{4 in} THF, ¹ at reflux (if A is other than COOR and NO ₂ );

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

Tier 7d ·

Renew Ni in an alcoholic solvent (e.g., isopropanol) at reflux (Hilton et al., J. Am. Chem. Soc., 90, 6887, 1968).

Step 7e

NaBH _{4 in a} suitable solvent (e.g. MeOH or EtOH or

DMSO) at -10-50 ° 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 )

... / .. i ..

(Degani et al., Ann. / Chim 1971;

Kurosawa, Bull. Chem. Soc. Jpn., 51, 1175, 1978).

Step 7f 5 • - Trityl perchlorate in acetonitrile at room temperature (Degani et al., Supra).

Tier 7g

Melting with P ₂ O ₅ at 80-180 ° C (HOrtman et al., J. Am. Chem. Soc., 96, 6118, 1974).

Tier 7h

NaBH _{4 in} EtOH or other suitable solvent at reflux temperature of 0 ° C (K.Anaya, Bull. Chem. Soc. Jpn. 40, 1884, 1.967).

Hydrogen (1-10 -atm) in EtOH (or other suitable solvent) in the presence of a catalyst at 5% or 10% Pd / C or in René Ni or PtO ₂ ; - 80 ° C (K. Hanaya, supra). Even when A is CH = CHCH ₃ . When A = NO ₂ , it is immediately reduced to NH ₂ .

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

The reaction scheme shows simple starting materials such as (4), (5), (6) and (9), where A represents the same as

IR reaction scheme, receipt. (1).,. Compounds (2), (3), (7), (8) can be obtained in 1, 2, 4, .5, 7, 9, 11

Reaction Schemes. The substitution of Reaction Scheme A in Compounds A (4), (5), (6) and (9) in Step lg may be converted to B as indicated in Reaction Scheme 1.

Tier 8a /, '1

- Pb (OAc) _{4 in a} suitable solvent (eg benzene, toluene) refluxed (GA)

Russel et al., J.J. Am. Chem. Soc., 1906, (1975).

Step 8b.

- NaBH _{4 in} alcohols (see Reaction Scheme 7, Step 7a) followed by alkaline hydrolysis. (when

A = COOR, this is converted directly into COOH);

aluminum isopropoxide as noted in 7

Reaction Schemes in Step 7f;

- diboranes in THF-e -10 ° C - b.p. followed by aqueous

H ₂ O ₂ in the presence of NaOH (not when A is CH = CH - CH ₃ ;

A = COOR, 'it is converted directly into COOH). (Kirkiacharian et al., C.R. Herb. Seances Acad. Sci. Ser. C, 289, 227, 1979);

- LiAlH ₄ and AlCl _{3 in a} suitable solvent (eg THF)

0 ° C - boiling point (not when A = COOR or

NO ₂ ) (Blokadia et al., J. Chem. Soc. 4663, 1961).

Step 8c.

hydrogen (100 atm), copper chromite in EtOH at 140 ° C, (see MA Vickars, Tetrahedron, 20, 2873, 1964.) When A = NO ₂ , it is directly converted to the NH ₂ group.

Step '8d

- KMnO _{4 in} t-butanol (or other suitable solvent) in the presence of anhydrous NaOH at -10-0 ° C. (K. Hanaya, Bull. Chem. Soc. Jpn. 40, 1884, 1967). (Not when A is CH-CH-CH ₃ ). (See also ¹ See AH Haines, Methods for the Oxidation of

Organic Compounds, Academic. Press Ine, (London), 1985, -chapter 3.2.2). .

- Osmium tetroxide (see A.H. Haines, supra

/.ę· chapter 3.2.1) in a suitable solvent (eg Et ₂ 0)

5 '. t at room temperature (Baranton et al., Bull.

• Soc. Chim. Fr., 4203, 1968) (not when A is present

CH = CH-CH ₃ )

- aqueous H ₂ O _{2 in} formic or acetic acid at 20-50 ° C; followed by NaOH, _{2 2} 0, 45 ° C (Baranton et al.,

10 'above; A.H '. Haines, supra, 'Section 3.2.7) (not when A is CH = CH-CH ₃ ; when A-COOR,' where it is immediately converted to COOH);

- Silver acetate and iodine in moist AcOH at 020 ° C (K. Hanaya, supra; A.H. Haines, supra, Chapters 3.2.3, 3.2.4, 3.2.9) (Not when A is

CH = CH-CH1).

... ·· .. ». · .-

SCHEME 9

R ₈ = alkyl, aryl, heteroaryl, H or nothing P = halogen, O-tosyl, O-mesyl, OC (S) .aryl, OC (S) heteroaryl, 1-imidazolyl, OC (S) O-aryl, OC (S) Oheteroaryl

4Ϊ ·

- 30% R ₂ O ₂ in NaHCO ₃ benzonitrile at 0-110 ° C followed by LiAlH _{4 in} THF at 0-40 ° C (not when A = COOR

5, and CH-CH-CH ₃ ) (Clark et al., Austr. Journ. Of

Chem. 27, 865 (1974). 7r5 ^- r33 37 7 <r: 77 </. Jr) \ '3;rr;; r ·

Step 8f

R /; hydrogen (1-50 atm) in a suitable solvent (e.g.

EtOH) · in the presence of metallic. catalyst (eg · PdCl ₂ ) at · · -78 ° C. (when A = NO ₂ , it is immediately converted to NH ₂ ) '(Bolger et al., Tetrahedron, 23, 341, 1967).

; / R5'ė;)); ėR; .R; RRR ^ Rif / IrUR ^ · 3 c3i 7. .

Tier 8g

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

Tier 8h

0.4 M cerium trichloride heptahydrate in MeOK, in a suitable solvent (e.g. MeOH); followed by $ iaBH ₄ at 0 ° -78 ° C (WO 89/06650);

- NaBH ₄ diglyme at 0 ° C - boiling point (GP

Thakar, Indian J. Chem. 3, 74, 1965) (when A = NO ₂ , it is converted to NH ₂ );

- NaBH ₄ and AlCl _{3 in a} suitable solvent (eg THF or benzene) at 0 ° C - boiling (not until

A = COOR) (G P.Thakar, supra);

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

Simple starting materials in which W = CH ₂ and with a single bond to the 2,3-positions can be obtained 9

Reaction Scheme where A represents the same as 1

Reaction Scheme .. 9 Compounds of Reaction Scheme (i)

'42 can be obtained 6 Reaction Scheme. Compounds of formula (1) in the reaction scheme may alternatively be obtained from compounds of (2) by converting the latter to the 4-toluenesulfonic acid ester. or an ester of methanesulfonic acid, or a halogen derivative which can be converted into the thiol by the thioether derivative (1). These simple conversions can be accomplished by methods known to those skilled in the art. 9 Compounds of Reaction Scheme (2) can be obtained from Reaction Scheme (9) wherein P = OC (S) -aryl or OC (S) -heteroaryl or OC (S) O-alkyl or OC (S) ) O-aryl or OC (S) S-alkyl can be obtained by reacting (2) with compounds with suitable chlorothioformate or chlorothiocarbonate or. 1,1'-thiocarbonyldiimidazole. (J. Org. Chem., 55, 924, 1990. And Synthesis, 362, 1991 and instructions cited therein). (4)

The compounds may be obtained from compounds (1) or (3) by simple isolation reactions with bases. The compounds of (5) can be obtained in Scheme 4. 9 Substitution of Reaction Scheme for Compounds A (6) lg

The steps may be converted into substituent B as indicated in Reaction Scheme 1.

Step 9a

Renee Ni in a suitable solvent (e.g.

in isopropanol), m.p. -100 ° C.

When A is NO ₂ , it is directly converted to NH ₂ ;

triethyltin hydride in benzene or other aromatic solvent at 30-150 ° C. Other methods, e.g. nickel chloride and NaBH _{4 in} MeOH or the borane-pyridine complex in trifluoroacetic acid or

- in dichlororhetane at A1C1 ₃ , see J.March,

Advanced Organic Chemistry, page 728, 'J. Wiley and Sons, New York, 1992 and the guidance herein (not when A is CH = CH-CH ₃ ).

⁴³ ///.- {7 ·.

Step 9b

- Hydrogen-Catalyst (Reaction Scheme 8, Step 8f.) When A is N0 ₂ , it is directly (

5- is converted to NH ₂ .

Step 9c 7 / - Where P is a 0-C derivative: · / 77:7--- ./(/7 · - Tributyltin hydride or tris (trimethylsilyl) silane in the presence of aza-butyronitrile in a suitable solvent (e.g. · toluene) ) at 80-150 ° C (M.

Drescher, Synthesis, 362, 1991; 'M. Sekine, J. Org. Chem., 55, 924, 199 · - a silane (e.g., triethylsilane or diphenylsilane) in a suitable solvent (e.g., dichloromethane) at -20 ° C, in the presence of CF ₃ COOH or BF ₃ (FM Mauser, J. Org. Chem. -55, 555, 1990);

triethylchlorosilane, sodium iodide in acetonitrile; followed by Zn powder in ACOH and acetonitrile at k.t. -80 ° C (T. Morita et al.,

Synthesis, 32, 1981). Where P is a halogen or an O-S derivative:

a reducing agent (e.g., sodium cyanoborohydride in hexamethylphosphotriamide or NaBH _{4 in} DMSO) was selected according to J.March, Advanc. Org. Chem., J. Wiley, New York, 1992, Chapter 0-76, 0-77.

Tier 9d

hydrogen (1-5 atm) in a suitable solvent (e.g.

EtOH) in the presence of a catalyst (e.g. 10% Pd / C at 100 ° C)

50-78 ° C) (Sarcevic, Helv. Chim. Act, 56, 1457,

1973). (When A = NO ₂ , it is immediately replaced by

NH ₂ ); 3 / - (/ 3

- Zn and gaseous HCL in Et ₂ O or AC ₂ 0 in toluene

0 ° -80 ° C. (Toda, Bull. Chem. S © Jpn. 45, 264, 1972) (not applicable when A = NO ₂ ). .

Tier. 9e

-Zn and aqueous HCl · in a suitable solvent (e.g. EtOH). at 0-78 ° C. -1 It t / <::.

- Step 9d, above (when A = NO ₂ ) · it is directly converted to NH ₂ ); '. .

- .hydrazine, · NaOH in ethano-1,2-diol at '20.0 ° C (Chemical Abstracts, 74, (1971): 22699) (not applicable when A = COOR, NO ₂ ) or other methods based on

J.March, supra (not applicable when A = COOR, NO ₂ );

- Step 7c (not applicable when A = NO ₂ ).

The reaction scheme shows the preparation routes for compounds where W represents a valence bond and X represents an oxygen atom or a sulfur atom:

SCHEME 10

A = COOAIk, NO ₂ , CH ₃ B «COOH, NH ₂ . 46 \

Step 10a

- a la step, but employing R 4 COCl or (R ₃ CČ) ₂ O instead of R ₃ CH ₂ COCl or (R ₃ CH ₂ CO) ₂ O, with or without isolation of the intermediate phenyl ester;

- hexamethyleriotetramine. CF ₃ COOH under reflux followed by addition of aqueous HCl. If A = COOAlk, it can be hydrolyzed to * COOH under such acidic conditions, so before

Step 10c requires re-esterification with an appropriate alcohol (e.g., thionyl chloride at reflux).

Step 10b

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

Step 10c

- R ₂ CH (Hal) COOAlk in an aprotic solvent such as DMF in the presence of a base, e.g. K ₂ CO ₃ at 70-100 ° C followed by hydrolysis of the crude intermediate. strong base (e.g. KOH) in an acidic solvent

Refluxing EtOH and finally under decarboxylation-dehydration conditions using a non-acidic solvent (e.g. xylene) and an acid catalyst (e.g. p-toluenesulfonic).

-30 acid) by refluxing or quinoline heating at 240 ° C; - - R ₂ CH ₂ HalirKOH by refluxing in EtOH, followed by treatment of the isolated intermediate phenyl (thio) ether with sodium methoxide

35 ''. . In DMF / MeOH mixture. When A is COOAlk, intermediates (4) wherein A = COOH may be obtained;

'' ⁴⁷ .

- Refluxing with ArCOCH ₂ Br and K ₂ CO _{3 in} acetone affords compounds (4) wherein R ₂ = ArCO. 7 /.

5. Step 10d

- Vigorous stirring of the heated polyphosphoric acid at 90-140 ° C; b;) '

- Lewis acid · (eg · A1C1 ₃ ) chlorobenzene.e at

70-90 ° C. (3) For compounds having R ₃ = C 1, cyclization / 'is carried out with Lewis Acid 7 (e.g., AlCl ₃ ) - odichlorobenzene at 45 45 ° C or BF _{3 in} Et ₂ O -2020 ° C. Compounds of formula (5) are obtained wherein R ₃ = OH (K.

. . Davies, J.Chem. Soc. PT, Iv, 2624, 1957 for z · - compounds where X = S and R ₂ = H).

Step lOe - /) / b sodium alcoholate (1 equivalent) / in the same alcohol at 0-90 ° C; when A = COOAlk, the reaction solvent is the corresponding AlkOH;

- when R ₂ = COOAlk, X = S, (4) the compounds can be hydrolyzed to the corresponding R ₂ = COOH in a saturated acetic acid mixture (if A = COOAlk it can give

A = COOH), and can be selectively decarboxylated with copper. anhydrous quinoline at 210-220 ° C.

Compounds of (4) are obtained wherein R _{2 is} -H (J.Cooper et al., J. Chem Soc (C) 1971, 3405). · '7/7 77' the lOf7- - R ₂ CH ₂ X H and one equivalent of sodium z '. ·' EtOH reflux or NaHCO ₃ EtOH:

in water at 60-90 ° C.

35 '

The step lOg

-U

- When A = COOAlk or NO ₂ , lg Footstep methods may be used. It should be noted that the reduction of the NO ₂ group to the NH ₂ group by catalytic hydrogenation can immediately lead to the hydrogenation of the double bond at the 2-3 positions · (SL Meiseli et al., Heterocyclic Compounds, Eds. Interscience Publ .; Compounds with Condensed. page 34, (1954), and M. Ahmed, ibidem,

Interscience; Benzofurans, p.56,

Ed. Viiley (1974)). When

The reduction of A = NO ₂ and R 1 = COAr is carried out with hydrogen in the presence of Pt on a carbon catalyst to give 2,3-dihydro compounds (5) where B = NH ₂ and R ₂ = CH ₂ Ar (WO 86/07056); _z when A = CH ₃ and K ₂ , R ₃ , R ₆ are not CH ₃ , or R ₂ does not have a C H y group, the compounds may be converted to the corresponding;

A = CH ₂ Br, reacting with N-bromosuccinimide CCl ₄ and 2,2'-azobisisobutyronitrile or benzoyl peroxide catalysts under reflux; A = CHO by reacting the above compounds with hexamethylenotetramine, refluxing in chloroform followed by hydrolysis of the salt with boiling AcOH> or reacting compounds with A = CH ₃ with refluxing dichromate, chloroform. , Arzneim. Forsch., 40, 122 1990);

A = COOH by oxidation of the above compounds (A = CHO) with silver oxide in an acidic aqueous solvent mixture (e.g., EtOH-DMF at 0-70 ° C, (HR Rodriguez et al. Tetrahedron 24, 6587 (1968))) or KMnO ₄ in butanol in the presence of aqueous solution of NaH ₂ PO ₄ 'at 70-75 ° C (S. Maruzama

Tetrahedron Letters 27, 4537 (1986)).

et al.,

L T 3038 B

The compounds of Reaction Scheme (4) above wherein R ₃ = C ₆ H ₅ or t-butyl, R ₂ = H and X = O can be converted to the corresponding intermediates wherein R ₂ = C ₆ H ₅ or t-butyl , and R ₃ = H, j 'by reaction with polyphosphoric acid at

132 ° C (Davies et al., J. Chem. Soc. 1958, 822);

When X represents an nitrogen atom and W has another defined one

Step 11a

- EtOC (R ₂ ) = C (COOEt) ₂ at 80 to 140 ° C in a solvent-free or polar solvent (eg isopropanol).

Step 11b

- R ₂ COC (R ₃ ) COOAIk and p-toluenesulfonic acid or methanesulfonic acid in a chlorinated solvent {e.g. in chloroform or dichloromethane) or

5 ° in an aprotic solvent (eg benzene) under reflux under azeotropic conditions.

Step 11c

2.f

- 'heating in' Ph ₂ 0 in the presence of 7-p-toluenesulfonic acid or phosphoric acid or ZnO catalysts at 245-255 ° C (Hung. Teljies 6251 (ChemicalAbstracts, 79> 92026v, 1973));

- heating in a high boiling solvent (eg Ph ₂ 0) followed by isolation of the compounds (4). Hydrolysis of (R ₃ = COOEt) with a strong acid (eg HCl) in an acidic solvent (eg acetic acid) to boil with. reflux (4). Compounds of formula (4) are obtained wherein R ₃ = COOH. The acids isolated above can be decarboxylated by heating in a high boiling solvent (e.g. Ph ₂ 0). Compounds of (4) 7 are obtained wherein R ₃ = H (Albrecht et al., Ber. 105, 3118 (1972);

Tier 11d

- heating in a high boiling solvent (eg Ph ₂ 0) at 255 ° C;

- where R = Alk, the compounds of (4) are obtained directly from the compounds of (1) without isolation of the compounds by condensation with RjCOCH (R ₃ ) COOAlk in polyphosphoric acid at 90150 ° C (F. Piozzi et al., Gazz. Chim. .It, 100,

678, 1970).

Stage lle

The Al / Hg amalgam in aqueous EtOH solution was refluxed, then acidified with strong acid (e.g. HCl) and treated with FeCl ₃ under reflux (Vi.A. Denny et al.

J. Med. Chem., 32,

396,

1989)

- Prior to carrying out step lle (4), the compounds where A = C0QAlk _c should be hydrolyzed to the corresponding a = cooh. '

- When A = NO ₂ , intermediate (5) is obtained. , -L.

wherein A = NH ₂ ;

Tier llf

R ₂ CH = CHCHO: and j ars e no: acid in e medium (e.g. concentrated H ₂ SO ₄ ) and water at 105-115 ° C (EP 0206802).

Before proceeding with step lf, compounds of (1) with A = COOA1k should be hydrolyzed to the corresponding A = COOH. In all compounds (1) R = H and in compound (5) R ₃ = H.

Tier Ill

- R ₂ CH (Hal) -CH (R ₃ ) COOH in acidic solvent (eg water) with strong base: NaOH at 100125 ° C, followed by isolation of the β-anilinopropionic compounds. acid cycling with preheated polyphosphoric acid at 120-125 ° C or phosphorus pentoxide at high boiling point. in an aqueous solvent (e.g. xylene) at 120-140 ° C. In some cases, it is useful to start with (1) compounds wherein R = tosyl or other suitable protecting groups; the resulting compounds (6) where R = tosyl can be easily converted to the compounds (6) where R = H by hydrolysis with a strong acid (e.g. HCl) in an acidic solvent (e.g.

AcOH) under reflux.

When A = COOAlk, compounds (6) are obtained wherein A = COOH.

Step 11h /: .53 ''

- i ^ CHO and ethylene in AcOH and HCl at 25-30 ° C (K.D. Hesse, Liebigs Ann. Chem. 741, 117 (1970)).

. When (1). in the compounds R = H, the starting materials (7) are obtained in which R = R ₃ = H.

- Epiehlorohydrin followed by cyclization of the isolated anilinopropanol derivatives by refluxing with Ν, Ν-diethylaniline or o-dichlorobenzene in the presence of a proton acceptor (e.g. NEt ₃ ) (SD Boyd et al., J. Org. Chem. · 30, ' : 2801 (1965)). In this case, the resulting. (7) compounds wherein R = R ₂ = H and R ₃ = OH.

/.yy Tier Iii. γ-Hydrogenation in the presence of a catalyst (e.g., platinum oxide) in an acidic solvent (e.g., EtOH) at 20-30 ° C and 2-4 atm _: (GM Coppola, J. Heter, Chem.

. 15, 645, 1978).

When A = NO ₂ , compounds (7) are obtained wherein A = NH ₂ .

Thus, compounds (4), (6) and (7) can be converted to the corresponding derivatives wherein A = COOH or NH ₂ , in the reaction of _Step 1g.

Synthesis of simple compounds of Reaction Scheme 11 (7) wherein R = H and A = COOH can be continued using the Scheme 12 method. . . . '

Step 12a

.... , -. / y .'yyyyyy; yy, / · \ yy.y -

- pxalyl chloride in polar solvent · (e.g. THF) under reflux followed by • internal Friedel-Crafts »chlorooxalylamide

-., .. 'λ. . . acylation with Levis acid (e.g. A1C1 ₃ ) in a non-polar solvent (e.g. CS ₂ ) under reflux (EP 0402859);

54Stage 12b.

- 30-35% of an aqueous H ₂ O ₂ and · strong base (eg. NaOH) pūliniame _v solvent (eg. Water) .30 to 205 ° C and then adding a strong acid (eg. HC1) (EP 0402859).

and 14 Reaction Schemes yield simple starting materials wherein X represents an imine group and W represents a valence bond. In these two. In the reaction schemes.

A represents the same as in Scheme 1 of Reaction 1 SCEMA 12.

W-CH2 or connector 25

SCEMA-13

R'Alkil • Tier 13a

- C1CH ₂ C (Cl) = CH ₂ in the presence of K ₂ CO ₃ at 40-80 ° C (L.

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

'i.yi. / J, J to- 'T JT'B'L' ''

Step 13b

- R ₂ COHal in pyridine or in a chlorine solvent (eg dichloromethane) in the presence of a proton acceptor (e.g.

NE.t 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 to 155 ° C;

- heating at 100-110 ° C.

(5) In the compounds of step 13c, always' R 2 = CH ₃ . ':

Tier 13d

R ₂ Reduction of COCH (OAlk) _{2 in a} nonpolar solvent (e.g. toluene) under iodine catalyst under azeotropic conditions after reduction of the isolated (or non-isolated) imine in NaBH ₄ polar solvent (e.g. MeOH) in the presence of a NaOH catalyst with reflux. If A = COOAlk, it will be hydrolyzed with 3, COOH.

Step 13e. to -.- sodium amide in a high boiling solvent e.g.

N, N-diethylaniline) at 220-250 ° C (F.Pipzzi et al., Gazz. Chim. It. 93, 1382, 1963); • - Potassium t-butoxide in a polar solvent (e.g.

DMF) at 20-100 ° C (EP 0042298).

Step 13f. . - BF _{3 in a} polar solvent (eg benzene) at 5 'to 10 ° C. . . .

Tier 13g. - Zn or 'Fe dusts in acidic media (eg AcOH) and water at 70-100 ° C. If A = NO ₂ , it will be reduced to NH ₂ . 7 ^; . ^:? .

Tier 13h

- Thionyl chloride, refluxed. Chlorinated anhydrides liberated Reacts with. sodium azide in an acidic medium (e.g. AcOH) at 10-20 ° C, followed by heating at 50-70 ° C.

Step 13i Diazotization with NaNO _{2 in} Concentrated H ₂ SO ₄ , • addition of aqueous ZnCl ₂ to 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 a copper salt (e.g. .CuCl ₂ ) at 25-30 ° C. Examples of steps 13g, 13h and 13i are given (A. Aliais et al., Eur. J. Med. Chem., 10, 187, 1975).

Step 13j

- R ₂ CH ₂ NO _{2 in} polar solvent (eg base (eg n-butylamine) from acid (eg AcOH) in amounts) under reflux.

The compounds thus obtained are the corresponding derivatives,

EtOH), in the case of catalytic boiling with (5), can be converted into A = COOH or NH ₂ , 1

Reaction Schemes by Methods of Ig Step.

59 '

As regards Reaction Scheme 14, it should be borne in mind that compounds of formula (4) wherein R ₃ = H correspond to compounds of reaction scheme (5). · <SCEMA 15 ''

¹ '' b ²

Step 14a. - NaNO _{2 in} aqueous acidic medium (e.g. HCl) at -5 to + 5 ° C;

- isoamyl nitrite in a polar solvent (eg.

EtOH) at 5-10 ^u C;

Tier l'4b

an aqueous solution of SO ₂ at 0-10 ° C (Pfannstich et al., Ber. ~ 75, 1096, 1942;

- tr'iphenylphosphine and isolated phosphorus salts. heating in aqueous alcoholic HCl with reflux (Horner * et al., Ber. 85,

1073, 1953.

Step 14c

- R ₂ COCH (R ₃ ) Hal in an alkaline high-boiling solvent (e.g., Ν, Ν-diethylaniline) at 160-180 ° C, or typically without solvent heating at 180 ° C;

- R ₃ COCH (R ₂ ) Hal in polar solvent · (e.g. acetone) in the presence of a suitable proton acceptor (e.g. K ₂ CO ₃ ) under reflux followed by isolation of the B-aniline-ketone intermediate.

refluxing in freshly molten ZnCl ₂ acidic solvent (eg EtOH);

• - R ₂ CH (Hal) CN in the presence of BCl ₃ and Lewis acid (e.g. TiCl ₄ ) in an apolar solvent (e.g. benzene) under reflux followed by cyclization of the 2 amino-α-haloacetophenone compounds with a suitable reducing agent (e.g. NaBH ₄ ) in a polar medium (e.g. dioxane-water) under reflux (Sagusawa et al., J. Org. Chem., 44,

578, 1979). - / (4) compounds wherein R ₃ = H are obtained by the above method;

.61

- R ₂ COCH (R ₃ ) Hal (half equivalent) in polar solvent (eg MeOH). refluxing followed by cyclization of the isolated Schiff base intermediates with strong acid (e.g.

CF ₃ COOH) at 20-30 ° C; .. /i·''.·'.'· :.

Tier 14d

- R ₂ COCH ₂ R ₃ , when heated to 100 ° C without solvents or ..

j. ba with reflux; in a polar solvent (e.g. MeOH) followed by cyclisation of the isolated hydrazone compounds with polyphosphoric acid at 100-130 ° C, or typically by heating in ethylene glycol or aqueous formic acid or ethanolic formic acid. Yeah?

The cyclisation may also be carried out by heating in ethanolic HCl at reflux or in an AcOH / HCl reflux condenser, or in orthophosphic acid at 95-10 5 ° C, or · typically in anhydrous ZnCl ₂ at 100-220 ° C. When

A = COOAlk, compounds (4) wherein A = COOH can be obtained.

. Tier 14e: '25 ^; · '/;? //// </'. to · ', · //: /:. ,;

- Borane-pyridine complex at 0-30 ° C followed by addition of an acidifying agent (e.g. HCl);

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

- NaBH ₄ in the presence of a levis acid (e.g. AlCl ₃ ) pyridine at 0-30 ° C or alternatively in the presence of a cobalt or zinc chloride salt;

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

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

Other common techniques are described in Houlihan in Heterocyclic Compounds, part one, Ed. Wiley-Interscience: Indoles, page 462 (1972). When A = NO ₂ ,., .62. ~ (4) compounds can be reduced to the corresponding compounds (5) wherein A = NH ₂ ;

Tier 14f

NaH and RHal in anhydrous polar at 20-80 ° C; .RHal in the presence of potassium carbonate e (e.g. acetone), boiling with

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

The compounds (4) having other reactive groups, such as NH ₂ or OH, must be protected using suitable protecting groups at the end of deprotection, which may be selective in nature;

Tier 14g

RHal in the presence of alkali metal carbonates (e.g., potassium carbonate) (Houlihan in. Heterocyclic Compounds, part two Ed. Wiley-Interscience: Indoles, page 90 (1972) and in the references cited therein). /: //; γ / 'Ζ / 1 / (5) compounds having other reactive groups, -.- as NH ₂ or OH, must be protected as described above; /-...._. Tier 14h

- tetrachloro - [1,4] - benzoquinone in a polar solvent (eg ethylene glycol methanomethyl ether) refluxed;

Copper (II) chloride with pyridine under reflux (Kikugawa et al., J. Heter. Chem., 16, 1325, 1979).

. '' 63 '/'. Compounds in which R ₂ and R ₃ other than H can be reduced to the corresponding starting materials <7) by lithium aluminum hydride according to (HC Printy et al., J. Am. Chem. Soc. 3206, 1949.)

The compounds of Reaction Scheme (4) wherein R 2 = H and R ₃ = OH can be obtained from the compounds of Reaction Scheme (7) wherein R = R ₂ = H and R ₃ = OH by compression of the ring. An oxidizing agent (e.g., sodium periodate and a base (e.g., NaOH) in aqueous EtOH is used under reflux (SD Boyd et al .;

. J. Org. Chem., 30, 2801 (1965).

The starting materials (4), (5), (6) and (7) can be converted to the corresponding end products of the reaction scheme A = COOH or NH ₂ 1, Step lg, and from these alternative alternatives. 'When

J '·· *' · '- ·' · participates in NH and may turbid for subsequent reactions, it may be protected (T.W. Green in Protective Groups · in Organic Synthesis, Wiley

Interscience, 1981). Alternatively, the nonreactive groups (eg. N0 ₂₎ can be 'into (eg. NH ₂₎ in the final keliopakopoje.

. Starting materials where W represents a valence · bond / X represents an imine group and a 7-substituent a carboxymethyl group can be obtained.

SCHEME 16

A> 3 ·

Rs »H, Alk

6.5 '//

- Hydrogen in the presence of 10% Pd / C catalyst at 45 lbs in water containing 1 NaOH equivalent, followed by diazotization with sodium nitrite in HCl at 050 ° C and in tin chloride. · (The cyclization is carried out by acidification of tin salt with H ₂ S and terminated. refluxed with xylene (HE

Baumgarter et. et al., J. Am. Chem. Soc., 82, 3977, 'Ί96.0). - // 7 / //.// 7- {.

Step 15b

- R ₃ CH ₂ COR ₂ in the presence of an acid (e.g. acetic acid) in a 15 'polar solvent (e.g. EtOH) under reflux (W.J. Welstead et al., J. Med.

Chem., 22, 1074 (1979) (where R ₂ = CH ₃ and R ₃ = C ₆ H ₅ , and steps 15c and 15d are also provided);

Step 15c

- Lower alkanol (eg MeOH, EtOH) under reflux (hydrogen chloride atmosphere;

- //. '/ -' · - / 7- {/.-(/. //;

Tier 15d

- strong base (eg KOH) in polar solvent (eg water) at reflux / reflux.

. / - / 7 // {(/ (/. / - {'-. (- //' -. {(- / .- / ,, '. .. j 3 ///. {7 ^; 7. / (77--.

Of simple starting materials in which

R ₃ = hydroxyalkyl and / or the corresponding ethers, obtainable,. or 1 Reaction Schemes for (3), 2 Reaction Schemes for (2), (4) or (7), 6, 10, 11 and 15 for Reaction Scheme (4), 13 for Scheme (5) and 14

Reaction Schemes for Compounds (4) / and (6) wherein R ₃ = H, CH ₃ 16 Reaction Scheme wherein A and B have the same meaning as in Reaction Scheme 1, R ₄ represents an alkyl or aralkyl group, and Rg represents H or alkyl;

Step 16a:

R ₃ = H, W = CO _r , CS (and absent activated phenyl rings): '

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

- Chloromethyl methyl ether and fuming sulfuric acid at 50-70 ° C (H. Nakarumo et al., Bull.

Chem. Soc. Jap., 57, 2323, 1984);

R ₃ = CH ₃ , W = CO, CS, bond and no other 15 methyl groups:

- N-bromosuccinimide in the presence of benzene peroxide or 2,2-azobisisobutyronitrile CCl ₄ at 50-80 ° C;

Step 16b

R ₃ -H, W = bond, X = 6, S, NH or N-Alk and other molecules do not have electron donor groups in the rings:. ,,

Phosphorus oxychloride and DMF at 50-140 ° C, or other Vilsmeyer - Haack reagents (see Jutz, Adv.

Org. Chem., 9, 225, 1976);

R ₃ = CH ₃ , W-bond, X = 0. S, NH or N-Alk; and no other CH ₃ group is present;

- Irradiation of Hg high pressure lamp in acidic solvent (e.g. AcOH) at 20-100 ° C (Frasca et al., Tetrahedron, 23, 603, 1973).

Step 16c. -. Sodium or potassium acetate. in an aprotic solvent (e.g. acetone, DMF) at 40-120 ° C.

L.T 3038 B

Step 16d compounds (5) R ₅ = ^H:;

- Reductive hydride (e.g. NaBH ₄ ) in a polar intermediate (e.g. MeOH or EtOH or dioxane) at 080 ° C; *.

In R ₅ (5) compounds = alkyl: /

- Alkyl magnesium bromide in aprotic solvents (eg ET ₂ 0 _r THF) at 0-60 ° C;

16e

- NaOH ar. LiOH in acidic solvents (e.g., alcohols, water) or a mixture thereof at 2515 'to 50 ° C. (In this case, when A = COOAlk, it can be directly hydrolyzed to COOH);

Tier 16f

- The same methods are described in Step 1 of Reaction Scheme 1, but CH = CHCH _{3 is} oxidized to COOH (5) for compounds;

• Tier 16g

- A strong base (e.g. NaH) and R ₄ = L reagent (where L is a halogen atom or tosyloxy group) in anhydrous aprotic solvents (e.g. DMF or THF at 20-140 ° C;

Tier 16h

- R _{4 0} H and a base (eg Na, NaH) in excess of R _{4 0} H or in aprotic solvents (eg DMF or THF) to

20-140 ° C. '

The simple compounds (6) thus obtained having the hydroxyalkyl group at the 3-position can be reacted. or alternatively substituted by known -reactants and methods in the hydroxymethyl group such that above. The listed groups of 5 do not interfere with the subsequent reaction / step required for the preparation of these compounds of formula (I) protected with hydroxyalkyl groups, R ₃ .

The protected final compounds are converted to the compounds of formula (I) wherein R ₃ = hydroxyalkyl by deprotection processes.

The prodrugs described above can also be prepared by Method 1 of the corresponding hydroxy compounds or Method 2 by the corresponding amide compounds. '·

Method 1

- by reaction with chloroformate. isocyanate or izotio20 cyanate, a carbonyl chloride or bromide or another activated acid derivative (eg. an anhydride) in a suitable solvent (eg. a chlorinated solvent · DMF, THF, didksane, acetonitrile, pyridine presence of a base, or when they are not (eg. up to ₃ pyridine , 4-dimethylamino-25-pyridine, NaOH, caustic carbonate or 10-diazobicyclo undecene or other non-specific at -2 0/10 0 ° C;

- reacting with carboxylic acid in the above solvents in the presence of a condensing agent, N, N '- carbonyldiimidazole, carbodiimides or ki; those known to professionals;

by reaction with a dialkyl or diaryl chlorophosphate or a dialkyl cyanophosphonate under the conditions described above (for examples of such replacement methods see Example 114 below and S.O. Thorberg et al., J. Med. Chem., 30,

2008, 1987

Method 2 7

The prodrug derivatives of the acidic NH · groups / described in the compounds of the invention can be synthesized from the compounds of formula I reviewed in the section to give the N-hydroxy substituted methyl derivative and reacted under exactly the same conditions above for oxygen substitution.

N-hydroxy (substituted) methyl intermediate. may be isolated or directly used to obtain the desired compound. N-hydroxy (substituted) methyl derivatives of the Ny-CH (R) OH type where R ₁ = H or CCl ₃ , of the type may be prepared by reacting the corresponding compounds of formula I with formaldehyde or CCl ₃ CHO (HE Zaugg, Organic Reactions, 14, Chapter 2, 52 J. Wiley and Sons New York, 1965 or JP Chupp, J. Org. Chem., 28, 2592, 1965).

In the case where R ₁ = phenyl, the above compounds may be synthesized by reaction with benzaldehyde and a cyclic amine (e.g. morpholine) in MeOH or dichloromethane: MeOH (1: 1) at 0 ° C and boiling hydrolysis of the intermediate. product in 0.1N NCl at pH 4. {O.

Jacobseen, Annalen, 157, 243, 1884; H. Bundgaard et al. Int. J. Pharm., 22, 45, 1984).

All reaction pathways and steps described above are exemplary and do not limit the scope of the invention.

It will be appreciated by those skilled in the art that the chemical changes described above are carried out using polyfunctional media and the reagents used may interfere with other groups present in the molecule. For example, by catalytic hydrogenation it is possible to convert nitro groups to / amino groups if desired, but also to isolate the separated double bonds and remove the halogen atoms; lithium aluminum / hydride can redu-

to conjugate the conjugated ketones to the alkanes if desired (e.g., Step 7c in Reaction sequence 7) but also COOAlk. groups to CH ₂ 0.H or N0 ₂ groups to -NN and 1.1. Unwanted side reactions can be avoided or reduced by choosing the right conditions, or by using alternative reagents or different synthesis pathways. If this alternative approach produces negative results, the resulting unwanted intermediates should be converted into suitable ones known to those skilled in the art.

DETAILED DESCRIPTION OF THE RECEIPT OF THE INTERMEDIATES

8- (3-Bromopropoxy-carbonyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate I).

To a suspension of 30 g of sodium 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylate in 150 ml of dimethylformamide and 35 ml of water was added 30 g of 1,3-dibomopropane. The reaction mixture was stirred at ambient temperature for 5 days. 100 ml of water was added and stirring was continued for 15 minutes. The precipitate was filtered off with suction, washed with water and purified by silica gel column chromatography eluting with chloroform; ethyl acetate (95: 5) The collected fractions were evaporated to dryness in vacuo and the residue was recrystallized from ethanol to give 27.7 g of the title compound, m.p.

104 g of the corresponding acid, dissolved in 560 ml of hot methanol and 280 ml of aqueous 31 g 'sodium bicarbonate solution are added. To the solution was added 850 mL of acetone and the precipitated benzopyranecarboxylate salt used in the subsequent synthesis was filtered under pressure (62g, mp 280 ° C). The corresponding acid was obtained (Da Re, P. et al., J. Med. Pharm. Chem., 2, 263, 1960).

8-hydroxymethyl-3-methyl-4-oxo-2-phenyl-4H-benzopyran (Intermediate II), R 3 // 7: / - _s' .'7 / 71; '; / 7

To a solution of 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic chloride in 1 liter of anhydrous dimethylformamide was stirred at ambient temperature over 30 minutes, 467 ml of a 1.48N sodium borohydride solution in anhydrous dimethylformamide was added. Reaction mixture 2 1/2 hrs. do> s was stirred at ambient temperature while maintaining the temperature at 0-5 ° C, 88 ml of 2N hydrochloric acid was added followed by 102 ml of 12.7N sodium hydroxide. The mixture was poured into 6 liters of water, stirred for 3 hours and filtered-per

Buchner funnel. The precipitate was filtered off. washed with 4N Na hydroxide solution followed by water .. The white solid product crystallized from methanol. 50 g of the title compound were obtained, m.p. 145-147 ° C.

Ε-δ- (2-Carboxyvinyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate III)

7.92 g of 8-formyl-3-methyl-4-oxo-2-phenyl-4 H -1-benzopyran (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 mixture was stirred at 100 ° C for 3 hours. The reaction mixture was cooled to 20-25 ° C and poured. to 90g of crushed ice and 933 ml of hydrochloric acid (d = 1.18). The resulting precipitate was collected by suction filtration, washed and twice crystallized from 95% ethanol. 5.5 g of the title compound are obtained, m.p. 226-229 ° C.

E-8- (2-Chloro-carbonylvinyl) -3-methyl-4-oxo-2-phenyl-4H-130 benzopyran (Intermediate 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. The mixture was cooled to 20-25 ° C. crystals were formed, filtered under pressure, washed with acetone and dried in vacuo. The above compound '

72- / 7 /.

.crystallized from toluene,. yielding 6.8 g, m.p. (190) 196-198 ° C. .

8-Acetyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran. 5 (Intermediate V).

l, 17 g of magnesium filings, 7> 4 ml of anhydrous ethanol and 0.2 ml. anhydrous carbon tetrachloride was placed in a round flask under nitrogen. When the temperature began to rise, 7.5 ml was added. anhydrous chlorobenzene followed by slow dropwise addition for 7-25 minutes) 5.28 ml of anhydrous diethyl malonate and 3.5 ml of anhydrous chlorobenzene in 16 ml of anhydrous ethanol. The reaction flask was heated at 75 ° C for two hours, cooled to 25 ° C, and a solution of 88 ml of 3-methyl-4-oxo, 2-phenyl4H-1-benzopyran-8-carbonyl chloride (88 ml) was added slowly, not exceeding 35 ° C. , anhydrous chlorobenzene. The reaction mixture was stirred at 35 ° C for 2 'and then cooled to 0 ° C.

. · '/. ·. · - .. ..... l ·

13 ml of water and 1.9 ml of sulfuric acid (d = 1.84) were added. The resulting solution was decanted from insoluble inorganic material and desorbed in vacuo.

The resulting crude acyl malonate was refluxed for 10 hours with 10, -4 ml of acetic acid, 7 ml of water and 1.3 ml of sulfuric acid (d = 1.84). The solution was cooled, poured into iced water, and the precipitate precipitated under suction and filtered. washed with aqueous sodium carbonate. Above, the compound was crystallized from 90% ethanol to give 6.5 g of melting point.

. 159-161 ° C. .., · ,, / · .// '·' '; S '·' to // '',

8-Bromoacetyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate VI) / To a solution of Intermediate 19.5 g in 700 ml of chromoform was added 11 hours at 20-25 ° C. , 2g bromine solution in 250 ml chloroform. Stirred for 1 hour at 20LT 3038 B '5 - '73

The solution was washed with 400 mL of 2N aqueous sodium hydroxide solution and then again with water, dried over anhydrous sodium sulfate and removed in vacuo. The crude product was treated with ethyl ether, collected by filtration under pressure and crystallized from acetone, - 16 g of the title compound, m.p. 134-135 ° C.

8- (2-Hydroxyethylcarbamoyl) -3-methyl-4-oxo-2-phenyl-4H10 -1-benzopyran (Intermediate VII)

The title compound was obtained in the same manner as intermediate XXXVI, but instead

3-aminopropanol using 2-aminoethanol. Melting ·

15. 206-208 ° C.

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

15g of 8-amino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Da Re, P / et al., II. Farmaco (Ed. Sci.), , 670, 1956) 150 ml of a solution of hydrochloric acid (d = 1,18) was added dropwise to a solution of 4,55 g of sodium nitrate in 12 ml of water. Stirring was continued for 30 minutes at 0 ° C. After 10 minutes at -5-0 ° C, the solution was poured into 120 ml of a 30% by weight solution of sulfur dioxide in acetic acid containing 1.53 g of copper chloride dihydrate and 13 ml of water. The mixture was kept for one hour at 0 ° C and for one hour at 20-25 ° C, followed by the addition of 300 ml of ice water. The precipitate was collected by suction filtration, washed with water and dried in a desiccator with sodium hydroxide to constant weight. 18g of the crude title compound was obtained, .lyd.t. 165-170 ° C, which was used without further purification.

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

This compound was obtained in the same manner as Intermediate XI, but employing l-bromo-3-chloropropane in place of l-bromo-2-chloroethane. Wash with petroleum ether: ethyl ether (7: 3), m.p. t. 98-102 ° C.

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

To a stirred solution of 5 g of 8-amino-; 3-methyl-4-oxo-2-phenyl-4H-10-benzopyran and 3 ml of triethylamine in 60 ml of anhydrous tetrahydrofuran was added 1.75 ml of acrylic chloride solution at -10 ° C. ml of anhydrous tetrahydrofuran The reaction mixture was stirred at 0 ° C for 1 hour and then at ambient temperature for 1 hour, after which the mixture was poured into water and filtered under pressure. The filtrate was washed with water and dried. 5.5 g of the title compound are obtained, m.p. 229-230 ° C.

8- (2-Chloroethoxy) -3-methyl-4-oxo-2-phenyl-4H-1,20 benzopyran (Intermediate XI)

7.52g of 8-hydroxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Da Re, P. et al., Ann. Chim. 1962, p. 506 et seq.). ), A mixture of 6.22 g of anhydrous potassium carbonate and 25.5 ml of 125 bromo-2-chloroethane in 70 ml of dimethylformamide was stirred at 60 ° C for 25 hours. The mixture was cooled to 20-25 ° C and poured into 600 ml of water. The organic solution obtained by extraction with dichloromethane was washed with aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvents and excess l-bromo-2-chloroethane were evaporated in vacuo. 8.8 g of the title compound is obtained which is crystallized from chloroform: hexane m.p. 141-142 ° C. '

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

^; '? ·' / · /

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. · The reaction mixture was cooled to 20-25 ° C, then poured into 1 1/2 liters of water and extracted with dichloromethane. The organic solution was washed with aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvents were evaporated in vacuo. The sediment was placed in water, collected by filtration under pressure and dried. 14g of the title compound is obtained, m.p. 119–120 ^θ Ο.

8- (N- (2-Hydroxyethyl) -N-methyl'-carbamoyl / -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran '(Intermediate XIII)

To a suspension of 6 g of 8-chlorocarbonyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran and 1.52 g of potassium carbonate in 60 ml of acetone was added 1.6 ml of 2-methylamino-ethanol in 10 ml in 5 minutes. water solution. The mixture was stirred at 20-25 ° C for 2 1/2 hours, then the solvent was removed in vacuo and the residue was taken up in 150 ml of acetone. The mixture was refluxed for 15 minutes, then filtered. The solvent was evaporated and the residue was dissolved in 20 ml of dimethylformamide, treated with 14 ml of 1.4% sodium carbonate solution at 20-25 ° C for 30 minutes and diluted with 150 ml of water. The mixture was stirred extracted with chloroform and the organic layer was washed with 0.5N hydrochloric acid followed by water. The solution was dried over anhydrous sodium sulfate and the chloroform evaporated. The resulting oil was added to 200 ml of ethyl ether and stirred at 20-25 ° C for 2 hours. The other particles were collected by filtration and crystallized from ethyl acetate. 4.97 g of the title compound, m.p. 128-130 ° C.

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

The title compound was obtained in the same manner as Intermediate XXXVII but using Intermediate VII instead of Intermediate XXXVI and reaction at ambient temperature. Melting point 181-182 ° C (ethyl acetate)

8- (N-Methyl-2-chloroethylcarbamoyl) -3-methyl-4-oxo-2-phenyl-4H-1-bis-isopyran (Intermediate XV)

To a solution of 3.37 XIII Intermediate in 20 ml of dichloromethane was added 1.1 ml of tonylbis chloride in 2 ml of dichloromethane. The mixture was stirred at ambient temperature for 4 hours. The solvent was removed and the resulting oil was poured into ethyl ether. The white solid was obtained by filtration and further used without purification. Melting point (118) 126-128 ° C (ethyl ether).

8- (4-Bromobutoxy) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XVI) g 8-Hydroxy-3-methyl-4-axo-2-phenyl-4H-1- benzopyran,

A mixture of 4.2 g of anhydrous potassium carbonate and 43.6 g of 1,4-dibromobutane in 45 ml of dimethylformamide was stirred at 75 ° C for 2 hours. The mixture was cooled to 20-25 ° C, poured into 100 mL of water and extracted with dichloromethane. The organic solution was washed with aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvents and excess 1,4-dibromobutane were evaporated in vacuo. The residue was washed with 55 ml of light petroleum: ethyl ether (7: 4) and collected by filtration under pressure. Yield: 5.6 g, m.p. 91-92 ° C.

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

This compound was obtained by the preparation of intermediate XVI using 1,5-dibromopentane instead of 1,4-dibromobutane.

The crude product was purified by chromatography on silica.

column, eluting with dichloromethane: ethyl acetate (99: 1), the product was washed with petroleum ether: ethyl ether (30: 4), m.p. 75-75 ° C '-8- (2-Chloroethoxymethyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XVIII)'

To a stirred solution of 23 g of Intermediate XXII and 11 ml of triethylamine in 185 ml of chloroform are added. At 0 ° C was added 6. mL of thionyl chloride in 18 mL of chloroform. The reaction mixture was heated to 70 ° C and stirred for 2 hours. The mixture was cooled to ambient temperature and then poured into water. The organic layer was separated, washed with sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. Yield: 24g of the titled compound. The sample was crystallized from ethanol, m.p. 102-103 ° C.

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

53, 4g II Intermediate and 38.8 mL of triethylamine anhydrous were dissolved in 440 mL of chloroform. «... to this. 19.8 ml of thionyl was added dropwise while maintaining the solution at -10-2 ° C

-chloride 80 ml anhydrous chloroform solution. The reaction mixture was stirred at ambient temperature for 4 hours, then diluted with 400 mL of water. The aqueous phase was extracted with chloroform, and the extracts were added to the chloroform phase. The chloroform solution was washed with brine, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. Yield: 56g of the title compound recrystallized from ethanol, m.p. 112-113 ° C.

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

')' RTRj '/' ORABE) 7AR) Jr '

To a stirred mixture of 58.8g of 8-formyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran in 60.7g of methylamido hydrochloride and 125 ml of triethylamine in 600 ml of anhydrous methanol was added 15, Ig. anhydrous zinc chloride and 14.5 g, 5 sodium cyanoborohydride. 400 ml of anhydrous methanol solution. After stirring at 20-25 ° C for 5 hours, the solvent was evaporated in vacuo and the residue was poured into? 3 R'R '3 R.'; 7Ry. A5RRr <R.R7. ^: R; ;;). · '3A A / R - 73 R3 ^; '•''/ RR · R' - '· /. ·.' A '7.Rr7;'. .Ar) Rr R ·?. y77R RA R ·. IR ·. R '. · R7 *:

200. ml of water and collected by filtration under pressure. The crude product was dissolved in aqueous acetic acid, washed. ethyl acetate and re-precipitated by adding cold 6N sodium hydroxide solution. The precipitate was crystallized from -75% ethanol. 49 g of the title compound are obtained, m.p. 97-99 ° C.

R. Is R 3 R. ^ 'R) R:' 3 R R 3 R'A 77 R 3 R A ^; 7a./:3'r3 _v RrRr; .r /) 3, 'rRR R RrA' r '\ R7..r. 3r?). R) r'RR ', rR ·' · R '.R _v RrR ·

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

37g. Intermediate XIX and '10.5g thiourea solution in 370 ml ethanol refluxed

1 hour. The reaction mixture was cooled to ambient temperature. 42 g of 8 amidinothiomethyl-3-methyl-4-oxo-2-phenyl-4 H -1-benzopyran crystallized spontaneously. The sample was recrystallized from ethanol, m.p. 233235 ° C.

To a vigorously stirred suspension of 35 g of the title compound and 1.05 g of benzyl triethylammonium chloride are added 440 ml of 1,2-dichlooethane. 48 ml of 35% aqueous sodium hydroxide solution was added. The mixture was stirred for 2 1/2 hours and then poured into 300 mL of water. The aqueous layer was extracted with 1,2-dichloroethane and the extracts were placed in an organic layer which was washed with brine, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The precipitate was crystallized from methanol to give 22 g of the title compound, m.p. 82-83 ° C.

'' / felT: ³ ® ³⁸⁶

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

A solution of 2.5 g.XIX Intermediate in 25 ml xylene 5 and 3 ml dioxane was prepared. 0.15 g of sodium was dissolved in 3.10 r.l · l of anhydrous ethylene glycol and this solution was added dropwise at ambient temperature to a solution of XIX-Intermediate. The mixture * was heated to reflux for 5 1/2 hours, then cooled. to ambient temperature and poured into 50 ml .. of water. The mixture was extracted with dichloromethane and the extract was washed with brine, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The solid precipitate was crystallized from ethanol to give 2.1 g of the above.

of the compound, m.p. 132-133 ° C.

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

To a solution of 5 g of B-amino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran in 50 ml of anhydrous dichloromethane was added -9.5 ml of trifluoroacetic anhydride in 20 ml of anhydrous dichloromethane. solution. Reaction mixture 2h. stirred at 20-25 ° C and then poured into crushed ice. The organic layer 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 crystallized from ethanol to give 5.2 g of the title compound, m.p. 175-176 ° C.

z .....

8-Aminomethyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XXIV) ³⁵

A mixture of 21 g of intermediate XXIX and 19 g triphenylphosphine in 160 ml of tetrahydrofuran was stirred at ambient temperature for 8 hours. A thin chromatographic slide indicated the disappearance of intermediate XXIX. 3 ml of water was added and stirring was continued for 24 hours. The solvents removed in the rotary evaporator, and when dissolved in water, are converted to the precipitate by acetate. The aqueous solution was washed with ethyl acetate; basified with 37% sodium hydroxide solution and filtered through a Buchner funnel. The filtered precipitate was washed with water and dried. 18 g of the title compound were obtained. The hydrochloride was recrystallized from ethanol, m.p. 25610 258 ° C.

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

To 26.2 g of intermediate XXI in 300 ml of glacial vinegar <

acid at 40 [deg.] C., 41.6 ml of aqueous 30% hydrogen peroxide was added dropwise over 20 minutes. The mixture was heated to 60 ° C, stirred at that temperature for 4 1/2 hours, cooled to ambient temperature and poured into 60 ml of water and filtered through a Buchner funnel. The filtered precipitate was washed with water and dried to give 29, 4g of the title compound. The sample crystallized from ethanol, l.t. (89) 159-161 ° C.

8- (2-Chloroethylsulfinylmethyl) -3-methyl-4-oxo-2-phenyl-4 H -1-benzopyran (Intermediate XXVI)

To a solution of 12 g of the intermediate in 84 ml of glacial acetic acid solution was added rapidly at 10 ° C 36 ml of aqueous .30% hydrogen peroxide. The reaction mixture was stirred at ambient temperature for 4 hours and then poured into 220 ml of water. The title compound was collected by filtration under reduced pressure, washed with water and dried. Yield: 12.4 g. 142-145 ° C (methanol).

8- / N-Methyl-o2-phenyl-4H-x-x »-isopropoxane iaavxx ladder prototype;

A mixture of 22 g of intermediate XX, 66 ml of l-bromo-2-chloroethane 5-i, in anhydrous potassium carbonate in 88 ml of dimethylformamide was stirred at 20-25 ° C for 12 hours. The mixture was then poured into 600 mL of water and extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous sodium and acidified with ethanol

HCl. . The solvent and excess l-bromo-2-chloroethane were distilled off in vacuo at 70-80 ° C. The precipitate was poured into cold 1N aqueous sodium hydroxide solution and extracted with dichloromethane. The organic solution was washed with water, dried over anhydrous sodium sulfate and.

dry evaporated at 25-30 ° C. The crude title compound was purified by column chromatography over silica gel eluting with ethyl acetate: petroleum ether (7: 3). 18 g of the title compound is obtained, which is crystallized from ethanol, m.p. 118-120 ° C.

1- (2-Hydroxy-2-methylpropyl) -4- (2-methoxyphenyl) piperazine (Intermediate XXVIII). 7g. 1- (2-Methoxyphenyl) -piperazine, 7.33 g anhydrous

A mixture of 2.5% potassium carbonate, 1.75 g potassium iodide and 5.6 ml 1-chloro-2-methyl-2-propanol was stirred at 70 ° C for 90 minutes and at 90 ° C for 6 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate, dried over anhydrous. sodium sulfate, evaporated to dryness in vacuo and crystallized from ethanol.

The hydrochloride of the title compound was obtained in the form of an oil, m.p. 225-227 ° C.

A solution of 22 _{g of} Intermediate XIX and 6.8 g of sodium azide in 110 ml of dimethylformamide was stirred at 100 ° C for 3 hours. The solution was cooled. 130 mL of water and 88 mL of ethanol were then added to ambient temperature. After 1 hour, the crystals were collected by vacuum filtration, washed with water, and dried. Yield: 22 g of the title compound. The sample was recrystallized. of ethanol, melting point 132-134 & C. '

8- (K- (2-Hydroxyethyl) -aminoethyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XXX)

To a stirred mixture of 9.24g of 8-formyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran and 9.12g of ethanolamine was added 2.38g of anhydrous zinc chloride and 2.30g of sodium cyanoborohydride in 90 ml of anhydrous methanol. 71 ml of anhydrous methanol. The mixture was stirred for 5 hours at 20-25 ° C and then the solvent was removed in vacuo. To the precipitate was added .25.0 ml of water, insoluble material was collected by filtration under pressure and washed with water. The crude product was dissolved in 1N acetic acid and the solution was washed with ethyl acetate. 2N sodium hydroxide solution, the precipitate was collected by suction filtration, washed with water and dried at 6 ° C. 8.5 g of the title compound is obtained, m.p. 117-121 ° C.

8- (N-methyl-N-chloroacetylaminomethyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XXXI)

To 2 g of intermediate XX and 10 ml of triethylamine in 200 ml of 1,2-dichloroethane solution at -5-0 ° C was removed 6 ml of chloroacetyl chloride in 60 ml of 1,2-dichloroethane solution. The reaction mixture was stirred at 20-25 ° C for 2 hours. , 150 ml of water were added and the phase separated. The organic phase was washed with water and dried

Anhydrous sodium sulfate of the title compound, m.p. 146-148 ° C.

8-Chloroacetamidomethyl-3-methyl-4-oxo-2-phenyl-4H-15-benzopyran (XXXII Intermediate) ·

3.2 L was added dropwise to 10 g of intermediate XXIV - 5.5 ml triethylamine in 80 ml * 1,2-dichloroethane. ml of chloroacetyl chloride in 32 ml .1,2-dichloroethane solution. The reaction mixture was stirred at ambient temperature for 1 hour, then 150 mL of water was added. The phases were separated; the aqueous phase was extracted with 1,2-dichloroethane and the extracts were combined with the organic phase, which was washed with cold saturated sodium.

bicarbonate solution, washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The precipitate 'crystallized from ethanol to give 10.7 g of the title compound, m.p. 152-155 ° C.

8- (N-Acetyl-N- (2-chloroethyl) -aminomethyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XXXIII). 8.65 g of XXX Intermediate and 4.15 ml of triethylamine were dissolved in 70 ml of tetrahydrofuran. To this mixture was added dropwise a solution of 2.35 mL of acetyl chloride in 23 mL of tetrahydrofuran at -10 ° C over 40 minutes. The mixture was stirred at 0-10 ° C for 3 hours and at 2025 ° C for 2 hours, after which the solvent was evaporated in vacuo. The residue was taken up in 100 ml of water, extracted with dichloromethane, the extracts combined one by one and the solvent removed in vacuo. The precipitate was dissolved in 50 ml of methanol and 3 g of potassium carbonate, 10 ml of water were added and the mixture was stirred at 50 ° C for 20 minutes.

The resulting N, O-diacetyl derivative was hydrolyzed by removing the solvent in vacuo and treating the precipitate with water and dichloromethane as described above.

The dichloromethane solution was again evaporated to dryness to give

5.9 g of 8- (N-acetyl-N- (2-hydroxyethyl) -aminoethyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran. melts -171-172 ⁰ C. To

To a solution of 6 mg of the resulting compound in 70 ml of dichloromethane was added 3.6 ml of thionyl chloride in 30 ml of dichloromethane at 0 ° C. The reaction mixture was stirred at 20-25 ° C for 90 minutes, washed with water and dried. The solvent was removed in vacuo. The crude title compound was obtained and was used without further purification.

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

To a solution of 6 g of intermediate VIII in 70 ml of acetic acid was added 20 mg of tin chloride dihydrate in 18 ml of hydrochloric acid (d = 1.18) over 5 minutes at 65 ° C. After 10 minutes, the reaction mixture was cooled to -30-35 ° C and the solvent removed in vacuo. The precipitate was poured into water and the insoluble material was collected by filtration under pressure, washed with water and dried. 3.2 g of 8-mercapto-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran are crystallized from ethanol, m.p. 115-118 ° C.,.

8 g of the compound prepared, 27 ml of l-bromo-3-chloropropane,

A mixture of 0.2 g of tetrabutylammonium bromide and 6.22 ml of 35% sodium hydroxide in 80 ml of benzene was stirred vigorously for 4 hours at 20-25 ° C. 100 ml of water and 40 ml of dichloromethane were added. The organic layer was separated, washed with water, and dried over anhydrous sodium sulfate. The solvents and excess l-bromo-3-chloro-propane were removed in vacuo. The residue was purified by chromatography on a silica gel column eluting with petroleum ether: ethyl acetate (9: 1) to give 5.7 g of the title compound. The compound was crystallized from methanol, m.p. 84-86 ° C.

'

8- (3-Chloropropylsulfonyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (XXXV Intermediate) into 3.45 g of intermediate XXXIV in 35 mL of acetic acid solution at 20-25 ° C was added with 7 mL of 30% hydrogen pSroxide. The reaction mixture was stirred at room temperature for 4 hours

60 ° C, cooled to 20-25 ° C and made up to 30 ml with water. The resulting precipitate was collected by suction filtration, washed with water and dried to give

3, 4g. of the above compound. The compound was crystallized from acetone, m.p. 160-163 ° C.

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

To a suspension of 30 g of 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carbonyl chloride and 15.2 g of potassium carbonate in 400 ml of acetone was added 7.6 ml of 3aminopropanol in 50 ml of water over 30 minutes, solution. The thick suspension was stirred at 20-25 ° C for 3 hours. The solvents were removed in vacuo and the precipitate was poured into 300 mL of water for 1 h with stirring. The resulting precipitate was collected by filtration under pressure and washed with water. The weightless product was purified by crystallization from 95% ethanol.

23.8 g of the title compound are obtained, m.p. 191193 ° C. The crystallization filtrate was concentrated in vacuo to give an additional 4.7 g of the title compound.

8- (3-Chloropropylcarbamoyl) -3-methyl-4-oxo-2-phenyl-4H-130 benzopyran (XXXVII Intermediate)

To a boiling solution of 3.37 g of intermediate XXXVI in 20 ml of chloroform was added 1.1 ml of thionyl chloride in 2 ml of chloroform. The solution was stirred for 90 minutes, the solvent was evaporated in vacuo at reflux and the precipitate crystallized from acetonitrile.

! '86

3g of the pure compound of the title compound, m.p. (188) 193-194 ° C.

8- [1-Hydroxy-4- (4-methylphenylsulfonyloxy) -butyl] -35-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XXXVIII)

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 p10 toluenesulfonic acid in 20 ml of tetrahydrofuran are stirred at 20-25 ° C. 30 ml of 1,2-dichloroethane mixture was added 1.12 g of sodium cyanide in 3 ml of water. The reaction mixture was refluxed for 4 hours, followed by the addition of 10 ml of cold water. Tetrahydrofuran was distilled off under normal pressure and 10 ml · 1,2-dichloromethane and 10 ml chloroform were added. The organic phase was separated, washed * with aqueous sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The precipitate was suspended in ethyl ether, filtered 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. To a stirred suspension of 22.8 g of the compound obtained at ambient temperature in 520 ml of anhydrous tetrahydrofuran was added 3.5 ml of a 30% solution of potassium hydroxide in anhydrous methanol. 6.3 ml of acrylonitrile in 20 ml of tetrahydrofuran were added dropwise and the reaction mixture was stirred at ambient temperature for 1 hour. The solvents were evaporated in vacuo and the residue crystallized from methanol. Received

23.22g .8- (1,3-Dicyano-1-morpholino-propyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran. 23.2g of the resulting compound. dissolved in 250 mL of dioxane. 250 mL of 6M hydrochloric acid was added and the mixture was refluxed for 2 1/2 hours. The mixture was cooled to ambient temperature, poured to 700. ml of aqueous sodium chloride solution and extracted with ethyl acetate. The extracts were washed with aqueous sodium chloride solution and exposed

700. ml of 1M sodium hydroxide solution. The aqueous layer was washed with ethyl acetate and acidified with 37% hydrochloric acid. The precipitate was collected by suction filtration and crystallized from ethanol. 10.2 g of 8 '. (3-carboxy-1-oxopropyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, m.p. 191-192 ° C.

2.1 ml of freshly distilled boron trifluoride diethyl ether in 10 ml of anhydrous diglyme were added dropwise to a solution of 19 ml of 66 M sodium borohydride in diglyme and the resulting diborane was added to 2.28 g of the product obtained. 23 ml of anhydrous tetrahydrofurar suspension and stirred under nitrogen atmosphere at 0 ° C. The mixture was further stirred at 0 ° C for 20 minutes and at ambient temperature for 20 minutes. Methanol was carefully added to the mixture at 0 ° C, and the reaction was stopped. The solvents were evaporated in vacuo and the residue was purified by silica gel column chromatography eluting with petroleum ether: ethyl acetate (3: 7). The collected fractions were evaporated in vacuo to give 2g of 8- (1,4-dihydroxybutyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, m.p. 133-134 ° C.

To a stirred solution of 3.17 g of the title compound in 32 ml of anhydrous pyridine was added 2.8 p-toluene sulfonyl chloride at 0 ° C. The mixture was stirred at 0 ° C for 6 hours and left overnight at -4 ° C without stirring. It was then poured into 200 ml of aqueous sodium chloride solution, acidified with 10 ml of 12N hydrochloric acid and filtered under pressure. The filtered precipitate was dissolved in chloroform, and the solution was washed with aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off in a rotary evaporator. The residue was purified by silica gel column chromatography eluting with petroleum ether: ethyl acetate (1: 1). The collected fractions were evaporated to dryness in vacuo to give 3.04 g of pure title compound, m.p. 123-124 ° C. / - /// - ^7, Ό ⁷ · / -; ^{7 '77} - ⁷ ,. ⁷ / '- /''/; .

4- / 4- (2-Methoxy ifeni1) -1-piperazinyl] -butyric anhydride (XXXIX Intermediate)

A solution of 5.4 g of 2- (3-cyloropropyl) dioxolane and 15.9 g of 1- (2-methoxymethylphenyl) -piperazine in 60 ml of dimethylformamide was stirred at 80 ° C for 4 hours. The reaction mixture was cooled to. 20-25 '° C, poured into 500 mL of ice-cold 0-, 5 N sodium hydroxide solution and extracted with dichloromethane. The organic phase was washed with water and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was chromatographed on a silica gel column with methane: ethanol (95: 5). 9.8 g of 2- {3- / 4- (2-methoxyphenyl) -1-piperazinyl / propyl) -dioxolane oil were obtained.

NMR CDC1 ₃ (δ)

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 (1H, t, OCHO)

6.7- 6.9 (4H, m, aromatic protons) cleaned chromatoišplaunant dichloro12,8 resulting compound 2.00 mL of tetrahydrofuran and '420 ml of 1N hydrochloric acid was maintained 24 hours at 25 20 25 ^Ci C' It was then basified with 5N sodium hydroxide solution and immediately extracted 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 column chromatography. eluting with dichloromethane on silica gel with methanol (97: 3). 6.4 g of the title compound oil are obtained.

NMR, CDCl ₃ (δ) 1.5-2.0 (2H, m, CH, CH, CH) 2.2-2.8 (8H, / 3 '? x CH, N and CH, CHO) 2.9-3.2 <4H, m, 2 x CH ₂ NAr) 3.8. (3H, s, OCH ₃ )

LT 3038 R

6.8 (4H, s, aromatic protons)

9.3, (1H, s, CHO)

8-; (2,3-Epoxypropoxy) '3-methyl-4-oxo-2-phenyl-4H-15 benzopyran (XL Intermediate)

To a stirred mixture of 5g of 9-hydroxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran and 9.7 mL of 2N sodium hydroxide in 10 mL of ethanol was added 7 mL of 2,310 epoxypropyl chloride at 20-25 ° C. The reaction mixture was kept at -20-25 ° C for 6 hours, then poured into 100 ml of water and the resulting 'precipitate *' collected by filtration under pressure. The precipitate was dried and purified by silica gel column chromatography (petroleum ether: ethyl acetate (65: 65)). 35): 4.45 g of the title compound is obtained, m.p. 128-129 ° C.

8- N -methyl-2- (4-methylphenylsulfonyloxy) -ethylsulfamoyl / 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran '(XLI. Intermediate)

To a mixture of 2.5 ml of 2-methylaminoethanol and 2.1 ml of triethylamine in 20 ml of dichloromethane was added a solution of 5 g -VIII Intermediate in 60 ml of dichloromethane and 20 ml of tetrahydrofuran at 0 ° C. The reaction mixture was stirred for 2 hours at 20-25 ° C, followed by addition of 100 ml of water and 100 ml of dichloromethane. 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 chromatography on a silica gel column eluting with petroleum ether: ethyl acetate (3: 7) and crystallized from ethanol. 4.5 g of 8- (N-methyl-2-hydroxyethylsulfamoyl) -3-methyl-4-oxo-2-phenyl-4H-17-benzopyran are obtained, m.p. 146-147 ° C.

..7-7755 / 7 /: ^,? 7: -7-. - 7/7 /. ^; 7: 77--7 '/—/'.//' 7The compound thus obtained was converted to the above compound by treatment with p-toluenesulfonyl as described below.

XLII The intermediate is in the second step. The above compound was used without purification.

. 8- (2- / 4-Methyl-phenylsulfonyloxy) -ethylsulfamoyl / -3-methyl-5-oxo-2-phenyl-4H-1-benzopyran (Intermediate XLII)

To a mixture of 2.5 ml ethanolamine and 2.5 ml triethylamine 25 ml. of tetrahydrofuran at 0 ° C 5 g VIII

Intermediate in 37 ml tetrahydrofuran solution. The reaction mixture was stirred at 20-25 ° C and then poured into 400 mL of water. The resulting precipitate was collected by suction filtration, washed with water, and air dried to give 4.6 g of 8- (2-hydroxyethylsulfamoyl) -3-methyl-15-pxo-2-phenyl-4H-1-benzopyran. . The compound was crystallized from ethyl acetate, m.p. 186-187 ° C.

To a solution of 3.6 g of the resulting compound in 25 ml of pyridine was added dropwise 2.1 g p-toluenesulfonyl chloride at 0 ° C. The reaction mixture was kept at 20-25 ° C, then slowly poured onto crushed ice with a slight excess of hydrochloric acid · The resulting precipitate was collected by suction filtration, washed with water and crystallized from ethyl acetate. 4.9 g of the title compound are obtained, m.p. (163) 166-169 ° C.

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

A solution of 17 g of 3- (2-methyl-2-propoxycarbamoyl) -propylamine (Saari, WS et al., J. Med. Chem., 33, 97, 1990) and 13 ml of triethylamine was stirred at 0-10 ° C. 21.6 g of a solution of 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carbonyl chloride in 250 ml of anhydrous tetra35 hydrofuran were added. The reaction mixture was stirred at ambient temperature for 2 hours, then poured into water and filtered to give 12.3 g of 3- (2-methyl-2-propoxy3038 B).

carbamoyl) ^{-propyl-3-methyl-4-oxo-2-phenyl-4H-i} benzopi- ran-8-carboxamide which was recrystallized from ethanol _. Melting point 178-180 ° C.

To a stirred solution of 3.3 g of the title compound in .35 ml of anhydrous.

in dichloromethane at -5 ° C was added dropwise 4.3 ml of trifluoroacetic acid in 15 ml of anhydrous _{dichlprometano%} The mixture was warmed to ambient temperature and then stirred for 8 hours. Dichloromethane and Trifluoroacetic

- excess acid · distilled at 20-25 ° C on a rotary evaporator. The fat precipitate 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 ethanol HCl was added to the filtrate. The precipitate was crystallized from ethanol to give 1.5 g of the title compound, m.p. 253-255 ° C.

8- (2-Chloroethylureido) -3-methyl-4-oxo-2-phenyl-4H-120 benzopyran (Intermediate XLIV)

To a stirred solution of 8-amino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (3.9 g) was added 4 ml of 2-chloroethyl isocyanate (52 ml) in o-toluene-dimethylformamide. Stirring was continued for 5 hours at 70 ° C. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic phase was evaporated to dryness in vacuo. The precipitate was suspended in ethyl ether with stirring. The above product was then filtered off and recrystallized from methanol. Yield: 3.74 g. 213-214 ° C.

(Z, E) -8- {4- / 2- (1,3-Dioxanyl) -3-methyl} -4-oxo-2-phenyl-4 H -1-benzopyran (XLV Intermediate)

To a solution of 1.5 g of 2- / 2- (1,3-dioxanyl) / ethyl triphenylphosphonium bromide in 10 ml of anhydrous tetrahydrofuran was added dropwise 1.6 ml of 2.5 N N-butyl lithium in hexane at -20 ° C.

The mixture was stirred at -2 ° C for 20 minutes. A solution of 0.8 g of 8-formyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran in 11 ml of anhydrous tetrahydrofuran was added to the mixture, which was then heated to 0 ° C for 90 minutes and then 30 minutes to ambient temperature. The solvents were evaporated in vacuo and the residue was purified by silica gel column chromatography eluting with ethyl acetate: petroleum ether (3: 7). The title compound was obtained, a mixture of E and Z diester stereoisomers, mp (93) 98-100 ° C. The ratio of the two isomers was determined by NMR spectroscopy and is equal to E: Z = 65: 35. -

NMR, CDCl ₃ (δ) 8.1-8.2 (m, IR, CH at the 5th benzopyran ring 15th position)? 7.2-7.8 (m, 7H, other benzopyran and phenyl IBSi® ring aromatic groups) 6.9 (dt, 1H, Fl »-CH E isomer) .6,8 (dt 1H, F1 * -CH a isomer) 20th 6.4 (dt, 1H, F1 * - CH-CH E isomer) 5.9 (dt, 1H, F1 - CH = CH isomer) 4.6-4.7 (m, 1H, OCH ₂ O) 3.6-4.2 (m, 4H, OCH ₂ Q dioxane ring) 2.4-2.7 (m, 2H, CHCH, CH) 25th 1.9-2.3 (m, 5H, CH ₃ and CH ₂ in the 5th dioxane oil position)

8- {4- / 2- (1,3-dioxanyl) -butyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate XLVI)

A mixture of 0.2g of 10% palladium-on-carbon catalyst and 1g of XLV Intermediate in 24 ml of methanol was hydrogenated in a Parr apparatus at ambient temperature under 1.5 atmospheric hydrogen. After the theoretical consumption of hydrogen, the catalyst was filtered off and the solvent evaporated in vacuo. The precipitate crystallized from cycle35 ./: / 7 /: 93 //:.

hexane to give the title compound, m.p. 118119.5 ° C.

8-; Carboxymethyl-3-methyl-4-oxo-2-phenyl-4H-15-benzopyran (Intermediate XLVII)

2.76 g of 8-allyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (P. Da Re, U.S. Pat. No. 3,350,411) were stirred at 0-10 ° C. 0.17 g Aliquat 336, 1.12 ml acetic acid, '56 ml dichloro10 methane, 3.2 ml. sulfuric acid (d = l, 84) and 60 mL water · 4.5 g potassium permanganate was added portionwise over 1 1/2 hours. After stirring for additional 5 hours at ambient temperature, 3.4g of sodium metabisulfite was added portionwise over 15 minutes. The organic layer was separated, washed with water and extracted with 60 mL of 1 N aqueous sodium hydroxide solution. The aqueous phase was acidified, diluted with hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness in vacuo. The precipitate was treated with carbon tetrachloride and the solids collected by filtration under pressure. The title compound was obtained. M.p. 191-192 ° C (acetonitrile).

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

The title compound was obtained by the preparation of intermediate X, using 430 chlorobutyryl chloride in place of acryloid chloride. The water was filtered off and the solid was dried, washed with hot ethyl ether and collected by filtration under pressure. The title compound was obtained. The sample was crystallized from 50% aqueous ethanol and washed with ethyl ether, m.p.

at (153) 162-164 ° C.

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

To a stirred 0 _t 045g of sodium hydride (80% mineral oil) suspension at -5 ° C was added dropwise Q 5 g of Intermediate XXIII in 1.5 ml of anhydrous dimethylformamide. After stirring for 1 hour at room temperature, 0.092 ml of methyl iodide was added dropwise to 0.6 ml of anhydrous dimethylformamide. The reaction mixture was stirred at 50 ° C for 1 hour, cooled to 20 ° C, poured into water, filtered under pressure and dried at 60 ° C for 3 hours. 0.6 g of 8- (N-methyl trifluoroacetamide) -3-methyl-4-oxo-2-phenyl-4 H -1-benzopyran is recovered;

NMR (CDCl ₃ , 8.15

7.10-7.60 3.30 2.10 (δ)) (dd, 1H, benzopyran CH (m, 7H, other benzopyran (s, 3H, CH ₃ -N)) (s, 3H, benzopyran CH ₃

5) and phenyl CHs)

3)

A mixture of 0.44 g of the title compound and 0.05 g of 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. The ethanol was evaporated in vacuo, the precipitate was washed 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 precipitate crystallized from ethanol. 0.22 g of the title compound is obtained, m.p. 143-146 ° C.

8- (N-Methylacrylamido) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate L)

This compound was prepared in the same manner as Intermediate X using 8-amino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran using the XLIX intermediate and the

^ .Τ3038Β evaporation in vacuo, no ^- diluted with water. The crude precipitate 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. 5 The above compound. Sample cleared.

Chromatograph on a silica gel column eluting with ethyl acetate: petroleum ether (4: 6) and crystallizing from cyclohexane, m.p. 136-137 ° C.

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

6.73g of N-hydroxyphthalimide, 3.73g of sodium acetate, and 10g

A mixture of 1- (2-chloroethyl) -4- (2-methoxyphenyl) -piperazine.

100 ml of anhydrous dimethylsulfoxide were 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 collected organic layers were washed with 1N sodium hydroxide, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. 7.58 g of the title compound is obtained. The sample crystallized from cyclohexane melted at (76) 80-83 ° C.

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

A solution of 6.59 g of LI intermediate and 1.10 ml of 85% hydrazine hydrate in 130 ml of 95% ethanol was refluxed for 4 hours. The ethanol was evaporated in vacuo. The precipitate was washed with water, after. with an excess of 37% hydrochloric acid and filtered. The acidic aqueous layer 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. 4.3 g of the title compound are obtained, which is converted to the hydrochloride,

' ^λ j; j to form a salt with ethanolic HCl in dichloromethane. The solvents were evaporated 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 (Lili Intermediate)

The above compound was obtained in the same manner as

XXXIV Intermediate l-bromo-3-chloropropane using l-bromo-4-chlorobutane. . Melting point 8184 ° C (ethanol).

8- (4-Chlorobutylsulfinyl) -3-methyl-4-oxo-2-phenyl-4H-1115 benzopyran (LIV Intermediate)

The title compound was obtained in the same manner as Intermediate XXVI using Lili Intermediate instead of Intermediate XXI. Example kristali20 was from cyclohexane: benzene (0.5: 1) melting at 124-125 C. ^Q

8-Carboxy-4-oxo-3-phenyl-4H-1-benzopyran (LV Intermediate) '·

22.5 g of 8-formyl-4-oxo-3-phenyl-4H-1-benzopyran (G.Atassi et al., Eur. J. Med. Chem. Chim. Ter., 20, 393) were stirred at 20-25 ° C. (1985)), a solution of 38.22 g of silver nitrate in 75 ml of water was added dropwise to 150 ml of 85% ethanol and 450 ml of dimethylformamide. Subsequently, while stirring at 1520 [deg.] C., a solution of 32.67 g of 85% potassium hydroxide solution in 195 ml of water was added dropwise. The reaction mixture was further stirred at room temperature, then filtered under pressure; the initial liquid was acidified with 37% hydrochloric acid and diluted with 1.2 liters of water. Filtered under pressure and washed with water to neutral pH. The resulting crude title compound was suspended in 150 mL of ethyl acetate 97 mL of acetate and mixed with 444 mL of 0.3 M sodium hydroxide. carbonate. After separation of the pure layers, 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, m.p. (215) 218 ° C. The sample crystallized from ethanol has the same melting point.

8-Chlorocarbonyl-4-o.xo-3-phenyl-4H-1-benzopyran (LVI 10 Intermediate)

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

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

3.5 g of 8-carbamoyl-3-methyl-4-oxo-2-phenyl-4 H -1-benzopyran (JP 61-238783), 4.8 ml of acetic anhydride and

0.25 ml of sulfuric acid (d = 1.098) solution for 3 min.

stirred at 140 ° C. The mixture was cooled to ambient temperature, diluted with water and filtered under pressure, washed with water and dried to give 3.88 g of the title compound.

NMR (CDCl ₃ , δ)

10.50 (pi.s, 1H, imidine NH)

8, 35-8.70. (m, 2H, CH at positions 5 and 7 of the benzopyran ring)

7.45-8.00 (m, 6H, other aromatic CH /)

2.60 (s, 3H, CH ₃ CO)

2.20

(s, 3H, CH _{3 at the} benzopyran ring position)

2- (2-methylthiophenoxy) -acetaldehyde diethyl acetal. 5 (LVIII Intermediate) .15.2 mL of 97% 2-bromoacetaldehyde ethyl acetal, 14g of 2-r (methylthio) -phenol, 13.7g of anhydrous potassium carbonate and 3.13g of tricaprylmethylammonium. chloride mixture 140 ml of anhydrous dimethylformamide was stirred at 95 ° C for 38 hours. The reaction mixture was then cooled to room temperature, poured into a liter of water and extracted with ethyl ether. The organic layer was washed with water, dried over anhydrous sodium sulfate, and dried in vacuo. The fat precipitate was purified by chromatography on a silica gel column eluting with petroleum ether; ethyl acetate (99: 1). The collected fractions were evaporated in vacuo. 12.9 g of the title compound is obtained. The sample crystallized from n-hexane * and melted at 50-52 ° C.

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

A mixture of 10.5 g LVIII Intermediate and 140 ml 2N hydrochloric acid in 8'5 ml anhydrous tetrahydrofuran was stirred at 50 ° C for 2 hours. The organic solvent was then evaporated 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 solid, above, which was used without purification. The sample was crystallized from cyclohexane to give the pure title compound, m.p. 102-104 ° C.

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

/.

The title compound was obtained in the same manner as Intermediate XXV using Lili Intermediate instead of Intermediate XXI. It crystallized from diisopropyl ether and melted at 112-115 ° C.

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

To 9.85 g of ethyl 3-acetyl-2-hydroxy benzoate was synthesized. tinto from 3-acetyl-2-hydroxybenzoic acid [R.E.

Ford, J. Med. Chem., 29, 538 (1986), 4.35 g of metallic sodium are added in portions at ambient temperature.

: The mixture was refluxed for 6 hours in 6N ethanol HCl, evaporated to dryness in vacuo, and uncleaned.

The product was purified by silica gel column chromatography / eluent ethyl acetate / petroleum ether (8: 2) / - 'm.p. 47 ° C (hexane) ·. 98 ml of ethyl formate.

The reaction mixture was refluxed for 20 minutes. refrigerator; followed by stirring for 4 hours. . at ambient temperature and the ethyl formate was evaporated to dryness in vacuo. The resulting impure solid product was washed

120 mL of ethanol and 67 mL of 5.6 M ethanolic HCl. The mixture was stirred for 30 minutes under reflux; it was then cooled to ambient temperature and evaporated to dryness in vacuo. The residue was chromatographed on a silica gel column with ethyl acetate: petroleum ether (3: 7-6: 4). 8.31 g of the title compound is obtained. A crystallized sample of 30 cyclohexane melted at 88-89 ° C.

8-Carboxy-4-oxo-4H-1-benzopyran (Intermediate LXII) was purified by leaching

To a solution of 4.0 g of LXI Intermediate in 30 ml of dioxaLo 35 was added 30 ml of 6N hydrochloric acid 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, the title compound was filtered under pressure at 5 ° C, washed with water, ethyl ether and dried. 2.8 g of the title compound was obtained, which was used without further purification. Example 4 Was washed with boiling acetonitrile (25: 1), filtered and crystallized from acetic acid, m.p. 253-254 ° C.

8-Carboxy-6-hydroxy-3-methyl-4-oxo-2-phenyl-4H-110 benzopyran (LXIII Intermediate) 1,5g 8-carboxy-6-methoxy-3-methyl-4-oxo-2- a mixture of phenyl-4H-1-benzopyran (JP 61-15880) and 28 ml of 57% hydroiodic acid was stirred in reflux for 47 hours with 47 ml of acetic acid. The reaction mixture was cooled to ambient temperature and poured into water; 1N sodium hydroxide was added to pH 4-5. 2g of sodium thiosulfate was added and stirred for an additional 15 minutes. The crude product was then filtered off with suction and dissolved in 0.5 M sodium hydroxide; the basic solution was washed with ethyl acetate and acidified to pH 1 with 37% hydrochloric acid. The title compound was collected by filtration after. under pressure and dried. Yield: 1.12 g of compound, further used without purification. The compound crystallized from 50% ethanol melted at 279-28PC.

2-Hydroxy-5-nitro-3-propionylbenzoic acid (Intermediate LXIV) ³⁰

To the stirred mixture at -25 ° C was added 97 mg of 2-hydroxy-3-propionylbenzoic acid (Brit. 1, 343, 119 (1974)) in 500 ml of sulfuric acid (d = 1.84) over 5 minutes. While maintaining the reaction temperature between 20 and -13 ° C, a mixture of 40 ml of 65% nitric acid and 100 ml of sulfuric acid (d = 1.84) was added over 40 minutes. The mixture was further stirred at -18 ° C for 30 minutes. It is then carefully poured out

-, / 101 ') • to ·. A mixture of 2.0 kg of crushed ice and -500 ml of water was stirred for 10 minutes, filtered, washed with water and dried at 50 ° C for 6 hours to give the title compound. The solid was crystallized from 50% ethanol to give 91.5 g of the title compound. accompanying 186-189 ° C, used further without purification. The sample was recrystallized from 50% ethanol, m.p. 1-189-191 ° C.

Ethyl 2-hydroxy-5-nitro-3-propionylbenzoate (LXV

Intermediate) '<

93.3 g of LXIV Intermediate- and 25 ml of sulfuric acid (d = 1.84) in 490 ml of ethanol were refluxed for 17 hours. The solution was cooled to ^- ambient temperature, there were added portionwise 47.7 g of sodium carbonate and the ethanol removed in vacuo. Sediment. washed with 1.2 liters of water, basified with 37% sodium hydroxide and stirred for 15 minutes. 37% Hydrochloric acid was added to the suspension at pH 6 and it was filtered.

85.4 g of the title compound were obtained, which was used without further purification (m.p. 75-77 ° C). The twice crystallized sample from ethanol melted at 76-77 ° C.

8-Ethoxycarbonyl-3-methyl-6-nitro-4-oxo-2-phenyl-4H-125 benzopyran (LXVI Intermediate)

48, Ig LXV Intermediate, 63 mL of benzoyl chloride and 85.6 g of sodium benzoate were stirred at 180 ° C (bath temperature) for 8 hours. The paste mixture was cooled to 60-70 ° C; 700 ml of 50% ethanol was added and the resulting mixture was stirred again at 50 ° C for 30 minutes. To prevent the temperature from rising above 15 ° C, 60 ml of 35% sodium hydroxide was added at 5 ° C. The mixture was filtered under. The crude product was washed with 50% ethanol / water and the crude product was purified by 2 column chromatography on silica gel eluting with dichloromethane: petroleum ether (8: 2 - 9: 1 gradient) followed by dichloromethane and finally dichloromethane: ethyl acetate. acetate (9: 5: 5). The collected fractions were evaporated in vacuo to give the title compound which was washed with 140 mL of ethanol. Yield 43g, m.p. 132.5 133 ° C (ethanol).

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

A mixture of 15, 9g of LXVI Intermediate and 48 mL of sodium hydroxide in 320 mL of ethanol was stirred for 30 minutes under reflux. The organic solvent was evaporated in vacuo and the resulting suspension was diluted .200. of water and acidified with 37% hydrochloric acid, filtered and washed with ethyl ether. 11 g of the title compound were obtained, which melted at (258) 286-292 ° C and was used without further purification. The title compound crystallized from dimethylformamide: water (6: 4) melting at the same point.

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

A mixture of 6.2 g of LXVII Intermediate, 5.2 ml of thionyl chloride and 0.1 ml of anhydrous dimethylformamide in 60 ml of toluene was stirred at 90 ° C for 2 hours, evaporated to dryness in vacuo and dried. 6.5 g of the title compound are obtained, m.p. 161-162 ° C used without purification. The crystallized sample from toluene had the same melting point.

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

7.94 g of 8-formyl-7-methoxy-3-methyl-435 oxo-2-phenyl-4 H -1-benzopyran (Da Re et al., J. Org. Chem., 25, 1097) were stirred at 75 ° C. , 1960) and 54 mL of 5% sodium dichydrophosphate in 162 mL of t-butanol over 40 minutes

103 was added dropwise to 216 ml of 0.3 M potassium permanganate water solution. The reaction mixture was stirred at the same temperature for 2 1/2 hours, then cooled to ambient temperature with 81 ml of 1 M 'sodium dithionyl added slowly. The mixture was extracted with ethyl acetate.

The organic layer was washed four times with 160 mL of 0.5 N sodium hydroxide; the collected basic aqueous layers were washed with ethyl ether acidified with 37% hydrochloric acid. The title compound was precipitated, filtered, washed with water and dried to give 3.3 g. of the compound used in subsequent reactions. The compound crystallized from .95% ethanol melted at 180-181 ° C.

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

To a solution of 7.13 g of ethyl 2-hydroxy-3-propionylbenzoate and 4.9 ml of triethylamine in 50 ml of chloroform solution was added dropwise.

6.7 g of 4-trifluoromethylbenzoyl chloride (obtained from the corresponding benzoic acid and thionyl chloride in benzene, refluxed and used without purification) in 50 ml of chloroform. The mixture was stirred at ambient temperature for 2 hours; then the solvent .25 was evaporated in vacuo and the residue purified by chromato-

•. i. 104d- _;

8-Ethoxycarbonyl-3-methyl-4-oxo-2-4-trifluoromethylphenyl) -4H-1-benzopyran (LXXI Intermediate). . > ·

6.96 LXX Intermediate, and 2.58g potassium t-butoxide • In 35 ml pyridine solution, the mixture was stirred at 100 ° C for 2 hours. The reaction mixture was then cooled to ambient temperature, poured into 50 mL of acetic acid and 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 to give 6.9 g (1- (2-hydroxy-3-ethoxycarbonyl) -2-methyl-3- (4-trifluoromethylphenyl) -1,3- A solution of the resultant compound, 2.2 ml of 37% hydrochloric acid and 35 ml of glacial acetic acid was stirred for 1 1/2 hours at 100 [deg.] C. The mixture was cooled to ambient temperature, poured into 630 ml of 1N sodium hydroxide and extracted. The organic layer was washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness in vacuo. of the inscribed compound, 'm.p.

111-113 ° C.

25; ....... '....._' '' '' '.....' '

8-Carboxy-3-methyl-4-oxo-2- (4-trifluoromethylphenyl) -4 H -1-benzopyran (LXXII Intermediate)

2.95 g of LXXI intermediate and 0.43 g of lithium hydroxide monohydrate in 12.5 ml of methanol and .12.5; ml of tetrahydro. a mixture of furan with 8 ml of water was stirred for 1 1/2 hours at ambient temperature. The mixture was poured into 30ml of 1N hydrochloric acid in 300ml of water. jr filtered under pressure. 2.47 g of the title compound is obtained, which is used without further purification. A crystallized sample of '60% ethanol melted at 253-254 ° C.

? ? ¹⁰⁵

8-Ethoxycarbonyl-2- (4-benzoylphenyl) -3-methyl-4-oxo-4H1-benzopyran (Intermediate LXXIII)

The above compound was synthesized according to the procedures of LXX and LXXI 5 and by reaction of 4-benzoylbenzoyl chloride with 4-trifluoromethylbenzoyl chloride instead of 4-trifluoromethylbenzoyl chloride in the presence of 4-dimethylaminopyridine instead of triethylamine. The usual steps were carried out and the residue was purified by silica gel column chromatography and washed. dichloromethane: ethyl acetate (9-: 1) and dry evaporation in vacuo. Fractions were collected and the title compound obtained was used without further purification.

A crystallized sample of cyclohexane melted at

125-136 ° C (dec.).

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

The title compound was obtained in the same manner as intermediate LXXII from intermediate LXXIII instead of LXXI. It was purified by dissolving the crude product in 0.5 M sodium hydroxide and washing the aqueous layer with ethyl acetate. 37% Hydrochloric acid was added and the pure title compound was precipitated. . The sample crystallized from acetic acid, m.p. 260-262 ° C.

Ethyl 2- (4-phenoxybenzoyloxy) -3-propionylbenzoate (intermediate LXXV)

The title compound was obtained in the same manner as LXX Intermediate from 4-phenoxybenzoyl chloride in place of 4-trifluoromethylbenzoyl chloride. Solvent

- evaporated to give a pure compound as above. . _; : -y'y -.y. / ?:

. . ₁₀₆

NMR spectrum at 200 MHz (CDC1 _3, δ)

8.17 (dd, 3H, phenyl CHs, ortho to carboxylate groups).

7.92. (dd, 1H, renil CH at the ortho position to the CO ^ group)

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

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

7.Q5; 7.10 (2d, 4H, other CHs phenoxy ring)

-4q 4.25, 2H, CH ₂ 0)

2.90 (q, 24, CH ₂ 0)

1.05-1.20 (m, 6H, 2 x CH ₃ )

8-Ethoxycarbonyl-3-methyl-4-oxo-2- (4-phenoxyphenyl) -4,1-b'enzopyran (Ι, ΧΧΝΪ Intermediate)

The above compound was obtained in the same manner as the LXXI Intermediate · from the LXXV Intermediate, instead of the LXX Intermediate, graphically on a silica gel column with ether: ethyl (6: 4) and

The resulting pure compound as above, m.p. 98100 ° C.

Purified chromate by evaporation of the kerosene in vacuo.

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

This compound was obtained in the same manner as. and LXXII Intermediate, from LXXVI Intermediate, instead

LXXI Intermediate, melt-1. 216-218 ° C. '

8-Carboxy-2- (t-butyl) -3-methyl-4-oxo-4H-1-benzopyran (LXXVII.I Intermediate) .35 To 8.9 g of ethyl 2-hydroxy-3-propionyl-benzoate 20 To 6 ml of anhydrous pyridine solution was added 6 ml of pivaloyl chloride. Reaction mixture for 6 hours

107 '7 was stirred at 80 ° C, cooled to ambient temperature and poured into a mixture of 200 g of crushed ice and 30 ml of 10 K hydrochloric acid. The mixture was extracted with ethyl ether and the organic phase was washed with brine, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo to give. 11.4 g of impure ethyl 2-pivaloyloxy-3-propionyl-benzoate.

2.4 g of this compound were dissolved in 4 ml of anhydrous pyridine and 1 g of anhydrous potassium t-butoxide was added. The resulting mixture was heated at 100 ° C for 15 minutes, cooled to ambient temperature and poured into 50 g of ice water with 8 ml of 10 N hydrochloric acid. The mixture was extracted with ethyl ether, the organic phase 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-pivaloylpropionyl) benzoate which was used in the next step without purification.

2g of the resulting compound was dissolved in a mixture of 15 ml of acetic acid and 1.5 ml of 37% hydrochloric acid, then heated at 100 ° C for 15 minutes, cooled to ambient temperature, then poured into 100 ml of water and extracted with ethyl ether. The organic phase was washed with 5% aqueous sodium bicarbonate followed by water, dried over anhydrous sodium sulfate and evaporated in vacuo to give 1.6 g of impure 8-ethoxycarbonyl-2- (t-butyl) -3-methyl-4-oxo-4H-1-benzopyran.

l, 5g of the above. of the ester was dissolved in 20 ml of methanol. While maintaining the temperature at 25-35 ° C, 3 ml of 10 N sodium hydroxide was slowly added. The reaction was run for 1 1/2 h at ambient temperature, then diluted with 100 mL / water / and extracted with ethyl acetate. The aqueous layer was acidified with 3N hydrochloric acid; The precipitate was collected under pressure, washed with water and crystallized 108.

of ethanol to give Q, 8g of the title compound, m.p. 225-228 ° C.

. 8-Carboxy-2-cyclohexyl-3-methyl-4-oxo-4H-1,5-benzopyran (LXXIXIntermediate)

This compound is prepared from cyclohexylcarboxylic acid, instead of pivaloyl chloride, instead of pivaloyl chloride, by the reaction method described and with slight differences. For example. The compound was stirred with pyridine at ambient temperature for 8 hours to give ethyl 2-cyclohexylcarbonyloxy-3-propionylbenzoate, regrouped. of ethyl 2-hydroxy-3- (2-cyclohexylcarbonyl-propionyl) -benzoate by heating 2 1/2 with potassium t-butoxide at 100 ° C. The compound was cyclized by heating for 1 1/2 hours in a mixture of acetic and hydrochloric acid at 100 ° C and hydrolysed at ambient temperature for 20 minutes and crystallized from 40% ethanol. The resulting 8-carboxy-2-cyclohexyl-3-methyl-4-oxo-4H-120 benzopyran, m.p. 224 ° C.

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

A mixture of 3.2 g XC Intermediate and 1.3 g anhydrous potassium t-butoxide in 8 ml anhydrous pyridine 15 iris. stirred at 60 ^Q C, cooled to ambient temperature. and poured into 60 ml of ice water with 15 ml of 10 N hydrochloric acid. The mixture was extracted with ethyl acetate and the organic phase was washed with 5% aqueous sodium bicarbonate. and water, dried over anhydrous sodium sulfate and evaporated in vacuo. 2.5 g of crude ethyl 3- (2-furoyl-propionyl) -2-hydroxy-benzoate are obtained.

2.5 g of the resulting compound was stirred at 100 ° C for 30 minutes with 10 * ml of acetic acid and 0.7 ml of 37% hydrochloric acid.

The mixture was cooled to ambient temperature and poured

C / C 109 'in, 180 ml water. The precipitated compound was collected by filtration under pressure, washed with water and crystallized from isopropanol. Yield 1.5g, m.p. 13J ~ 139 ⁰ C. J- · ''A'RąčBjJJJc''.

ISishhR / JJjJ J. i ^: '' to?

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

A mixture of 3.5 g of LXXX Intermediate and 6 mL of 10 N sodium hydroxide in 40 mL of methanol was stirred for 1 hour at ambient temperature and poured into 500 mL of water. The mixture was extracted with ethyl acetate and the aqueous layer was acidified with 3N hydrochloric acid. After precipitation, the title compound was collected by filtration under pressure, washed with water and crystallized from methanol ': chloroform (7: 3). Yield 2.55 g, m.p. 272-277 ° C.

8-Ethoxycarbonyl-3-methyl-4-oxo-2- (2-thienyl) -4H-120 benzopyran (LXXXII Intermediate)

These compound were prepared in two steps, as described for the LXXX Intermediate, using the XCI Intermediate instead of the XC Intermediate. The mixture ^was crystallized from isopropanol to give the title compound, m.p. 116-118 ° C.

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

This compound was prepared for LXXXI Intermediate in the same manner as described for LXXX Intermediate using LXXXII 'Intermediate. The mixture was crystallized from a mixture of methanol and chloroform (7: 3), m.p. 287-294 ° C.

'.''j; s _; i; / J <

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

110 L of a mixture of 8-methoxycarbonyl-4-oxo-2-phenyl-4H-1-benzothiopyran (XCII Intermediate), 2.2 mL of a mixture of 12.5 N sodium hydroxide, 15 mL of methanol and 5 mL of dioxane 2 L / Stir at ambient temperature for 2 hours. The solution

5. evaporated in vacuo, added water and extracted with chloroform. The separated aqueous phase was acidified, diluted with hydrochloric acid and the precipitate separated off. the material was filtered and purified by crystallization from acetic acid. Yield 0.62 g, m.p. 302 ° C.

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

This compound was prepared in a three step manner as described in XC

Intermediate (first step) and LXXX Intermediate (second and third step). In the first step, (E) -cin / amoyl chloride was used in place of 2-furoyl chloride to give (E) -ethyl 2-hydroxy-3- (2-styrylpropionyl) benzoate. used in the second step without purification. The title compound was crystallized from isopropanol, m.p. 129-130 ° C.

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

This compound was obtained for LXXXI Intermediate in the same manner as described for LXXXV Intermediate instead of LXXX Intermediate. The reaction was carried out for 10 hours at ambient temperature. The title compound was crystallized from ethanol, m.p. 284-286 ° C.

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

1.9 g of 2-hydroxy-3-propionyl-benzoic acid (Brit.

1, 343, 119, 1974) 5,2g of anhydrous sodium 4-metIIbenzoato iri 3.9 ml of 4-methylbenzoyl chloride 8 ^'m /

Stirred at 185-195 ° C for 1/2 hour. The mixture was cooled to ambient temperature and 100 ml of chloroform was added to the solidified mass and left overnight. The mixture was then shaken with 5% aqueous sodium carbonate solution until the aqueous phase reached pH 8.9. The organic phase was extracted with 3% sodium carbonate and the aqueous phases were combined, re-extracted with ethyl ether and acidified with 10N hydrochloric acid. The residue was purified by silica gel column chromatography eluting with chloroform: methanol (100: 2-100: 20). The compound fractions were evaporated in vacuo to give the title compound as crystallized from ethanol. Melting point 249-251 ° C.

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

This compound was obtained in three steps, - XC Intermediate as described (step one) and LXXX

Intermediate (second and third step). In the first step, 4-fluorobenzoyl chloride was used instead of 2-furoyl chloride and the reaction was carried out for 20 hours at ambient temperature to give ethyl 2- (4-fluorobenzoyloxy) -3-propionylbenzoate. This compound was used in the next step without purification. The title compound was washed with ethyl ether and crystallized from ethanol, m.p. 128-130 ° C.

8-Carboxy-2- (4-fluorophenyl) -3-methyl-4-oxo-4H-11-benzopyran (LXXXIX Intermediate)

Solution of 3.3 g of Intermediate LXXXVIII and 0,6g of lithium hydroxide hydrate in 50 ml of tętrahidrofuf ^- tors, 10 ml of water for 5 hours was considered to be at ambient temperature, and then poured into 300 ml of 1N hydrochloric acid. The resulting precipitate was collected under pressure, washed and r to give 2.3 g of the title compound. The compound was crystallized from 95% ethanol, m.p. 249-250 ° C.

Ethyl 2 (2-fluoro-hydroxy) -3-phenyl-benzoate (XC Intermediate 5)

A mixture of 8.9 g of ethyl 2-hydroxy-3-propionylbenzoate and 5.4 g of 4-dimethylaminopyridine in 25 ml of dichloromethane was added dropwise at 10-15 [deg.] C. to 4.35 mmol. Of 2-furoyl chloride. The reaction was run at ambient temperature for 2 hours, then 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 silica gel column chromatography eluting with petroleum ether: ethyl acetate (4: 1) to give 9.4 g of the title compound, a low melting solid, which was used in the next step without purification.

NMR spectrum at 60 MHz (CDCl ₃ , δ}

8.2 (1H, dd, CH 4 at the benzene ring position) 8.0 . (1H, dd, CH 6 at benzene ring position) 7.7-7.8 (1H, dd, CH 5 in furan ring position) 7.43 (1H, t, CH 5 at the benzene ring position) 7.45 (1H, s, CH 3 in furan ring position) 6, 6-6.8 (1H, Φ, CH 4 in furan ring position) 4.3 <2H, g COOCH ₂ CH ₃ ) ' 2, 9 (2H, q, COCH ₂ CH ₃ ) 0.95-1.35 (6R, m, 2xCH ₃ )

Ethyl 3-propionyl-2- (2-thienylcarbonyloxy) benzoate (XCI Intermediate)

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

113

NMR spectrum at 7.1-8.35 <6H, m, 4.25 <2H, qz 2.9 (2H, 0.95-1.3 '(6H, m,

COOCH ₂ CH ₃ )

COCH ₂ CH ₃ )

2xCH ₃ )

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

16.8. A mixture of 25 ml of methyl thiosalicylate, 25.6 ml of ethyl benzoyl acetate and 360 g of polyphosphoric acid was stirred at 90 ° C for 3 hours. The mixture was cooled to ambient temperature and poured into crushed ice. The impure product was collected by filtration, washed with water and purified by crystallization from ethanol. Lyd. t. 17 DEG -171 DEG C .;

Elemental analysis for Ci ₇ H ₁₂ O ₃ S:

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

NMR spectrum at 200 MHz {CDC1 _3, δ)

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

8.45-8.53 (dd, 1H, benzothiopyran in CH 7). 7.68-7.80 (m, 2H, 2-phenyl CHs at 2 and 6)

7.55-7.65 (t, 1H, benzothiopyran in CH at 6) '

7.45-7.55 (m, 3H, 2-phenyl CHs at 3, 4 and

5th)

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

4.00 (s, 3H, COOCH ₃ )

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

9.2g of 8-ethoxycarbonyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Da Re, P.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 mixture 1 1/2

.114 hours stirring under reflux. The mixture was cooled to ambient temperature, the resulting succinimide was collected under pressure and washed with cold carbon tetrachloride. Starting fluids dry. . After evaporation in vacuo, the residue was washed with ethyl ether and collected by filtration under pressure. 9.2 g of the title compound is obtained which is crystallized from acetone: n-hexane, m.p. 133-134 ° C.

8-ethoxycarbonyl-3-acetoxymethyl-4-oxo-2-phenyl-4H-1-. Benzopyran JXCIV Intermediate)

A solution of 10.2 g of sodium acetate trihydrate in 30 ml of water was added dropwise to a solution of 29 g of XCIII Intermediate in 300 ml of dimethylformamide at ambient temperature. The reaction mixture was stirred at 50 ° C for 1 1/2 hours and poured into 2 liters of water. The precipitated title compound was collected by suction filtration and crystallized from acetone to give 20 g (two yields), m.p. 151-152 ° C.

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

To a stirred suspension of 14.8 g of XCIV Intermediate in 300 mL of 95% ethanol was added 116 mL of 1N sodium hydroxide over 10 minutes. The reaction mixture was then heated to 60-65 ° C for 15 minutes. The resulting clear solution was stored at ambient temperature for one hour and evaporated in vacuo. The precipitate was dissolved in 200 ml of water and the solution was acidified by the slow addition of 10 ml of hydrochloric acid (d = 1.18) and stirred for 1 hour at ambient temperature; The above compound was collected by suction filtration. water and crystallized from isopropanol to give 9.3 g of melting point. (225) 237-240 ° C. 7-77;: ;; << / E _(3038B ^+?: - / 115

F'-tile 2- (4-nitrobenzoyloxy) -3-propionyl-berizoate (Intermediate XCVI)

The title compound was obtained as described for Intermediate 5 XC using 4-nitrobenzoyl chloride in place of 2-furoyl chloride. A low melting solid was obtained (m.p. (40-7880 ° C).

NMR spectrum at 60 MHz (CDCl ₃ , 6)

7.85-8.50 (m, 6H, aromatic CHs) 7.50 (t, 1H, CHs at the 5 'position of the phenol ring) 4.25 <q, 2H, CH ₂ 0) 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 (XCVII Intermediate)

A mixture of 29, 7 g of XCVI Intermediate and 10.18 g of anhydrous potassium t-butoxide .89 ml of anhydrous pyridine was stirred at room temperature for 13 hours. 100 ° C. The reaction mixture was cooled to ambient temperature, poured into 400 mL of 4 N hydrochloric acid and extracted with dichloromethane.

The organic layer was repeatedly washed with water, after. of which 2.5% sodium bicarbonate, dried over anhydrous sodium sulphate and evaporated to dryness in vacuo. The crude product was purified by column chromatography on silica gel eluting with hexane: ethyl acetate (7: 3).

The collected fractions were evaporated in vacuo. 7g of the title compound is obtained, which melts at (130) 145-148 ° C.

8-Carboxy-3-methyl-2- (4-nitrophenyl) -4-oxo-4H-135 benzopyran (XCVIII Intermediate)

.116

A suspension of 0.38 g of XCVII Intermediate in 4.75 mL of dioxane and 4.75 mL of methanol was stirred at 50 ° C. 1.29 ml of 1 N sodium hydroxide was added and stirred at the same temperature for 3 hours. The reaction mixture was cooled to ambient temperature and treated with 3N hydrochloric acid until the pH reached 1. The suspension was filtered under pressure to give 0.13 g of the title compound, which was crystallized from dioxane, m.p. 320-321 ° C.

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

To a stirred mixture of 3g of ethyl 2-hydroxy-3-propionylbenzoate at 0 ° C and 5.53 ml of trifluoroacetic anhydride was added 3.16 ml of 1,8-diazabicyclo / 5-4.0/ undec-7-ene via syringe. The reaction mixture was stirred at 60 ° C for 4 hours; then cooled to ambient 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). 0.8 g of the title compound is obtained.

NMR spectrum at 200 MHz (CDC1 _3, S)

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

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

4.46 (q, 2H, COOCH ₂ )

2.22-2.27 (m, 3H, ^. ^ 2.16Hz, CH _{3 in} the position of the benzopyran ring) 1.39 (t, 3H, CH ₂ CH ₃ )

8-Carboxy-3-methyl-4-oxo-2-trifluoromethyl-4H-1-benzopyran (Intermediate C); D · ⁷ ''

The title compound was obtained as the LXII Intermediate using the XCIX Intermediate instead of the LXI Intermediate. The solution was diluted with water, extracted with ethyl acetate rather than filtered, and dried over anhydrous sodium sulfate. The organic layer was evaporated to dryness in vacuo to give the title compound as a solid, m.p. 175-178 ° C

3- / 4- (2-Methoxyphenyl) -1-piperazinyl · N - methylpropylamine 10 (Cl Intermediate)

To 8.2 g of 3- [4- (2-methoxyphenyl) -1-piperazinyl] -propyl. chloride 48 ml. 42 ml of dimethylformamide solution was added

35% aqueous methylamine. The mixture was heated at 60 ° C for 5 hours, then cooled to 30 ° C. The solvent was evaporated in vacuo and the residue was stirred with 100 ml of ethyl ether for 30 minutes. The solids collected by filtration under pressure were dissolved in 200 ml of chloroform: 5 N methanol / ammonia. (100: 3). The solution

After stirring for 30 minutes at ambient temperature, the mixture was adsorbed onto a chromatographic column eluted with chloroform: 5 N methanolic ammonia (100: 15 gradient). The fractions containing the title compound were collected and evaporated in vacuo to give 3 g of a clear oil intermediate Cl.

NMR spectrum at 60 MHz (DMSO-d _6, δ) 6.80 (s, 4H, aromatic CHs); 3.75 (s ,, 3H, OCH ₃ ) 3.20-2.75 (m, 4H, p ipe raisins CH ₂ sh Item 3.5 2.75-2.10 (m, pu r 8H, Ή piperazine CH ₂ s Πλ - / - ^- Item 2.6 2.40 (s, 1H, NH) 2.30 (s, 3H, NCH ₃ ) 1.80-1.40 (m, 2H, CH _? CH _? CH ₉ )

118

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

11.1 g of ethyl 2-hydroxy-3-propionyl-benzoate, 9.9 g of 5-phenacyl bromide, 6.9 g of anhydrous potassium carbonate and

The 200 ml acetone mixture was stirred at reflux for 7 hours. The mixture was cooled to ambient temperature and the inorganic salts were filtered off and the solution was evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with toluene. The collected fractions were evaporated and the title compound crystallized from 90% ethanol. Yield 9.8 g, m.p. 64-66 ° C.

7-Carboxy-2-benzoyl-3-ethyl-benzo / b / furan (CIII Intermediate) g CII Intermediate, 275 mL of 0.95 N sodium. of hydroxide and 400 ml of dioxane was stirred at reflux for 4 hours. The mixture was cooled to ambient temperature, the dioxane evaporated in vacuo and replaced with the same volume of water. The solution was filtered through charcoal, acidified with dilute hydrochloric acid. The precipitate was filtered off and purified by crystallization from acetone. Yield 4.94 g, m.p. 193-195 ° C.

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

This compound was obtained in three steps as described for XC Intermediate (Step One) and LXXX Intermediate (Step Two and Third). In the first step, 4-methylbenzoyl chloride was used in place of 2-furanocarbonyl chloride and 2-hydroxy-3-propionyl benzoate was used instead of ethyl 2-hydroxy-335 propionylbenzoate. The reaction was carried out for 4 hours at room temperature to give methyl 2- (4-methylbenzoyloxy) -3LT3938B p'ropinylbenzoate. This compound was used in the second step without purification by chromatography at 100 ° C for 1.5 hours. In the third step, 96% sulfuric acid was used instead of 37% hydrochloric acid. The title compound crystallized from methanol, m.p. 174-175 ° C.

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

This compound was obtained in three steps as described for 'XC Intermediate (Step One) and CIV Intermediate (Step Two and Third).

In the first step, 4-phenylbenzoyl chloride was used in place of 2-furanocarbonyl chloride and the reaction was carried out for one hour at room temperature under reflux on silica gel and refrigerated for 13 hours. Purification by column chromatography on petroleum ether - ethyl acetate (100: 5 to 100: 10 gradient) gave 2- (4-biphenylyl) -3-propionylbenzoate.

The title compound was washed with 95% ethanol, m.p. 165-167 ° C.

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

A mixture of 4.3 g of intermediate and 35 ml of 35% hydrochloric acid was stirred for 16 'hours in 50 ml of 1,4-dioxane and 15 ml of water.

The mixture was poured into 200 mL of water and extracted with ethyl acetate. The organic layer was separated and extracted with 20% sodium carbonate water.

Aqueous precipitate is added and the precipitate formed is diluted with salt.

P °

pressure washed with water and dried to give 2.5 g of the title compound, m.p. 242, 5-244 ° C <,

2- (4-Hydroxyphenyl) -3-mephryl-4-oxo-4H-1-benzopyran-85 carboxylic acid (CVII Intermediate) g Ethyl 2- (4-methoxyphenyl) -3-methyl-4-oxo-4H- A mixture of 1-benzopyran-8-carboxylate (JP 58, 225, 083; CA 100, 191648 h (1984)) and 60 ml of 48% hydrobromic acid in 80 ml of acetic acid was stirred at reflux for 8 hours. The mixture was cooled, poured into 500 ml of water were collected under suction and pressurized with water, and the crude product was purified by chromatography on chloroform-isopropyl alcohol (9: 1-7: 3 gradient) followed by methanol to give 1 g of the title compound, which melts at 300 ° C. .

1- (2-Methoxyphenyl) -4- (4-methylaminobutyl) piperazine (CVIII Intermediate). ·

2.53 g of 4- / 4- (2-methoxyphenyl) -1-piperazinyl / butylamine was stirred at 0 ° C _; of anhydrous dichloromethane solution, dilute with 3.8 ml of trifluoroacetic anhydride in 25 ml of anhydrous dichloromethane,

The reaction mixture was stirred at room temperature for two hours, then diluted with dichloromethane and washed with water. The organic layer was dried over sodium sulfate and evaporated to dryness in vacuo to give 3.3 g of pure 1- (2-methoxyphenyl) -4- (4-trifluoroacetylamine) as determined by NMR. butylpiperazine.

NMR spectrum at 60 MHz (CDC1 ₃ (§))

7.70-8.00 (pi.s, 1H) NH

6.80-7.20 (m, 4H) aromatic CH _S

3.85 (s, 3H) CH ₃ O /

2.90-3.80 (m, 12H) piperazine in CF, CH ₂ N and CH ₂ , NHCO

121////

1 / 50-2.05 (m, 4Η) C-CH ₂ CH ₂ -C

To a stirred solution of 3.3 g of the above intermediate in 46 ml of anhydrous dimethylformamide was added 0.88 g of 50% sodium hydride in portions. After stirring for 1 hour at the same temperature, 0.57 ml of methyl iodide was added. . The reaction mixture was further stirred at 10 ° C for 1> 5 hours; after that poured out. water and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. 1.13 g of crude 1- (2-methoxyphenyl) -4- (N-methyltrifluoroacetylamino) butyl / piperazine was obtained, used in the next step without purification.

0.18 g of sodium borohydride was added to 1.13 g of this intermediate in 30 volumes of ethanol and the resulting mixture was stirred for 1 hour at 60 ° C. The reaction mixture was cooled to room temperature, poured into water and extracted with dichloromethane. The organic layer was washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. 0.82 g of the pure compound above is obtained.

NMR spectrum at 60 MHz (CDC1 ₃ (δ))

6.80-7.20 (m, 4H) aromatic CHs' 3.85 (s, 3H) CH ₃ 0 2.90-3.20 (m, 4H) piperazine CH ₂ S, 3 and Position 5 2.30-2.80, (m, 8H) piperizine CH ₂ S, 2 and Heading 6, 2 x CH ₂ N 2'.5 / </ ·, '/' (3, 3H) ch ₃ n 1.80 (S, 1H) NH 1.40-1.80 (m, 4H) c-ch ₂ -ch ₂ -c.

/ J · '/;

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

122 ''

The above compound can be obtained by treating 1- (2-methoxyphenyl) -piperazine with isobucyraldehyde, 37% formaldehyde in water and acetic acid at or about 90150 ° C. in ethanolic HCl (Mannich reaction), 1- (2-formyl-2-methylpropyl) -4- (2-methoxyphenyl) -piperazine * 'is aminated by treatment with ammonia under reducing conditions. The latter may be hydrogen and a catalyst (for example, palladium on carbon / Raney nickel or platinum dioxide). * in a solvent (such as ethanol, methanol, isopropanol, dichloromethane, chloroform or dimethylformamide) at ambient temperature.- 80 ° C, or alternatively, a metal hydride (such as sodium borohydride, sodium or potassium cyanoborohydride, or sodium triacetoxide) (e.g. ethanol, chloroform, benzene or 1,2-dichloroethane) in the presence of an acid (e.g. gaseous HCl, or * acetic acid). ;

The compound can be reacted with 8-chlorocarbonyl-3-methyl-420-oxo-2-phenyl-4H-1-benzopyranone as described in Example 12 to give 8- (2,2-dimethyl-3- / 4- (2-methoxyphenyl) - 1-piperazinyl (propylcarbamoyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran.

j B '·' / ·· '· /? B / '/' '· ϋ · B', iii iiiiii'iiii / f ii'iii'ii .i iii '·? »$ ·'. '/ Ii -i -''-'.- • i; - -i- '··.' .'ii 'i- B / their.; '..' .- '. J; -f j / ·· /. '' '' i '.

e-Trifluoroacetamidoethyl-S-methyl-4-oxo-Z-phenyl-H-1-benzopyran

This compound can be obtained in the same manner as Intermediate XXIV instead of 8-amino-3-methyl-4-oxo-2-phenyl 30 4H-1-benzopyran. It can be used as starting material instead of XXIII

- .Intermediate product 32. In the reaction described in the example. 8- {2- / 4- (2-methoxyphenyl) -1-piperazinyl / ethylaminomethyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran is obtained.

8- (2-Chloroethylureidomethyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran: / 123: b

This Intermediate can be obtained in the same manner as for the XLIV Intermediate using 8-Amino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran in Intermediate XXIV. The intermediate in Path (a) can react with the compound of formula H-B to give the desired compounds as described above.

8-Ethenylsulfoxylaminomethyl-3-methyl-4-: oxo-2-phenyl-4H-benzopyran This compound may be present. obtained by reaction of Intermediate XXIV with 2-chloroethylsulfonyl chloride in a halogen solvent in dichloromethane in the presence of triethylamine at 0-40 ° C (A.A.Goldberg, J. Chem. Soc.

464/1945). Reaction of HB with the corresponding compounds (m), the path can be accessed by end-Fl' Y36 _(CH?) 2-B compound prepared from 8-amino-3-methyl-4-oxo-2-phenyl-4H-l-benzopyran.

8-Chlorosulfonylmethyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran 'b. · B' b '·' - ·? B '': 'b / ·' / · 'b ··· :: ·· './.,/ ·'']':]. · .. - ·:; - _i b: b.'bb b ·· '· j,

This intermediate can be prepared by reacting 8-amidinothiomethyl-3-methyl-4-oxo-2-phenyl-4H-l-benzopyran (synthesized as intermediate XXI) with chlorine gas in water at -10 to 10 ° C (TBJohnson). et al., J. Chem. Soc.> 61, 2598, 1939).

Reaction of this intermediate with the appropriate ANH-Z-B compounds, the n-route, may yield the desired end products.

EXAMPLES

Example 1

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

'LT 3038 B

124

To a stirred mixture of 21.4 g of the intermediate and 4.1 g of potassium carbonate in 120 ml of methanol was added dropwise a solution of 11.5 g of 1- (2-methoxyphenyl) -piperazine in 120 ml of methanol at 2025 ° C. The reaction mixture was stirred at the same temperature for 4 hours, suctioned off. that vacuum. The residue was extracted with chloroform and the organic solution was washed with 'water, dried.: 77 /: 3AR / RaRAA RRARR / Aa AAAAAAa / AA'AAA R / ·' / ').) · Ai? Α ^; Ά'ί R / R. -77-.3 373 '.: 3 R / R .RAtęRA'-ARRRR / TRARA.'R'A'';, R ..- .. 33. 3 R 7; -7j 3 7733 A // AR 3 AR · '. * /.

anhydrous sodium sulfate f calcium chloride, filtered and .. suction vacuum. The resulting impure product was dissolved in acetone and a slight excess of ethanol HCl was added. The title compound was collected by pressure filtration and recrystallized from 95% ethanol to give 16.3 g, m.p. (189) 195-199 C.

Example 2

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

This compound was prepared in Example 1 instead of 1- (2-methoxyphenyl) -piperazine using 1- (2-methylphenyl) piperazine and reaction for 1 hour in dimethylformamide instead of 4 hours in methanol. M.p. (194) 203-206 ° C (isopropanol).

Example 3

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

This compound was prepared in Example 1 instead of 1- (2-methoxyphenyl) -piperazine using 1- (2-ethoxyphenyl) piperazine and reaction for 2 hours in dimethylformamide instead of 4 hours in methanol. Melting point 20835 210 ° C (isopropanol).

125

Example 4

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

To a solution of 5.75 g of 1- (2-methoxyphenyl) -piperazine in 10 ml of methanol at 0 ° C. 10 ml of 37% formaldehyde in 15 ml of methanol was added dropwise over 3 minutes. After 12 hours at 0 ° C, the mixture was vacuum removed and redissolved twice in 15 mL methanol. To 0 ° C was added 20 'mL of HCl in ethyl ether. The mixture was removed in vacuo and the residue suspended in 15 mL of 1> 4 dioxane. 8.3 g of intermediate V per 100 ml were added at 20-25 ° C with stirring

1,4-Dioxane solution. The reaction mixture was stirred at reflux for 8 hours and cooled to 30-40 ° C. To the mixture was added 50 ml of methanol and ^: '' ii.:. '' // .'III-Ir. · '. '·''·' - ^J; ;. ·· / '' ·. 't''7. . ' ii · 11: j ' ^ύ ''1?. ·. ·: · y ·.' · '··', · ':'. · / '''·' y ':''y'l''to ·: '· ..-'. · 'J,'.

The mixture was further refluxed for 2 hours. The resulting mixture was cooled to 20-25 ° C, diluted with 300 ml of ethyl ether and further stirred.

3 hours at the same temperature. The title compound was collected by pressure filtration and recrystallized from ethanol to yield 4 g, m.p. 209210 ° 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 dimethylformamide was stirred at 80 ° C for 30 minutes. After that added. 5.23 g of 1- (3-chloropropyl) -4- (235 methoxyphenyl) -piperazine and stirring was continued for 3 1/2 hours at 80 ° C. The reaction mixture was cooled to ambient temperature, poured into ice water, and

126 was extracted with ethyl acetate. The organic extracts were washed with aqueous sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The precipitate was poured into ethanol and added to the solution. . -V excess ethanol HCl. Yield: 8.16 g of the title compound, m.p. 198-203 ° C.

Example 6.

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

The title compound was obtained by following Example 5', replacing 1- (3-chloropropyl) -4- (2-methoxyphenyl) -piperazine with 1- (2-chloroethyl) -4- (2-methoxyphenyl) -piperazine, .t. 200-203 ° C from ethanol.

• Example 7.

8- {3- / 4- (2-Chlorophenyl) -1-piperazinyl / propoxycarbonyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran dihydrochloride

A mixture of 2.8 g of 1- (2-chlorophenyl) -piperazine hydrochloride and 4.2 g of anhydrous potassium carbonate in 25 ml of dimethylformamide was stirred at ambient temperature for 15 minutes. 4.81 g of Intermediate I was added and further stirred for 2 days. The reaction mixture was then poured into

200 mL of cold water and extracted with ethyl ether and ethyl acetate. The organic extracts were washed successively with aqueous sodium chloride solution, 0.1 N acetic acid, aqueous sodium chloride solution, 4% aqueous sodium carbonate solution and water, then evaporated to anhydrous sodium sulfate. The precipitate was evaporated to dryness in vacuo, then dissolved in 160 mL of excess acetonitrile and excess HCl. in ethyl ether.

/ 7 // λ 127 ·

The precipitating compound above was recrystallized from acetonitrile. Yield: 3.6 g, m.p. 138-143 ° C.

Example 8;

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

The above compound was obtained in Example 7 instead of. 1- (2-Chlorophenyl) -piperazine hydrochloride, using 1-phenyl-piperazine. The compound was recrystallized from methanol, m.p. 229-231 ° C.

Example 9

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

The title compound was obtained in Example 7 instead of 1- (2-chlorophenyl) -piperazine. hydrochloride using 1- (2-methoxyphenyl) -piperazine hydrochloride. This is an alternative route to Example 5 product.

Example 10

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

. ·

To a solution of 6-g of 8-chlorocarbonyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran in 2.2 ml of 1,2-dichloroethane at 60 ° C was added 5.29 g of intermediate XXVIII in 25 ml of 1, Of 2-dichloroethane. The reaction mixture was refluxed for 16 hours, then cooled to ambient temperature and poured into cold 0.5 N sodium hydroxide solution. Water and dichloromethane were added.

^ι2θ "· The organic phase is separated off, washed with aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvents were evaporated and the fat precipitate was purified by chromatography on silica gel eluting with petroleum ether: ethyl acetate (85:15). The collected fractions were evaporated to dryness in vacuo and the residue was dissolved in ethanol. Excess ethanol HCl was added and 0.71 g of the title compound was obtained, m.p. 203204 ° C. .

Example 11 8- (3- (2-Methoxyphenyl) -1-piperazinyl / -propylcarbamoyl) 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran dihydrochloride polyhydrate.

A mixture of 6.28 g of 1- (2-methoxyphenyl) -piperazine and 5.34 g of intermediate XXXVII was heated at 180 ° C for 5 hours. The mixture was cooled and the dark mass was purified by silica gel chromatography eluting with dichloromethane: methanol (100: 3). Fractions containing the above compound were combined. The solvents were removed in vacuo and the residue was dissolved in the titrated ethanol. The solution was filtered, acidified with ethanol

HCl and left at '20 -25 ° C for the night. The crude product was collected by filtration and crystallized from ethanol. 5 g of the title product are obtained, m.p. (177) 182-186 ° C.

Example 12

8- {3- (4 '- 2-Methoxyphenyl / -1-piperazinyl / propylcarbamoyl) -3-methyl-4-oxo-2-phenyl-4H-1335 benzopyran dihydrochloride polyhydrate

129

Add 3.74 g of 3- / 4- (2-methoxyphenyl) -1-piperazinyl / propylamine (GB 2161807) and 1.97 g of triethylamine in 50 ml of chloroform solution at room temperature. 4.48 g of 8-chlorocarbonyl-3-methyl-r45 were added dropwise over 10 minutes. oxo-2-phenyl-4H-1-benzopyran 40. * ml chloroform 'solution. The solution was stirred for 2 hours and then washed with 0.5 N hydrochloric acid, saturated aqueous sodium bicarbonate solution and water. The chloroform solution was dried over anhydrous sodium sulfate and the solvent was evaporated in vacuo. / The precipitate was treated with 11 To give 6.67 g of the title compound, m.p. (177) 182-186 ° C. This corresponds to an alternative path to Example 17 product.

. . The following salts were also obtained:

monohydrochloride hydrate, l.t. 151-154 ° C, monomethanesulfonate, m.p. 162-164 ° C, and {±> -hemimalate hydrate, m.p. 110-112 ° C.

This example depicted the condensation of an amino, 3- / 4- (2-methoxyphenyl) -1-piperazinyl / -propalamine. with carbonyl chloride, 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carbonyl chloride '. It should be noted that the amine may be present. condensed with the corresponding free acid or the corresponding ethyl ester by heating their equimolar amounts with or without solvent. The solvent used is a hydrophilic or hydrophobic high boiling point solvent. The amine may also be condensed at room temperature with an equimolar amount of the corresponding free acid in the presence of N, N-tricyclohexylcarbodiimide and 4-dimethylaminopyridine in a solvent such as dichloromethane, chloroform, tetrahydrofuran or dimethylformamide. '

Example 13

8- {2- / 4- (2-Methoxyphenyl) -1-piperazinyl / ethylcarbamoyl) 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran monohydrochloride polyhydrate

The title compound was obtained in the same manner as in Example 16 instead of Intermediate XV using Intermediate XIV and heating at 5560 ° C for 32 hours. The way forward has changed as follows. The base was collected by filtration, purified by chromatography on silica gel, elution with chloroform: methanol (100: 0.5), followed by (100: fractions), the title compound collected and the solvents removed in vacuo. The solids were collected in boiling water and diluted hydrochloric acid was added, and the crystalline salt was separated by freezing and collected by filtration under pressure, mp 119-123 ° C.

Example 14

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

The above compound was obtained 11 · By way of example, instead of

1- (2-methoxyphenyl) -piperazine using 2- (2-methoxyphenoxy) -ethylamine (Augstein, J. et al., J. Med. Chem., 8, 356, 1965) under heating for 2 hours 5 hours. Elution solvent was dichloromethane: methanol (100: 5). Melting point 200-202 ° C (ethanol).

Example 15

8- {3- (4-Phenyl-1-piperazinyl) -propylcarbamoyl-3-methyl-4-oxo-2 "phenyl-4H-1-benzopyran monohydrochloride Poly 35 HydrateLT3038B / - 131

The title compound was obtained in Example 11 using 1- 1-phenylpiperazine instead of 1- (2-methoxyphenyl) -piperazine and heating for 2 hours instead of 5 hours. Dichloromethane: methanol (100: 4) was used as eluent.

Melting point (251) 255-258 ° C by 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.

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 for 6 hours _{that is} at 100 ° C. The mixture was cooled, the solvent removed in vacuo, and the residue was poured into 50 mL of water, stirred at ambient temperature for 1 hour, collected by filtration, washed with water and crystallized from 95% ethanol in low activated carbon (decolorization). quantity. The base was dissolved in 105 ml of boiling 0.086 N hydrochloric acid and cooled. The crystallized salt was filtered to give 4.3 g of the title compound (mp 201-203 ° C);

.. 'vi ijiliisfsji' ^γ ~ yy ^{? 7} y ⁷⁷

Example 17

8- {1-Hydroxy-2- / 4- (2-methoxyphenyl) -1-piperazinyl / ethyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride '

15.5 g of the compound obtained in Example 1 in 1500 ml of methanol at 0 ° - 5 ° C was added in proportions of 1.36 g of sodium borohidrido.Reakcijos stirred for 90 minutes at 0 ° - 5 ^Q C readily was acidified with 3N hydrochloric acid, ¹ mixture was then suctioned off under vacuum. The residue was shaken with 2N aqueous sodium hydroxide solution '132 and extracted with chloroform. The organic layer was dried over sodium sulfate / calcium chloride, filtered, acidified with ethanol HCl and suctioned off in vacuo. The crude product was washed with ethyl ether and crystallized from ethanol. 9.5 g of the title compound is obtained, 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 obtained in Example 17 from the compound obtained in Example 2 instead of the compound obtained in Example 1. Melting point 25715 258 ° C (ethanol).

Example 19

8- {1-Hydroxy-2- [4- (2-ethoxyphenyl) -1-piperazinyl] -ethyl) -320 methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride

This compound was obtained in Example 17 from the compound obtained in Example 3 instead of the compound obtained in Example 1. Melting point 2412.42 ° C (methanol).

'

Example 20

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

This compound was obtained from Example 17 from Example 4 and .ne from Example 1. The crude product was purified by chromatography / silica gel, eluent 35 ethyl acetate: chloroform (4: 1) /. The fractions were combined with a clean base, acidified with ethanol HCl

133 and adsorbed in vacuo. '' Precipitate · Crystallized from ethanol. Melting point (126) 156-160 ° C.

Example 21 5

8H 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 XXXVIII Intermediate and 2.45 g of 1- (2-methoxyphenyl) -piperazine in 21 ml of anhydrous dimethylformamide was stirred at ambient temperature for 5 hours. 1.22 g of 1- (2-methoxyphenyl) piperazine was added and the mixture stirred for 4 hours, poured into

300 ml. water and extracted with ethyl acetate.

The organic extracts are combined, washed with water

j., '. ·' / '/·.·; / <Λ / ··· /' ύ, Χ; /. in / 'In: 7 - /// /' / 7, //-y·'./·.';';·/'·-·· / in / C, / · /// '· i / '/.'? ·?; - ·. / - // '·. 7 / 'sodium bicarbonate solution followed by aqueous sodium chloride solution and evaporated to dryness in vacuo. The residue was purified by chromatography on silica gel eluting with ethyl acetate: methanol (95: 5). The fractions were collected by rotary evaporation and the residue was dissolved in 0.81 M ethanolic HCl and again evaporated in vacuo. The solid precipitate was crystallized from water: ethanol (9: 1). 2.43 g of the title compound is obtained, m.p.

144-146 ° C.

Example 22

8- {1-Ethoxy-2- [4- (2-methoxyphenyl) -1 - * - piperazinyl] -ethyl} 30 3-methyl-4-oxo-2-benzenyl-4H. '- 1-benzopyran hydrochloride

To 6.55 g of sodium hydride (50% in mineral oil, repeatedly washed with hexane) was added 6 ml of anhydrous dimethylsulfoxide under nitrogen. 3 to 20-25 ^G C 'was added to the mixture. g 17 50 ml of dimethylsulfoxide solution of the compound obtained in the example. After stirring for 1 hour at 20 ° C, 0.66 g of ethyl bromide was added.

134

The reaction mixture was further stirred for 20 minutes at the same temperature and then poured into ice water. The crude product was filtered off with suction and purified by chromatography (silica gel, eluent: chlorine5: ethyl acetate (8: 2) /. Fractions containing pure title compound. and dried in vacuo at 140 [deg.] C. Yield: 1.6 g of the title compound, mp (155) 209 [deg.] C.

Example 23

8- {N-Methyl-2- / 4- (2-methoxyphenyl) -1-piperazinyl / ethyl15 aminomethyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran dihydrochloride polyhydrate

5.2 g of intermediate XXVII, 3.1 g of 1- (2-methoxy-phenyl) -piperazine and 2.2 g of anhydrous potassium carbonate

In 50 ml of dimethylformamide, the mixture was stirred at 70 ° C for 7 hours. The reaction mixture was cooled to 20-25 ° C, poured into 500 mL of water and extracted with dichloromethane. The organic phase was washed with water and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by chromatography on silica gel eluting with ethyl acetate: petroleum ether (98: 2). The title compound was obtained by formation of a salt with ethanolic HCl. Melting point 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.

³⁵ g of XXXIIIT intermediate and 5.3 g of j- (2-methoxyphenyl) -piperazine in 75 ml of dimethylformamide 2

Stirred at 95 ° C for 135 hours. The reaction mixture was cooled to 20-25 ° C, poured into 200 mL of water, basified with potassium carbonate, and extracted with ethyl acetate. The organic phase was washed with water and dried. anhydrous sodium sulfate. The solvent was removed in vacuo. The precipitate was cleaned. chromatography on silica gel eluting with dichloromethane: methanol (100: 092). The salt was formed by reacting the free base with ethanol HCl and recrystallized from methanol. Received

4.4 g of the title compound containing one equivalent of methanol. Melting point (200) 227-228 ° C.

Example 25

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

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 are stirred for 2 hours at 0 ° C. The reaction mixture was poured into a funnel and filtered under pressure. The resulting solid product was purified by chromatography on silica gel eluting with ethyl acetate: petroleum ether (6: 4). The fractions were collected, evaporated to dryness in vacuo and the residue crystallized from ethyl methyl ketone. The base was treated with a molar equivalent of ethanolic aqueous 2.25 N hydrochloric acid. The title compound was obtained, m.p. 168-170 ° C.

Example 26

8- {N-Methyl-N- [4- (2-methoxyphenyl) -1-piperazinyl] -acetamidomethyl) -3-methyl-4-oxo-2-phenyl-4H-1 + benzopyran hydrochloride Hydrate XXXI Intermediate 2.9 g of 1- (2-methoxyphenyl) piperazine and 2 g of anhydrous potassium carbonate in 50 ml

Λ; ////) 13 β '_;2'-dimethylformamide mixture was stirred at 2025 ° C for 3 hours. The reaction mixture was then poured into 500 mL of water and extracted with dichloromethane. The organic phase was washed with water and dried over anhydrous sodium sulfate.

The solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel eluting with ethyl acetate: petroleum ether (6: 4) and crystallized from acetone. 3.6 g of the title compound of the title compound are obtained, m.p. 144-145 ° C. The base was dissolved in ethanol, 8N hydrochloric acid and water were added to give the title compound, m.p. 218-220 ° C, (dried at 100 ° C in vacuo).

Example 27

2L | §22lSl! Tiill2fi®

8- {2- [4- (2-Methoxyphenyl) -1-piperazinyl] -ethoxymethyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran dihydrochloride g. XVIII Intermediate, 2.4 g. A mixture of (2-methoxyphenyl) 20-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. The mixture was cooled to room temperature, then poured into water and extracted with dichloromethane. The extracts were combined, washed with aqueous sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The precipitate was crystallized from ethyl acetate and the collected crystals were dissolved in ethanol and treated with excess ethanol HCl. 5.21 g of the title compound are obtained, m.p. 199-20.1 ° C.

Example 28

8- {2- / 2- (2-Ethoxyphenoxy) -ethylamino / -ethoxymethyl) -335 methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride.

137

The above compound was prepared by the action of Example 27 using 2- (2-ethoxyphenoxy) ethylamine in place of 1- (2-methoxyphenyl) -piperazine. The product was purified by chromatography on silica gel eluting with ethyl acetate: methanol (97: 3). 4.25 g of compound are obtained, m.p. 191-193 ° C.

Example 29 '8- {2- / 4- (2-Methylphenyl) -1-piperazinyl / ethylthiomethyl} 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride

To 5 g of Intermediate XXI in 50 ml of dimethylformamide solution was added 2.5 g of potassium carbonate, 2.13 g of potassium iodide and 3.15 g of 1- (2-methoxyphenyl) -piperazine and the mixture was stirred for 4 1/2 hours. 90 ° C. The reaction mixture was cooled to room temperature, then 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. The precipitate solution was treated with acetone

3.8 M HCl in ethyl ether, filtered 'and recrystallized from ethanol. Yield: -6.15 g of the title compound, 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 dihydrochloride hemihydrate

The title compound was prepared by the method of Example ⁷ 29 using Intermediate XXVI instead of Intermediate XXI and stirring 2.21 hours, B more than an hour. The usual steps were performed and the residue was purified by silica gel chromatography eluting with ethyl acetate: methanol (97: 3). The collected ^fractions: / '138:

acidified with excess ethanol HCl, evaporated to dryness in vacuo. The precipitate was crystallized from ethanol to give 5.2 g of the title compound, m.p. 170-172 ° C. This compound has 1 equivalent of ethanol.

Example 31

- {2 - / 4 - (2 -Me toksifeni 1) -1 -pyridin pe raisins 1 / - et 1s u i-1 1 10 foni methyl} ^{-3-methyl-4-oxo-A,} 2-phenyl-4H- l-benzopyran hydrochloride - - - ''

A mixture of 4.5 g of XXV Intermediate, 2.36 g of 1- (2-methoxyphenyl) piperazine and 0.84 g of potassium carbonate in 45 ml of anhydrous dimethylformamide 2. 1/2. hours stirred at ambient temperature. The reaction mixture was poured into 300 mL of water and filtered under pressure, washing with water. The solid support was crystallized from ethanol, m.p. 143-146 ° C. The crystalline was dissolved in 1,220 dichloroethane i-r acidified with ethanol HCl. The title compound was recrystallized from methanol: water (1: 3.5). 4.4 g of compound are obtained, m.p. 229233 ° C.

.

Example 32

8- (2- / 4- (2-Methoxyphenyl) -1-piperazinyl / ethylamino} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran dihydrochloride

To 0.9 g of sodium hydride (50% in mineral oil) was added dropwise a solution of 3.7 g of XXIII Intermediate 10 ml of dimethylformamide in 9 ml of dimethylformamide at 0 ° C. Removed cold bath and after 30 minutes at. A solution of 4.1 1- (2-chloroethyl) -4- (2-methoxyphenyl) piperazine in 10 ml of dimethylformamide was added at 20-25 ° C. The mixture was stirred at 90 ° C for 5 hours, then cooled to 20LT 3038B. 139 '

25 ° C. 1 36 g of 1- (2'-chloroethyl) -4- (2-methoxyphenyl) -piperazine in 5 ml of dimethylformamide were added followed by 0.25 g of sodium hydride '(in 50% mineral oil). The mixture was stirred at 90 ° C for 8 hours and cooled again to 205 -25 ° C. 200 ml of water 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 chromatography on silica gel eluting with n-hexane:

ethyl acetate (3: 2). A base mixture of the title compound and the corresponding N-trifluoroacetyl compound are obtained. . .

3.8 g of this mixture. dissolved in 35 mL of ethanol and 35 mL of dimethyl sulfoxide. To this solution was added Q, 55 g of sodium borohydride in portions at 20-25 ° C. The mixture was stirred at the same temperature for 3 hours, then poured into 200 ml of water and extracted with ethyl acetate. The organic extracts were washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The precipitate was dissolved in dichloromethane and 2 eq equivalents of ethanol HCl were added. Above is inscribed

- '' · / /: 1 +. / · '·' + +.,. + 7 · .. ·· ..,. '7 ·' · .. ./ '7' · '/'. + /, .- / - 7o / · ',. ·: · - /'.

the compound was recrystallized from ethanol. Yield 3.8 g, m.p. 231-234 ° C.

Example 33

8- {3- [4- (2-methoxyphehyl) -1-piperazinyl] -propylamino} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride + 30 '+ - ///> 35. -hydrabash'7 ///./. ^? ./'/ -7-.- .- 7 ... - .- //. The above compound was obtained by way of example 32 instead of 1- (2-chloroethyl) -4- (2-methoxyphenyl) -piperazine. on 1- (3-chloropropyl) -4- (2-methoxyphenylpiperazine).

Lyd, vol. 206-208 ° C (10% ethanol).

Example34

8- {4- / 4- (2-Methoxyphenyl) -1-piperazinyl-butyllamino) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride polyhydrate

4.5 g of XXXIX, Intermediate, - 3.9 g of 8-amino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8.3 g of sodium triacetoxyborohydride and 3.4 ml of acetic acid. ml of 1,210 dichloromethane mixture was stirred at 2025 ° C for 6 hours. A 5% sodium bicarbonate solution was added and the mixture was stirred for 10 minutes. The mixture was then basified with 0.5 N sodium hydroxide solution and extracted with dichloromethane. Organic extracts were washed with water and. dried over anhydrous sodium sulphate. The solvent was evaporated in vacuo and the residue was purified by silica gel chromatography eluting with ethyl acetate: petroleum ether. (9: 1). . The resulting base was dissolved in dichloromethane and 1 ethanol HCl equiv. The solvent was removed in vacuo and the residue crystallized from 50% ethanol to give 1.6 g of the title compound, m.p. _r (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 polyhydrate

4 g of the compound of Example 33, 4.35 ml of 37% aqueous formaldehyde and 1.15 g of sodium cyanoborohydride in 25 ml of acetonitrile were stirred at 20-25 ° C. Acetic acid was added during the reaction while maintaining the pH at 5-6. ;. After 4 hours, the solvent was evaporated in vacuo. To the precipitate was added 80 ml of ethyl acetate and 200 ml of ice-cooled sodium hydroxide solution. The organic phase is hydrofluoric; dried over anhydrous sodium sulfate

141 and dry evaporated in vacuo. The residue was purified by chromatography on silica gel eluting with ethyl acetate: petroleum ether (3: 1). A clean base was obtained. dissolved in ethyl ether, 1 equivalent of ethanol HCl was added and the solvent removed in vacuo. The precipitate was crystallized from water to give 2 g of the title compound, m.p. 186-187 ° 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 of Example 33, 2.8 ml of acetic anhydride and 33 ml of pyridine was stirred at 80 ° C for 4 hours. The reaction mixture was cooled to 20-25 ° C, poured into 200 g of glacial water, acidified with 10 g. N · hydrochloric acid and extracted with dichloromethane.

The organic extracts were washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The residue was purified by chromatography on silica gel eluting with ethyl acetate: methanol (95: 5). The pure base was dissolved in dichloromethane, 1 equivalent of ethanol HCl was added and the solvent evaporated in vacuo. The precipitate was crystallized from acetonitrile to give 3 g of the title compound containing 0.33 equivalents of acetonitrile, mp 208.5-210.5 ° C.

Example 37

8- {3- / 4- (2-Methoxyphenyl) -1-piperazinyl] -propionamido} 3-methyl-4-oxo-2-phenyl-4H-1-benzopyrand 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. After that, the reaction mixture

142 was cooled to ambient temperature and poured into water. The mixture was extracted with dichloroethane, then the organic phase was washed with water and dried over anhydrous sodium sulfate. The solvent was removed in vacuo. The crude residue was crystallized from ethanol to give above. base of the compound ·, which is then dissolved in hot ethanol. 1 mol of 0.81 M ethanolic HCl was added to the solution. 4 g of the title compound were obtained. melts 255257 ° C;

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 XLIV Intermediate and 7.22 g of 1- (2-methoxyphenyl) -piperazine was stirred at 100 ° C for 5 hours. An additional 1.8 g of 1- (µg-methoxyphenyl) piperazine was added and stirred at 100 ° C for 2 hours. The reaction mixture was cooled to room temperature, poured into water and extracted with ethyl acetate. The organic phase was washed. aqueous sodium hydroxide solution, dried over anhydrous sodium sulfate, and. dry evaporated .vacuum. The crude residue was purified by silica gel chromatography eluting with ethyl acetate: methanol (98: 2), the collected fractions were evaporated to dryness in vacuo and crystallized from water: ethanol (4: 6). The crystals were twice dissolved in dichloromethane and treated with 1 mol of methanesulfonic acid. The solution was evaporated in vacuo.

while the crude methanesulfonate was crystallized from ethyl acetate: ethanol (1: 1). 2.35 g of the title compound is obtained, m.p. 191-193 ° C.

Example 39

8- {2- / 4- (2-Methoxyphenyl) -1-piperazinyl / ethoxy) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride hydrate

143

A mixture of 6, .61 g of intermediate XI, 8.34 g of 1- (2-methoxyphenyl) piperazine and 1.26 g of sodium iodide in 70 ml of dimethylformamide was stirred at 80 ° C for 17 hours. The reaction mixture was cooled to 20-25 ° C, 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 chromatography on silica gel eluting with dichloromethane: methanol (99: 1), followed by (98: 2). Fractions containing the title compound as above were combined and the solvent removed in vacuo. The precipitate was dissolved in ethanol and ethanolic HCl was added. The title compound was crystallized, collected by pressure filtration and recrystallized from 95% ethanol. Yield 6.5 g, m.p. 224-225 ° C.

Elemental Analysis:

Found%: C = 66, '38, H = 6.34, N = 535, Cl = 6.76, H ₂ 0 = 3.35 Calculated%: 66.34, 6, 14, 5.33, 6, 75, 3.43 NMR spectrum at 60 MHz (CDC1 ₃ -CD ₃ OD)

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

7.1-6.6 (aromatic protons of m, 4H, 2-methoxyphenyl group)

4.8- 4.4 (m, 2H, OCH ₂₎

4.4 to 4.1 (m, 3H, H ₂ 0 and ΝΉ)

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

144

This compound was prepared as described in Example 39 using Intermediate IX instead of Intermediate XI. In this case, compound purification is not required. Melting point 226-227 ° C. ~ '

Example 41

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

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 28 ml of the dimethylformamide mixture was stirred at 75 ° C for 2 hours. The reaction mixture was cooled to 20-25 ° C, poured out, poured into $ 00 mL water and extracted with dichloromethane. The organic extracts were washed with water and dried over anhydrous sodium sulfate, and the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography, eluting with ethyl acetate. The resulting base of the title compound was converted to the dihydrochloride by treatment with ethanol. HCl. , The above compound crystalline-. Ethanol to give 6/5 g, 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 in the same manner as in Example 41 using Intermediate XVII instead of Intermediate XVI. Melting point 173 ° C (ethanol). The corresponding base melts at 117-118 ° C (ethanol).

Example 43 // // 145; ^?

8- (3- / 4- (2-Methoxyphenyl) -1-oxo-1-piperazinyl / propoxy) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran 1,75 hydrate to 4.34 g A solution of the compound of Example 40 and 0.1 'g of benzyl (triethyl) ammonium chloride in 20 ml of dichloromethane and 20 ml of methanol was added dropwise at -15 ° C to 2.93 g of magnesium monoperoxyphthalate. The mixture was stirred at 0 ° C for 2 hours, then warmed to ambient temperature, poured into water and basified with aqueous sodium hydroxide solution. Normal operations were carried out, followed by extraction with dichloromethane and purification of the resulting solid by chromatography, eluting with dichloromethane: methanol (9: 1). The fractions containing the pure compound were evaporated to dryness in vacuo and the residue crystallized from acetonitrile. 0.5 g of the title compound is obtained, m.p. 89-92 ° C.

Example 44

8- {2- / 2- (2,6-Dimethoxyphenoxy) -ethylamino / -ethoxy) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride.

4.5 g of intermediate XII, 3.7 g of triphenylphosphine and

A mixture of 2.85 g of 2,6-dimethoxyphenoxyacetaldehyde (Nelson, WL et al., J. Med. Chem., 22, 1125, 1976) was stirred in 45 ml of benzene for 18 hours at 20-25 ° C and refluxed for 5 hours. . The solvent was evaporated in vacuo and the residue was dissolved in 80 ml of anhydrous methanol. A molecular sieve of 3A was added.

0.61 g of sodium borohydride was then added at 0 ° C. The mixture was stirred for 1 hour at '0 ° C and for 1 hour at 20-25 ° C, then poured into aqueous water 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 silica gel chromatography eluting

146 dichloromethane: methanol (49: 1). The resulting base was treated with ethanol HCl. The title compound was crystallized from ethanol. Yield 40%, m.p. 200202 ° C.

Example 45 8- {2-Hydroxy-3- [4- (2-methoxyphenyl) -1-piperazinyl / propoxy) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride. A solution of XL Intermediate and 4.64 g of 1- (2-methoxyphenyl) -piperazine in 40 ml of dimethylformamide was stirred at 80 ° C for 3 hours. The reaction mixture was cooled to 20-25 ° C, poured into 4.00 mL of water and extracted with dichloromethane. The aqueous phase was basified with 1 N hydroxide solution and extracted with ethyl acetate. The organic extracts were combined, washed with water and dried. anhydrous sodium sulfate. The solvents were evaporated in vacuo. The residue was purified by chromatography on silica gel eluting with ethyl acetate. Fractions containing the above compound are based on the base and adsorbed in vacuo. The precipitate was dissolved in dichloromethane and 1 equivalent of ethanol HCl was added.

The solvents were removed in vacuo and the residue crystallized from ethanol. 5 g of the title compound was obtained containing one mole of ethanol. Melting point (122) 126-128 ° C with decomposition.

Example 46.

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

A mixture of 4.4 g of XXXIV Intermediate, 2.5 g of 1- (2-methoxyphenyl) -piperazine, 1 g of potassium iodide and 1.8 g of anhydrous potassium carbonate in 40 ml of dimethylformamide was stirred at 100 ° for 3/147 hours. C. The reaction mixture was cooled to 20-25 ° C, poured into 350 mL of water and extracted with dichloromethane. . The organic extracts were washed with water, dried over anhydrous sodium, sulfate and the solvent evaporated in vacuo. The precipitate was purified by silica gel column chromatography, eluting with ethyl acetate: petroleum ether (3: 2) and crystallized from ethanol. 3.9 g of the title compound is obtained, m.p. (70) 96-9 ° C.

^10th

Example 47

8- (3- (4-methoxyphenyl) -1-piperazinyl / propylsulfonyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride

A solution of 3.8 g of XXXV Intermediate and 4 g of 1- (2-methoxyphenyl) piperazine in 40 ml of dimethylformamide was heated at 60 ° C for 7 hours. The reaction mixture. cooled to 20-25 ° C, 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 chromatography on silica gel eluting with ethyl acetate: petroleum ether (1: 1). The base of the title compound was obtained, dissolved in ethanol and 1 equivalent of ethanolic aqueous chloride was added. 4.5 g of the title compound are obtained, m.p. (215) 226-228 ° C.

Example 48

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

A solution of 4.5 g of XLII Intermediate and 3.8 g of 1- (2-methoxy35-phenyl) -piperazine in 40 ml of dimethylformamide was heated at 70 ° C for 7 hours. The reaction mixture was cooled to 20-25 ° C, poured into 150 mL of water and extracted with 3038 B

treated with dichloromethane. The organic solution was washed with water and dried over anhydrous sodium sulfate, and the solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel eluting with ethyl acetate:

petroleum ether. The title compound was obtained by formation of a salt with ethanolic CH1. Yield 2.9 m.p. 236-238 ° C.

Example 49

8- {N-Methyl-2R, 4 - (2-methoxyphenyl) -1-piperazinyl / ethylsulfamoyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride

The above compound was obtained. 48 By way of example, using XLI Intermediate instead of XLII Intermediate. Melting point 194-198 ° C (ethanol).

Example 50

8- {N-Carbamoyl-3- [4- (2-methoxyphenyl) -1-piperazinyl] propylamino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methanesulfonate polyhydrate

4.06 g A mixture 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 chromatography on a silica gel column eluting with ethyl acetate: methanol (98: 2). The fractions containing the title compound as a base were evaporated to dryness in vacuo. The precipitate was dissolved in 30 mL of dichloromethane and one equivalent of methanesulfonic acid was added.

35 / The solvent was evaporated in vacuo and the residue crystallized from ethanol to give 3.1 g of the title compound

IT 3038 R

149 '(m.p. 157-160 ° C with decomposition). This compound contained one mole of ethanol.

y /./'./ into ''.

'8- (4- / 4- (2-Methoxyphenyl) -1-piperazinyl / -1-oxobutyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methanesulfonate <

To a solution of 0.74 ml of oxalyl chloride in 6 ml of dichloromethane was added 1.33 ml of anhydrous dimethylsulfoxide in 9 ml of dichloromethane solution at -70 ° C · The solution was stirred at -70 ° C for -15 minutes and then 2.8 g was added. eel (base) in 14 ml of dichloromethane solution. After: 4.7 ml of anhydrous triethylamine was added at the same temperature for 15 minutes and the temperature was raised to -30 ° C within 30 minutes. Stirring was continued for 30 minutes at -30 ° C and the temperature was raised to 0 ° C. The mixture was diluted with 120 mL water and extracted with dichloromethane. The organic phase was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The residue was purified by chromatography on silica gel eluting with ethyl acetate: dichloromethane (9: 1). The fractions containing the title compound as base were dry evaporated in vacuo.

The precipitate was dissolved in 30 mL of dichloromethane and 1 equivalent of methanesulfonic acid was added. The solvent was evaporated in vacuo and the residue was crystallized from ethanol to give 2.9 g of the title compound, m.p. 194-195 ° C. . 30 '. // · /

Example 52

8- (3- / 2- (1,4-Benzodioxoxanyl) methylamino / propylcarbamoyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methanesulfonate

3038Β

A mixture of 5.56 g of XLIII Intermediate Base, 4.58 g of 2- (ptoluenesulfonyloxymethyl) -1,4-benzodioxa, 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 ambient temperature, poured into water and extracted with dichloromethane. The organic phase was washed with water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness in vacuo. The residue was purified by silica gel column chromatography eluting with ethyl acetate: methanol {95: 5} The fractions containing the title compound as the base were evaporated to dryness in vacuo. The precipitate was dissolved in ethanol and 1 equivalent of methanesulfonic acid dissolved in ethyl acetate was added. . The crystallized product was filtered off and recrystallized to give 2/1 g of the title compound, m.p. 172-174 ° C.

Example 53 '8- {4- / 4- (2-Methoxyphenyl} -1-piperazinyl-but-butyl) -3-methyl-4-hydroxy-2-phenyl-4H-1-benzopyran methanesulfonate

A solution of 2.8 g of XLVI Intermediate and 0.13 g of p-toluenesulfonic acid in 150 ml of methanol was refluxed for 5 hours. The solution was cooled to 2 ° C-25 ° C, 0.8 g of anhydrous potassium carbonate was added and stirring was continued for 3 hours. The reaction mixture was filtered, evaporated to dryness in vacuo to give 2.5 g of 8 (4,4-dimethoxybutyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran.

? 30.

m, CHCfkCi ^ CH) s, f corpse CH ₃ ) t, F 1'-CH ₂ ) s, 2 x OCH ₃ ) t, CH (OCH ₃ ) ₂ ) dd, flavon in CH 6)

NMR (CDCI.3, δ) 1.6- 1.9 «Η, 2.2 <3H, 2.9 (2H, 3.3 (6H, 4.4 (1H, 7.3 (ih;

151 (6H, m, flavon CH at 7 and 5 X phenyl at CH)

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

2.5 g of the product obtained in 10 ml of water and 30 ml of vinegar 5. -acid solution heated to 50 ° C / 2 for 1/2 hour ·.

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

NMR (CDCl ₃ , 5) • dd, CH ₂ CH 2 CH ₂ CHO) s, flavone CH ₂₎ 1.9-2.1 2.2 (2H, (3H, 2, .5 (2H, t, CH2CHO) 2.9 (2H, t. F1'-CH ₂ ) 7.3 (1H, dd, flavon in CH 6) 7.5-7.7 <6H, m, flavon CH at 7 and 5 x phenyl CH) 8.1 (1H, dd, flavon in CH 5) 9.7 (1H, s, CHO)

2.3 ml of 6N hydrochloric acid in ethanol, 2.1 g of the compound obtained, 40 ml of methanol solution and 0.45 g of sodium cyanoborohydride are successively added to 8 g of 1- (2-methoxyphenyl) -piperazine. In 30 ml of methanol solution.

The reaction mixture was stirred at ambient temperature for 24 ', then poured into 500 mL of ice water and extracted with dichloromethane. The organic phase was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The residue was purified by chromatography on a silica gel column eluting with ethyl acetate: petroleum ether (9: 1). Fractions containing the above product as the base were evaporated to dryness

152 under vacuum. The precipitate was dissolved in 30 mL of dichloromethane and 1 equivalent of methanesulfonic acid was added. The solvent was evaporated in vacuo and the residue was crystallized from acetone to give 2.35 g of the title compound (m.p. 141-143 ° C).

Example 54

8- (3- (4-phenyl-1-piperidinyl) -propylcarbamoyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methanesulfonate ·. '·

This compound was prepared by the method of Example 11 instead of 1- (2- methoxyphenyl) -piperazine using 4-phenylpiperidine. and reaction for 1 hour instead of 5 hours. The product was purified by chromatography on a silica gel column eluting with dichloromethane: methanol (100: 5).

t ·

Melting point 157-159 ° C (ethyl acetate). The corresponding base melted at (127) 147-149 ° C (ethanol).

Example 55 '8- (3- (4,4-Diphenyl-1-piperidinyl) -propylcarbamoyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methanesulfonant

This compound was prepared in Example 11 using 4,4-diphenylpiperidine ridine in place of 1- (2-methoxyphenyl) -piperazine and carrying out the reaction for 2 hours instead of 5 hours. Melting point 221-22.3 ^Q C (ethyl acetate).

Example 56.

8- {3- [4- (4-Fluorobenzoyl-1-piperidinyl-propyl-carbamoyl) -3-methyl-4'-oxo-2-phenyl-4H-1-benzopyran

This compound was prepared in Example 11 using 1- (2-methoxyphenyl) -piperazine instead of 1- (2-methoxyphenyl) -piperazine using 4- (4-fluorobenzenoyl) -piperidine and carrying out the reaction for 30 minutes instead of 5 hours. The product was purified by chromatography on a silica gel column eluting with dichloromethane: 5 N methanolic ammonia (100: 1- 100: 20 gradient). Melting point 181-183 ° C (ethanol).

Example 57 -.R. _; RRj.

R 'RR .. -'. R

8- {3- / 4- (2-oxo-l-benzimidazolinyl) -1-piperidinyl / propyl-carbamoyl) -3-methyl-4-oxo-2-phenyl-4H-l-benzo pyran ^J

This compound was obtained. By way of example, instead of 1- (2-methoxyphenyl) -piperazine using 4- (2-oxo-1-benzimidazolinyl-piperidine), the product was purified by chromatography on a silica gel column eluting with 5 N methanolic ammonia (100: 3). 23815-241 ° C (ethanol).

Example 58 - · '_

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

The title compound was obtained in Example 11 using 1- (2-pyrimidinyl) -piperazine in place of 1- (2-methoxyphenyl) -piperazine and carrying out the reaction for two hours. The product was purified by column chromatography over silica gel eluting with chloroform: methanol (100: 3). The desired fractions were dissolved in dic ^{1 in} loromethane and one equivalent of methanesulfonic acid was added. The solvent was evaporated in vacuo and the precipitate was boiled with ethyl acetate for 1 hour and then collected by filtration. Melting point Mp 209-210 ° C. The product had .0 ^ 2 equivalents of ethyl acetate and 0.1 equivalent of water.

The corresponding base melted at 178-180 ° C (ethanol).

• '/ z.?/154 /' / zy // ·? /: /

Example 59

8- (3- [4- (2-Hydroxy-phenyl) -1H-piperazinyl] -propylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, Above The compound was obtained in Example 11 using 1- (2-hydroxyphenyl) -piperazine instead of 1- (2-hydroxyphenyl) -piperazine for 1 1/2 hours, instead of 5 hours, using dichloromethane: methanol (100: 3-100) as eluent. Mp 118-110 ^° C (95% ethanol).

Example 60

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

This compound was prepared in Example 12 using 4- [4- (2-methoxyphenyl) -1-piperazinyl] -butylamine in place of 3- / 4- (2- ¹ 'methoxyphenyl) -1-piperazinyl / -propylamine. The reaction mixture was stirred at room temperature for 22 hours, diluted with water, filtered under pressure and the insoluble solids washed with water. The crude residue was dried and purified by silica gel column chromatography eluting with ethyl acetate: methanol (9: 1). Fractions containing pure product based, collected, -. evaporated to dryness in vacuo and dissolved in dichloromethane. Methane30 sulfonic acid and 2 volumes of ethyl acetate were added to the solution. The precipitated salt was filtered and recrystallized from ethanol to give the title compound, m.p. 230-232 ° C. This product contained 0.3 moles of ethanol.

/./

155

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

This compound was prepared using Example 12 instead of 8 chloro-carbonyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran. VIII Intermediate and stirring · 24 hours instead of 2 1/2 hours. The crude product was purified by column chromatography over silica gel eluting with ethyl acetate: methanol (98.5: 1.5). The fractions containing the pure product as base were collected, 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 product crystallized. from ethanol to give m.p. (196) 198-200 ° C.

Example 62 '-: < _? / ^: / '- /' - / · - ': //;.

'-i. - ///: /// / /Z--'.////./: - /. /. 'To / //

8- {3- / N-Methyl-2- (2-methoxyphenoxy) -ethylamino} -propylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran: ': \': <. .: - _< : hydroichloro <^ s ^: /

To a suspension of 6.66 g of Example 14 in 55 ml of acetonitrile and 20 ml of water was added 10.5 'ml of a 40% formaldehyde solution. . The red solution was stirred at room temperature for 15 minutes, then 2.70 g of 95% sodium cyanoborohydride was added, and after 15 minutes, under the same conditions, 1.38 ml of acetic acid was added.

The solution was stirred for 3 hours, the solvents removed in vacuo, and the residue was washed with 250 mL of water and 250 mL of chloroform. 3N sodium hydroxide was added, the organic phase was separated, and the aqueous phase was extracted twice with chloroform. The organic phases are collected, the solvent is removed in vacuo and the residue is purified by chromatography on silica gel eluting with chloroform: 5.2

156 / <7> N in methanolic ammonia (100: 0.5-100: 2). The fractions containing the pure compound as a base were collected, evaporated to dryness in vacuo, and the residue was dissolved in hot ethanol. The solution was acidified with ethanol HCl, the solvent evaporated in vacuo and the residue was washed with ethyl ether and stirred at room temperature. The crude product was filtered and crystallized from acetonitrile to give 3.1 g of the title compound, m.p. t. 146-148 ° C.

ΙΌ '; / ² './';····/; ² ';''··' - // · '' 7 / '/' / ... / <·. ·.

Example 63

8- {N-methyl-3- (4- (2-methoxyphenyl) -1-piperazinyl) - _; (propionamido) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methanesulfonate 7- / 7

The crude base of the title compound was obtained in 37 Example using L Intermediate instead of X Intermediate base and stirring at 90 ° C for 4 hours, instead of 6 hours at 60 ° C. The product was purified by column chromatography over silica gel eluting with ethyl acetate: methanol (95: 5). The resulting impure methanesulfonate (Example 61) was 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 dimethylsulfonate) ^; / i / i // 7..7 //..-.,

The title compound was obtained in Example 12 using the LVI intermediate instead of 8-chlorocarbonyl3-methyl-4-oxo-2-phenyl-4H-1-benzopyran and stirring for 2 1/2 hours instead of 2 hours. The crude product was purified by chromatography eluting with ethyl acetate: methanol (92: 8). The collected fractions were evaporated in vacuo and the resulting pure base was dissolved in dichloromethane.

7- \ LT3038B

1-57 / '- / • Two equivalents of methanesulfonic acid were added, the solvent was evaporated, and the resulting crude olimethanesulfonate was recrystallized from acetone, m.p. 153-156 • (2oo ° c). /+..> ./:

// s <77; / ++ // '' + ..- + / to '/ <. -;> ./+ 7ą + '++ /' Example 65

8- (3- / 3,4-Dihydro-1-oxo-2H-naphthyl) -methylamino-propylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran 7 methanesulfonate

6g A mixture of intermediate XLIII, 2.4 g of 2-methylene-atetralone (Org. Synth., 60, 88, 1981) and 3.14 ml of triethylamine in 48 ml of anhydrous dimethylformamide. Stir at room temperature for 6 hours, 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 chromatography eluting with dichloromethane: methanol (9 5: 5), followed by dichloromethane: methanol: 5.8 N methanolic ammonia (98: 2: 0.2). ). 1.74 g of the title compound is obtained in base. The base is converted to methanesulfonate 61 By way of example.

The salt was recrystallized from acetone followed by acetonitrile to give the title compound, m.p. (69) · · 157-159 ° C. : .-, / h- / / '7 / +' + / + / + '7 / //.7? An example

- + + - / '' h · '' .. into t '' · y - / /, '. /,''. +. /;? .- /. // -' // h // ... _; <h /? 'i'7;

8- {2- / 4- (2-Methoxyphenyl) -1-piperazinyl / ethoxycarbohylmethyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran dihydrochloride

The title compound was obtained according to Example 5 /, instead of 8-carboxy-8-methyl-4-oxo-2-phenyl-4H-1-benzopyran, using XLVII Intermediate, and i- (2LT 3038 B chloroethyl) -4- ( 2-methoxyphenyl) piperazine instead of 1- (3y 'chloropropyl) -4- (2-methoxyphenyl) piperazine; no. Lyd. t. 193196 ° C from ethanol: ethyl ether.

Example-67 ./. 8- {4- [4- (2-methoxyphenyl) -1-piperazinyl] -obutylsulfanoyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran. dimethanesulfonate 'yi ° / 7 7' · ^A '^; - ////// - / 7 ^ '7/7' 7 // '7.-7/7 / .//7 7/7.

The title compound was obtained in the following manner by way of example 61 instead of 3- / 4- (2-methoxyphenyl) -1-piperazinyl / -propylamine using 4- (4- (2-methoxy xenyl) -1-piperazin) in i 1 / -bu ti 1 amine. The crude dimethanesulfonate was crystallized from acetonitrile followed by ethanol. M.p. 172-174 ° C.

Example 68

8- {N- (2-Tetrahydropyranyloxy) -3- [4- (2-methoxyphenyl) -120-piperazinyl] -propylcarbamoyl) -3-methyl-4-oxo-2-phenyl4H-1-benzopyran methanesulfonate polyhydrate

3.92 g of 0- (2-tetrahydropyranyl) hydroxylamine (R.N. Viatrener et al., Angewandte Chem.

'Int. Ed., 5, 511, 1966), a solution of 3.6 g of 1- (3-chloropropyl) -4- (2-methoxyphenyl) -piperazine in 30 ml of anhydrous dimethylformamide was added dropwise. Stirring was continued for 2 hours at 0 ° C, followed by 12 hours at 110 ° C. The reaction mixture was cooled to room temperature and dimethylformamide was removed by distillation in vacuo. The precipitate was washed with water and extracted with ethyl acetate. The organic layers were combined, washed with water, and dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo to give 4.39 g of 1- [3- (235 tetrahydropyranyloxyamino) propyl] -4- (2-methoxyphenyl) piperazine.

159 ¹ H-NMR (CDC1 _3, 6)

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

5.20 v, (pi.s, '1H, NH);

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

3, 30-4, 00 (m, 5H, OCH ₃ and tetrahydropyran CH ₂ 0).

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

2.20-2.80 (m, 6H, piperazine 2 x CH ₂ , alkyl • chain CH ₂ N): to ·· · / '.1,30-2,00 (m, 8H,' tetrahydropyran 3 x CH ₂ , alkyl chain C-CH ₂ -C)

To a mixture of 3.26 g of the title compound and 1.42 g of potassium carbonate in 47 ml of chloroform at room temperature; A solution of 2.79 g of 8-chlorocarbonyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran in 47 ml of chloroform was added dropwise. The reaction mixture was stirred for 3 hours, then diluted with 75 ml of chloroform and washed three times with 1 M 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 over silica gel eluting with ethyl acetate: methanol (98: 2). The collected fractions were evaporated to dryness in vacuo to give 2.99 g of pure base of the title compound. It was dissolved in dichloromethane and methane-sulfonic acid was added to the solution. The solvent was evaporated in vacuo and the crude salt crystallized from ethyl acetate to give the title compound, m.p. 159-160 ° C.

'/

8- {4- / 4- (2-methoxyphenyl) -1-piperazinyl-butyramide} -3. methyl 4-oxo-2-phenyl-4H-1-benzopyran methanesulfonac polyhydrate

- ⁶ °

The title compound was obtained in Example 38 using, instead of XLIV Intermediate. The XLVIII intermediate was purified by chromatography on a silica gel column eluting with ethyl acetate: methanol (95: 5) for 1 hour at 70 ° C and 2 hours at 4 ° C to 130 ° C instead of 7 hours at 100 ° C. The fractions containing the pure compound base described above were collected and evaporated to dryness in vacuo. The precipitate was dissolved in dichloromethane and 1 equivalent of methanesulfonic acid was added to the solution. The solvent was evaporated to dryness in vacuo and the crude salt crystallized from acetone, m.p. 175-176 ° C.

·. Example 70

...

E-8- {2- / 4- (2-Methoxyphenyl) -1-piperazinyl / ethoxyiminomethyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran

5.4 g of 8-formyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran and 5.13 g of LII Intermediate in 10 mL of chloroform with 3A molecular sieve were stirred for 6 hours under reflux. The molecular sieve was removed by filtration and the solution was evaporated to dryness in vacuo. The crude product was purified by column chromatography over silica gel eluting with ethyl acetate:

petroleum ether, (7: 3). Two groups of fractions were collected and evaporated to dryness in vacuo. First washed (less polar). fractions, the group had an almost pure compound; the second group (more polar) by NMR was a mixture of E and Z diasteriomers (1: 1).

1 H-NMR (CDCl ₃ , δ), δ-7 / 8.75 (dd, 0.5H, benzopyran in CH 7, Z)

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

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

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

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

7.60-7.75 (m, 2H, phenyl at CH 'and 6')

161

7.50-7.60 7, 45 7 / (m, 3H, phenyl CH 3, 4 'and 5' E + Z) (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, / (- ^ / 7 (t, 2H, CH ₂ 0, E + Z) 3.86 (s, 3H, CH ₂ O, E + Z) 3.05-3.20 (m, 4H, Piperazine 2XCH ₂ , E + Z) 2.70-2.90 (m. 6H, piperazine '2XCH _{2 and'} CH ₂ N) E + Z 2.20 (s, 1.5H, 7: benzopyran CH ₃ -3-position, Z) ' '2.18 (s, 1.5H, benzopyran CH, at 3, E) diastereomer » ^R '.' · ^; Crystallized from methanol: (water : 1), obtaining 2.5 g pure compound as above,

melts Mp 107-109 ° C. '(><< /// 7/7 ./'. 7 '/, /. (, //2//(77..--/ / 7 /// // 77- ^: 7 _: {/ · · /., 7, - //; /// {// (, ^ /. - /,. 7 {7 (.- 'J ////./. _? - / (.; - /, / -; (/

Example ^ 71

8- {N-hydroxy-3- / 4- (2-methoxyphenyl) -1-piperazinyl / -propylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-benzopyran methanesulphonate 0.25 L20 H ₂ 0

2.04 g of the compound of Example 68 in 104 ml of 1.6 N ethanolic hydrogen chloride solution was stirred at ambient temperature for 12 hours. Ethane was evaporated in vacuo and the residue was washed with 1 N sodium hydroxide and dichloromethane. The organic layer was collected, ^- filtration, washed with water, dried over anhydrous (sodium sulfate and evaporated to dryness in vacuo. The solution of the residue in dichloromethane was added. 1 molar equivalent of methanesulphonic acid.

The solvent was removed and the crude methanesulfonate was crystallized from acetone to give 1.02 g of the title compound, m.p. t. 211-213 ° C. The product contained 0.25 moles of water.

Example 72

162

E-8- <2- {2- / 4- 2- (2-methoxyphenyl) -1-piperazinyl / ethylcarbamoyl} ethylene -3-methyl-4-oxo-2-phenyl-4H-1-benzopyranomethanesulfonate 1, 2 H ₂ 0

The title compound was obtained in Example 61 using Intermediate IV instead of Intermediate VIII and the corresponding propylamine 2- / 4- (2-methoxyphenyl) -1 H -piperazinyl / ethylamine in 1,1,2,2 tetrachloroethylene solvent. Finally, the reaction mixture was diluted with water and chloroform and washed with 1N aqueous sodium hydroxide followed by water. The organic layer was dried over anhydrous sodium sulfate, methanesulfonic acid was added and the solvents evaporated in vacuo. The crude product was twice crystallized from isopropanol to give the title compound containing 1.2 moles of water. Melting point 124-127 ° C.

Example 73

f. · '' 7 '· ^? ·. f: '; - '/ ... f: λ. ;

8- {4- / 4- (2-Methoxyphenyl) -4-piperazinyl / butylsulfinyl} • 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methanesulfonate

The above compound was obtained in Example 38 instead

XLIV Intermediate using LIV -Intermediate ⁷ .

After stirring for 3 hours at 70 ° C and for 3 hours at 90 ° C, a catalytic amount (0.01 equivalent) of potassium iodide was added. Purification by column chromatography on silica gel eluting with ethyl acetate: methanol (9: 1) gave the title compound as above. One mole of methanesulfonic acid was added to the dissolved dichloromethane impure base and the solvent evaporated in vacuo. The salt was crystallized from acetone to give the title compound, m.p. 183-184 ° C.

163

Example 74

8- (3- / 3- (2-Methoxyphenoxy-propylamino) -propylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methanesulfonate emihydrate

The title compound was obtained in Example 76 using ^γ 3- (2-methoxy-phenoxy) -propyl chloride (B.Willhalm, 'Tet10 Rahedron, .20) in place of 2- (2,6-dimethoxyphenoxy) -ethyl' bromide. , 1185, 1964. The precipitate was extracted with dichloromethane, purified by column chromatography on silica gel, eluting with dichloromethane: methanol: 5N methanolic ammonia (9: 1: 0.3), and the pure base converted into methanesulfonate, twice crystallized from ethyl acetate: acetonitrile (9: lj to give the title compound, mp (60) 87-90 ° C.

Example 75

8- {3- / 2- (2-Methylthiophenoxy) -ethylamino / -propylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methanesulfonate

1.85 g of 95% sodium borohydride were added to the stirred mixture

0 ° C 7 g LIX Intermediate in 70 ml methanol solution.

The solution was stirred at the same temperature for 1 hour and the solvent evaporated in vacuo. The precipitate was diluted with water, 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo to give 6, 6. g of pure 2- (2-methylthiophenoxy) -ethanol oil. '

8.57 g of p-toluenesulfonyl chloride were added portionwise to a stirred solution of 35-eml pyridine at 0 ° C. The reaction mixture was stirred at ambient temperature for 14 hours, poured into cold 2N hydrochloric acid and ^, Τ3038Β

164 '· extracted with di chlorine t ar. The organic layer was washed twice with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo to give 7.8 g (3: 1) of 2- (2-methylphenylthiophenoxy) ethyl p-toluenesulfonate and

Of a mixture of 2- (2-methylthiophenoxy) -ethyl chloride (as determined by NMR), a low melting point solid, which was used without further purification.

A homogeneous mixture of 3.3 g of the title compound and 8 g of 10 XLIII Intermediate was kept in an oil bath at 140 ° C for 20 minutes. The molten mass was then cooled to ambient temperature and solidified. The solid precipitate was washed with dichloromethane and 4N sodium hydroxide. The organic layer was washed with water, dried over anhydrous sodium ⁷ '· sulfate and evaporated to dryness in vacuo.

The impure product was purified by silica gel chromatography; in a gel column by washing. dichloromethane: methanol (9: 1) to give 2.07 g of the title compound as the base. This is converted into the usual methanesulfonate, which is crystallized from acetone, followed by acetonitrile. Melting,. 143-146 ° C.

Example 76

8- {3- / 2- (2,6-Dimethoxyphenoxy) -ethyl, amino-propylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyranohydrochloride · '

Homogeneous mixture of 3.3 g of 2- (2,6-dimethoxyphenoxy) -ethyl bromide (J. Augstein et al., J. Med. Chem. 8, 356, 1965) and 8/4 g of XLXI1 Intermediate was heated for 10 minutes. oil bath at 150 ° C. Melted mass cooled to ambient temperature and solidified. The solid precipitate was washed with ethyl acetate and 2N sodium hydroxide. Organic layer - washed with water.

¹⁶⁵ dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The fat precipitate was purified twice by silica gel column chromatography, eluting with ethyl acetate: methanol: 5N methanolic ammonia (97: 3: 0.3), followed by dichloromethane: methanol: triethylamine (90: 10: 0.3). 3 g of pure base of the above compound. The usual way is not clean. hydrochloride crystallized from acetone followed by acetonitrile.'Melt.t. 179-181 ° C.

to 2222/2 '. "//', /? / ': / -: a ./e//2··2 // <

Example 77

8- {3- [4- (5-chloro-2-methoxyphenyl) -1-piperazinyl / propylcarbamoyl] -3-methyl-4-oxo-2-phenyl-4H-1-.

beri z op and ·

This compound was prepared in Example 11 instead of 1- (2-methoxyphenyl) piperazine using 1- (5-chloro-2-methoxyphenyl) piperazine and / or reaction for 6 hours instead of 5 hours. ./

Purify by chromatography on silica gel eluting with chloroform: 5 N ammonia in methanol (100: 1). The title compound was crystallized from 95% ethanol, m.p. 163-166 ° C.

Example 78 2 R, N (E) -8- {4- [4- (2-Methoxyphenyl) -1-piperazinyl] -1-butenyl} 30 3-methyl-4-oxo-2-phenyl- 4H-l-Benzopyran

33.4 ml of a 1 molar solution of lithium bis (trimethylsilyl) amide in anhydrous tetrahydrofuran over 15 minutes

- in a suspension of 6.4 g of -3-hydroxy-35 propyltriphenylphosphonium bromide in 60 ml of anhydrous tetrahydrofuran, cooled to -15 ° C. Thereafter, 4 g of 8-formyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran in 40 ml are merely a solution of 1666 hydrofuran. The reaction mixture was stirred at 0 ° C for 30 minutes, then at ambient temperature for 1 1/2 hours.

The mixture was quenched with methanol, evaporated to dryness in vacuo and the residue was purified by silica gel chromatography eluting with ethyl acetate: petroleum ether (6: 4). The collected fractions were evaporated in vacuo to give 4.17 g of 8- (4-hydroxy-1-butenyl) -3-methyl-4-oxo-2-phenyl10 4 H -1-benzopyran. 'NMR was found to be a mixture of diastereoisomers of E-2 (3.5: 1).

TR-NMR 200 MHz (CDC1 _3, δ)

8.10-8.20 (d, IR, benzopyran in CH at 5, E + Z) 15th 7.30-7.80 (m, 7H, other aromatics, - E + Z) 6.80; 7.00 (2d, 1H, Aryl-CH =, E + Z) 6.41 (dt, 0.78H, CH-CH ₂ , E) 5.90 (dt, 0.22H, CH-CH ₂ , Z) 3.60-3.80 (m, 2H, CH ₂ 0, E.LZ) 20th 2.45-2.60 (m, 2H, CH ₂ Cfl, E + Z) · 2.18 (s, 3H., benzopyran in 3, E + Z) 1.60-1.90 (sa, IR,, OH, ElZ) 1 stirring at 0 g 2.2 g of the mixture obtained above

anhydrous pyridine. 1.65 g of ptoluenesulfenyl chloride are added to the solution. : The reaction mixture was further stirred at the same temperature, then poured into cold 1N hydrochloric acid and filtered under pressure. The elastic solid was washed with water and washed with dichloromethane. The solution was dried over anhydrous sodium sulfate and evaporated to dryness in vacuo to give 2.30 g of (E, Z) -4- {8- / 3-methyl-4-oxo-2-phenyl-4H-1-benzopyranyl} 3-butenyl p -toluenesulfonate having the same diastereoisomeric composition as obtained above

Intermediate.

mixed with acetate.

extracted ethyl washes with water, sulfate and safely purified chromate10

2 ₁ 85 g of the above pt-olsulfonic acid ester obtained and · 2.98 g of 1- (2-methoxyphenyl) -piperazine in anhydrous dimethyl formyl formide for 4 hours at ambient temperature. After that, the mixture into 2 5 0 m 1 water and

Organic. layer dried b.hydrous sodium evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with ethyl acetate: petroleum ether (6: 4). The collected fractions were evaporated to dryness in vacuo and the crude product crystallized from 70% ethanol to give 1.48 g of the title compound, m.p. 119-121 ° C.

¹ H-NMR, 200 MHz (CDCl ₃ , δ)

8, 4 (dd, 1H, benzopyran in CH at 5)

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

7.41-7.70 (m, 5H, phenyl CHs) .7.34 (dd, 1H, benzopyran CH 6)

6.70-7.10 (m, 5H, aryl-CH = and methoxyphenyl CHs)

6.30-6.50 (dt, 1H, J = 16.5Hz, CH-Cl)

3.86 (s, 3H, CH ₃ 0)

3.00-3.15 (m, 4H, 2 piperazine CH ₂ )

2.50-2.80 (m, 8H, 2 piperazine CH ₂ , CHCl 3 ClN)

2.18 (s, 3H, benzopyran in CH _{3 at} 3)

Example 79 (E) -8- <2- (2- [4- (2-Methoxyphenyl) -1-piperazinyl] ethoxycarboxylate} ethenyl} -1,3-methyl-1- - oxo-2 - f en i 1-4H-1 · benzopyran methanesulfonate

Above; The title compound was obtained in Example 6 using Intermediate III instead of 8-carboxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran. Normal operations were performed, followed by precipitation twice.crystallized from ethanol. The resulting solid product is purified on chromatoLT 3038 B

*. <7 graphically on a silica gel column eluting with chloroform: ethyl. acetate ζ (8: 2) / Obtained a pure base dissolved in chloroform: ethanol (1: -1). Addetic acid sulfonic acid was added to the solution and 7 solvents were evaporated in vacuo. The crude salt crystallized from isopropanol to give the title compound, m.p. 193-195 ° C. This. the compound contains 0.33 equivalents of isopropanol and 0.25 equivalents of H ₂ 0.

Example 80

8- (2- / 4- (2-methoxyphenyl) -1-piperazinyl / ethylcarbamoylmethyl) -4-oxo-2-phenyl-4H-1-benzopyran methanesulfonate hydrate 3 '''-··''/ ¹⁵ ' · ^;? / Γ ^{/ 7} ΰ · ' ⁷ / .. k .'.... . ;

A mixture of 2.8 g of XLVII Intermediate and 1.28 g of 1-hydroxy <benzotriazole in 20 ml of anhydrous dimethylformamide was stirred at 0-5 ° C for one minute. A solution of 1.96 g of dicyclohexylcarbodiimide in 20 ml of anhydrous dimethylformamide was added dropwise over 40 minutes and stirred at ambient temperature for 8 hours. Thereafter, 2.24 g was added

1- (2-Aminoethyl) -4- (2-methoxyphenyl) -piperazine 15 ml of anhydrous dimethylformamide solution. The mixture was stirred for 5 hours, then left at the same temperature overnight. The insoluble material was filtered off, the filtrate was poured into 300 ml of water and made basic with N sodium hydroxide. The mixture was extracted with dichloromethane, the organic layer separated, dried over anhydrous sodium sulfate and evaporated in vacuo. The crude product was purified by chromatography on silica gel eluting with chloroform: methanol (95; 5). One molar of methanesulfonic acid was added to the crude base solution in ethanol. Ethyl ether was added until the salt crystallized. The salt was then filtered off and recrystallized from ethanol: ethyl ether (1: 2) to give 1.15 g of the title compound, m.p. 160 '·' 162 ^e C. 7 · '' LT 3038 B

169 '·

Example 81

8- {N-acetyl-3- [4- (2-methoxyphenyl) -piperazinyl] -propylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran ^; '' 5 ^? BB / BB i B.'b'B, <vBB'B

B'2.86 LVII Intermediate solution of 5.04 g of 1- (3-chloropropyl) 4- (2-methoxyphenyl) -piperazine and 2.58 g of anhydrous potassium carbonate: 50 ml of dimethylformamide was stirred at 90 ° C for 7 hours. The reaction mixture was cooled to ambient temperature and poured into 500. ml of water and extracted with dichloromethane. Organic layer washed with water, dried over anhydrous

B sodium sulphate and evaporated to dryness in vacuo. Sediment cleared _? Chromatograph on a silica gel column eluting with ethyl acetate: petroleum ether (7: 3). Received. 1.89 g of the title compound, m.p. (55) 62-63 ° C. Example 82 ~ .j B

8- {2- / 4- (2-methoxyphenyl) -1-piperazinyl / ethylsulfonyl20 amino} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methanesulfonate 'Bj'B

To a stirred solution of 5 g of 8-amino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran and 1.4 ml of triethylamine solution at 0 °

1.05 ml of 2-chloroethanesulfonyl chloride was added dropwise at 0 ° C.

The reaction mixture was stirred for 2 days at ambient temperature. The precipitated solid was filtered off, and the solution was evaporated to dryness in vacuo to give an impure precipitate of ^ - (ethenylsulfonylamino) -3-methyl-4-oxo-2-phenyl-4H-130 benzopyran. A mixture of 7.54 g of this precipitate was mixed with 5.8 g of 1- (2-methoxyphenyl) -piperazine-4.15 g of potassium carbonate in 100 ml of dimethylformamide at ambient temperature, poured into 600 ml of water and extracted with ethyl acetate. Organic; the layer was evaporated to dryness in vacuo and the residue was purified. '· -chromatography on a silica gel column eluting with petroleum ether: acetone (8: 2). Collected

fractions were evaporated to dryness in vacuo and crystallized from 70% ethanol to give 0.75 g of the title compound as above. The solid was dissolved in dichloromethane and one was added to the solution

.. · ... .. V · equivalent of methanesulfonic acid. The mixture was evaporated in vacuo and the resulting crude methanesulfonate was crystallized from acetone to give 0.6 g of the title compound, m.p. 202-203 ° C.

Example 83

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

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 g of sulfur in 5 ml of pyridine mixture was refluxed for 6 hours.

The solvent was evaporated in vacuo for. the precipitate was purified by chromatography on silica gel eluting with chloroform. The resulting compound (base), as above, was dissolved in dichloromethane and added with one equivalent / liter. y // '? // z? ·''?·'. · '/// -, -'? ž \; '- / 7z'. '·'. ·; ··: '' V · / ' Λ · .'T: '// y. ·· //: /' / 'φ /''''·///' · / '' ^: 'boards methanesulfonic acid. The solution was evaporated in vacuo and the residue was crystallized from acetonitrile. Yield 0.7 g, m.p. 189-190 ° C.

Example 84

8- {4- / 4- (2-Methoxyphenyl) -1-piperazinyl / butylsulfonyl} 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methanesulfonate, 1/4 H ₂ O

The above compound was obtained in Example 73 instead of

LIV Intermediate using LX Intermediate. The product was purified by silica gel column chromatography eluting with ethyl acetate: petroleum ether <1 -. '/:?. 171 (7: 3). 11 mol of methanesulfonic acid was added to the dichloromethane base solution. The solvent was evaporated in vacuo and the salt crystallized from acetone. Melting point 212214 ° C. ^ό / 1 i ^; '//// f- ⁷ '^;/; / 57

8- {3- / 4- (2-methoxyphenyl) -1-piperazinyl / propylcarbamoyl} -3-hydroxymethyl-4-oxo-2-phenyl-4H-1-benzopyran, · 0.4 ethanol

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

Example 86

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

0.25 H ₂ 0 1 / '

4g of 8-Carboxy-4-oxo-2-phenyl-4H-1 H -benzopyran (Da Re et al., Ber, 99, 1962, 1966) and 3.75 g -1 (3 g) were stirred at 0-5 ° C. -aminopropyl) -4- (2-methoxyphenyl) -piperazine A solution of dimethylformamide (3 ml) was added dropwise with 3.6 ml of diethyl cyanophosphonate and 2.5 ml of triethylamine was added immediately at the same temperature. Reaction mixture 30

172, <mi «ūciitt. _; ; snarled '. at 0-5 ° C for 3 hours at ambient temperature, then poured into 350 ml of 2.5% aqueous sodium carbonate. The precipitated precipitate was stirred at ambient temperature for 1 hour, filtered under pressure and crystallized from ethanol. The obtained base of the title compound was dissolved in dichloromethane, 1 equivalent of methanesulfonic acid was added and the mixture was evaporated in vacuo; The resulting glassy solid was obtained. which was cleaved and refluxed in acetone for 1 hour to give 5 g of the title compound, m.p. 191-194 ° C. .

'15 - / '' y '/ to' '·.

Example 87

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

0.84 ml of thionyl chloride solution was added dropwise to 17 ml of anhydrous dichloromethane. to 2.0 g of 8-carboxy-2,3-dihydro-4-oxo-4H-1-benzo25 pyran (Lichtenberger et al., Bul1. Chem. Soc. Fr. 275, 1963) and , 75 ml triethylamine in 17 ml dichloromethane solution. The reaction mixture was further stirred for 11/2 hours at the same temperature; then evaporated to dryness in vacuo to give crude 8-chlorocarbonyl30 2,3-dihydro-4-oxo-4H-1-benzopyran. Product used

In the exemplary embodiment, instead of 8-chorocarbonyl-3-methyl-4-oxo-phenyl-4H-1-benzopyran, the base of the title compound is obtained which is purified by chromatography.

column, eluting with ethyl acetate: methanol (85:15). Yield: 1.91 g of pure base which was dissolved in dichloromethane, acidified with methanesulfonic acid and evaporated to dryness in vacuo. Dirty salt was obtained

173. . crystallized from acetonitrile to give 1.57 g of the title compound, which melts at 175-177 ° C.

8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -4-oxo-4H-1-benzopyran methanesulfonate. 1.25 H ₂ 0

The title compound was obtained in Example 87 instead of 8-carboxy-2,3-dihydro-4-oxo-4H-1-benzopyran.

using the 'LXII Intermediate. Dirty methane ...... ·>

sulfonate. washed with ethyl ether, filtered and recrystallized from acetonitrile. Melting point 155-157 ° C. .

Example 89

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

This compound was obtained in Example 86 using 8-carboxy. 6-Bromo-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (EP

107804) instead of 8-carboxy-4-oxo-2-phenyl-4H-1-benzopyran. The support was purified by chromatography on a silica gel column eluting with dichloromethane: methanol (100: 3) and crystallization from 95% ethanol. Melting point

- (150) 154-159 ° C. ·, Example 90 - “R

3 ° R ')' · (T '·' / '</ R7r- · .ų-R

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

1.1 g of diethyl cyanophosphonate and 0.85 ml of triethylamine were added with stirring at 0 ° C to 1.7 g of 8-carboxy-6-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (JP 61- 15880)

T 3038 B

174 and 1.51 g of 1- (2-methoxyphenyl) -4- (3-aminopropyl) -piperazine in 20 ml of anhydrous dimethylformamide solution. The reaction mixture was stirred at 0 ° C for 5 h, poured into 100 mL of water and 10 mL of 1 N

- sodium · hydroxide mixture. Precipitate - the base of the above compound filtered off; and washed with water. The base was precipitated, converted in the usual way to methanesulfonate, which crystallized from acetonitrile. yield 1.7 g; ^lyd.11; 18-5-186 ° C. · '' ¹⁰ '

Example-91

8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -6-hydroxy-3-methyl-4-oxo-2-phenyl-4H-11β-benzopyran methanesulfonate. .

0.8 g of Example 114 and 5.8 mL of 1N sodium hydroxide in 10 mL of methanol were stirred at ambient temperature for 4 hours. After stirring overnight, 15 mL of 1 N sodium hydroxide and 15 mL of methanol were added, and the mixture was stirred at ambient temperature for 1 hour.

The methanol was evaporated in vacuo and water was added to the precipitate · The suspension was filtered under pressure to give 0.48 g of the title compound as a base. It is converted into its methanesulfonate salt by conventional means and recrystallized from acetonitrile. Melting point 200-202 ° C. . - .c ''

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

The title compound was obtained, for example, by replacing 8-carboxy-6-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzo35pyran with 8-carboxy-3,6-dimethyl-4-oxo. 2-phenyl-4H-1-benzopyran (Da Re et al., Arch. Pharm.

> - /. 175

296/714 (1963). The crude methanesulfonate crystallized from acetonitrile, m.p. 196-197 ° C.

• -5 // 7 ///-...// ../ .//:.,/,/---:///.7/-/7-:.

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

This product was prepared in Example 12 using Intermediate LXVIII instead of 8-chloro-carbonyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran and 1,1,2-trichloroethane instead of chloroform. The crude product was purified by chromatography, eluting with dichloromethane: methanol (98: 2). The collected fractions were evaporated to dryness in vacuo and crystallized from ethanol to give the title compound, m.p.

159.5-161 ° C. . '

Example 94

8- {3- / 4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -6-amino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran g of the compound of Example 93, A mixture of 109 ml of 1N hydrochloric acid, 105 ml of water and 8.78 g of Renee Nickel in 950 ml of ethanol was stirred at 40 ° C, hydrogenated in a Parr apparatus under 2 atmospheres. The catalyst was then filtered off and washed with 80% ethanol. The stock solutions were evaporated in vacuo to a volume of 80 ml and filtered. * Six ares. the product was washed with water and suspended in water; 37% hydrochloric acid was added to pH 1. The insoluble material was filtered off / under pressure and the filtrate was basified with 35% sodium hydroxide. Sedimented above / compound recovered - filtered, rinsed with water and sucked off. 26 g of melting point (108) 215-217.5 [deg.] C., used in Example 95 without purification, are obtained, and 4.7 g of product are crystallized from ethanol, followed by 85%:

'' 176.

ethanol to give 3 g of the title compound, m.p. 218-219 ^Ū C. j / ^l '^; 7y / j '.

Example 95 *. v / 7

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

The title compound was obtained in Example 37 using the compound obtained in Example 94 instead of -33 in Example. The reaction mixture was diluted with water and filtered under pressure, washing the solid product with water. The product was dried at 80 ° C, and the solid was purified by silica gel column chromatography eluting with chloroform: methanol (95: 5). The collected fractions were evaporated in vacuo and the residue crystallized from 95% ethanol to give the title compound, m.p. (150) 218-220 ° C. ¹ .

Example 96

8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl) -6-ethylamino-3-methyl-4-oxo-2-phenyl-4H-1-benzo [25] pyran '

A mixture of 8.42 g of Example 94, 0.45 mL of acetaldehyde, 0.59 g of 85% sodium cyanoborohydride and 3.3 mL of 4.85 N ethanolic HCl, 75 mL of methanol was stirred at ambient temperature for 5 days. . The reaction mixture was then poured into water and filtered under pressure. The precipitate was filtered off with suction, purified by column chromatography over silica gel eluting with chloroform: methanol (10: 3). Fractions were collected, evaporated in vacuo and recrystallized from 6 g of ethanol to give 6 g of Example 94 and 2.67 g of the title compound, m.p. 198-201 ° C. . 7th

177

Example 97

8- (3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -6-dimethylamino-3-methyl-4-oxo-2-phenyl-4H-1-benzo [5 '] pyran

The above compound obtained in Example 35, instead of Example 33 using the compound obtained in Example 94 and reacting 10 moles of 40% formaldehyde,

10 'instead of 7 moles and 3 moles of sodium cyanoborohydride, instead of 2 moles under stirring at ambient temperature' for 18 hours, instead of 4 1/2. ' ). The fractions were collected, evaporated in vacuo, and the residue crystallized from ethanol to give the title compound, which melted at i83-186 ° C.

Example 98

8- {3- / 4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -7-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran

The title compound was obtained by the procedure of Example 87 but using LXIX Intermediate 8-carboxy-2,3-dihydro-4-oxo-4H-1-benzopyran. The solid was purified by silica gel column chromatography eluting with ethyl acetate: methanol (8: 2). The collected fractions were evaporated to dryness in vacuo and the residue crystallized from acetonitrile to give the title compound, mp 151-152 ° C.

178

8- (3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3-methyl-4-oxo-2- (4-trifluoromethylphenyl) -4H-1-.

benzopyran methanesulfonate ^; '

The title compound was obtained in 90 Example from the intermediate LXXI, crystallized from acetonitrile, m.p.

Example 100

8- {3- / 4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -2- (4-benzoylphenyl) -3-methyl-4-oxo-4H-1-benzopyran methanesulfonate polyhydrate

The above compound was obtained in Example 90 from

LXXIV Intermediate instead of 8-carboxy-6-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran. The crude methanesulfonate was crystallized from acetonitrile. Melting point 208210 ° C.

. Example 101

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

The title compound was obtained in Example 90 from Intermediate LXXVII in place of 8-carboxy-6-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran. Weightless me '..- Z' ''., ·; .. ';'. S tansulfonate was crystallized from acetonitrile. Melting point

200-202 ° C.

179

Example 102

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

This compound was prepared in Example 86 using 8-carboxy-2,3-dimethyl-4-oxo-4H-1-benzopyran (Da Re, Farmaco Ed.

Sci., 11, 678, 1956) instead of 8-carboxy-4-oxo-2-phenyl-4H-1-benzopyran. The reaction was carried out for 5 hours at ambient temperature. The product was purified by chromatography on silica gel eluting with chloroform: methanol (98: 2) and crystallized from acetone. Melting point 155158.5 ° C.

Example 103 '

8- (3- / 4- (2-methoxyphenyl) -1-piperazinyl / propylcarbamoyl) -2- (t-butyl) -3-methyl-4-oxo-4H-1-benzopyran dihydrochloride dihydrate

This compound was obtained in Example 86 using LXXVII1 Intermediate instead of 8-carboxyl-4-oxo-2-phenyl-4H-1-benzopyran. The base was purified by chromatography on silica gel eluting with chloroform: methanol (49: 1) and

..... · converted to dihydrochloride in methanol: ethyl ether. The product was crystallized from methanol: ethyl ether (1: 1), m.p. 226-229, 5 ° C.

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

This compound was prepared in Example 86 using LXXIX Intermediate instead of 8-carboxy-4-oxo-2-phenyl-4H35 1-benzopyran and reaction for 5 hours at ambient temperature. The product was purified by chromatography on silica gel,. After washing with chloroform: methanol

180 '(49: 1) and crystallized from acetonitrile (m.p. 155' J · /// - 157 ° C).

Example 105 /) / ..

· './'////',.//Vb)^

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

This compound was obtained in Example 86 using LXXXI

Intermediate instead of 8-carboxy-4-oxo-2-phenyl-4 H -1-benzopyran. The reaction was carried out for 5 hours at ambient temperature and then quenched. The title compound was isolated by chloroform extraction and purified by silica gel column chromatography. chloroform: methanol (49: 1) followed by crystallization from acetonitrile. Melting point 151-153 ° C.

Example 106

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

This compound was obtained in Example 86 using LXXXIII Intermediate instead of 8-carboxy-4-oxo-2-phenyl-4H25 1-benzopyran. The product was purified by stirring in water (removing dimethylformamide) followed by chromatography on a silica gel column, eluting with chloroform: methanol (49: 1) and crystallizing from acetonitrile. Melting point 174-175 ^U C.

Example 107 8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -4-oxo-2-phenyl-4H-1-benzothiopyran ·

.) 7/77) 7: / - i, '////. / /.'/,7-))]

A mixture of 2.8 g of LXXXIV Intermediate and 3.4 g of 1,1 'carbonyldiimidazole in 60 ml of anhydrous formamide

181 • δ10

Stirred under nitrogen at ambient temperature for 1/2 hour. Was added 2.7 g of 1- (3-aminopropyl) -4- (2-methoxyphenyl) -piperazine .Reakcijos ^- the mixture is stirred for 2 hours at ambient temperature, and then poured into 300 ml of water and extracted with chloroform.

The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with chloroform: methanol (49: 1), washed with water and crystallized from acetonitrile to give 2 g of the title compound, m.p. 144-146 ° C. . J -J ··?

Example 108 · (E) -8- {3- [4- (2-Methyl-Phenyl) -1-piperazinyl] -propylcarbamoyl} -. (2 - s ti ri 1) - 4 H -1 -be nz op and an as

This compound was obtained in an intermediate of 86 instead of 1-benzopyran. Product rilo.Lyd.t.191-194 ^c C.

As an example, used on LXXXVI 8-carboxy-4-oxo-2-phenyl-4H- crystallized from acetonitrile?

Example 109

8- (3- [4- (2-Methoxy-phenyl) -1-piperazinyl] -propylcarboxylic acid, 3-methyl-2- (4-methylphenyl) -4-oxo-4H-1-benzopyran) '' The title compound was obtained in Example 86 using the intermediate LXXXVII ^ in place of 8-carboxy-4-oxo-2-phenyl-4H-benzopyran and carrying out the reaction for 4 hours at ambient temperature The reaction was stopped and the title compound isolated by extraction with ethyl acetate. , dried over anhydrous sodium sulfate and evaporated in vacuo, then washed with ethyl ether and crystallized from acetonitrile, mp 161-163 ° C.

<

Example 110. ^, / - ////, / - /,.// i82

8- (3- / 4- (2-methoxyphenyl) -l-piperazinyl / -propilkarba- Moilan _i} -2- (4-methoxyphenyl) -3-methyl-4-oxo-4H-1-benzopyran / /// / '7 /? / -' // '' · y ', / 77, /., /, /.///:7..-,,7., //. Y

This compound was prepared in Example 86 using 8-carboxy-2- (4-methoxyphenyl) -3-methyl-4-oxo-4H-1-benzopyran (EP 108986) instead of 8-carboxy-4-oxo-2-phenyl-4H-. l-benzopyran. The reaction was carried out for 3 1/2 hours at ambient temperature. The product was purified by chromatography on silica gel eluting with chloroform: methanol (49: 1) followed by crystallization from acetonitrile. Lydt. 158-161 ° C.

Example 111

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

This compound was obtained in Example 86 using the LXXXIX Intermediate instead of 8-carboxy-4-oxo-2-phenyl-4H1-benzopyran. The product was purified by chromatography on silica gel eluting with chloroform: methanol (100-: 2-100: 6) and crystallized from '95% ethanol. Melting point

166-168 ° C.

Example .112,

8- {3- / 4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbyl ··· / -, ·. moil} -6-methanesulfonylamino-3-methyl-4-oxo-2-phenyl-4H-l,, -. benzopyran hydrochloride

0.032 ml of methanesulfonyl chloride was added dropwise over 10 minutes to a stirred solution of 0.21 g of Example 94 and 0.062 ml of triethylamine in 4 ml of dimethylformamide at -20 ° C. At the same temperature

// '2 - //, // 2 / .183 7/2 // g, ///. · Stirred for 3 1/2 hours'. The reaction mixture was then poured into water and the suspension filtered under pressure to give 0.1 g of the title compound, which was recrystallized from 80% ethanol. Melting point 272-275 ° C.

5 · - Example 113

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

10 '··.

The title compound was obtained in Example 90 from Intermediate XCVIII in place of 8-carboxy-6-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran. The reaction mixture was stirred at ambient temperature for 1 hour, then poured into cold 2% sodium carbonate solution and the precipitated solid collected by filtration under pressure. The title compound was dried and crystallized, m.p. (60) 185-187 ° C.

Example 114 8- (3- [4- (2-Methoxyphenyl) '- 1-piperazinyl] -ptopylcarbamoyl} -6-diethoxyphosphinonyloxy-3-methyl-4-oxo-2-phenyl-4H-benzopyran

The title compound was obtained in Example 90 from Intermediate LXIII instead of 8-carboxy-6-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran using 2 equivalents of diethyl cyanophosphate instead of 1.1 equiv. '. Filtration of the water gave the title compound 7, m.p. 48-80 ° C (dec.). The above compound may be 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl / propylcarbamoyl] -6-hydroxy-3-methyl-4-oxo-2-7

Prodrug of 7-phenyl-4H-1-benzopyran.

357.2 / - / 7 2.7 / '. 22: 72222/22. ///. 22 / '

184

Example 115 /./, '

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

. methanesulfonate, 2/3 H ₂ 0 The crude product of the title compound is obtained from intermediate C, instead of 8-carboxy-6-methoxy-3m-1 - 4 - o x o - 2 -phen i 1 - 4 H -1 - ben z op and an O The solvent was removed by chromatography on a silica gel column eluting with ethyl acetate: methanol (9: 1). The product was converted to methanesulfonate by conventional procedures and recrystallized from ethyl acetate. Melting point 145-148 ° C.

-Example 116 ^: 8- {N-Methyl-3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran « hydrochloride

This compound was prepared in Example 12 using the CI Intermediate instead of 3- / 4- (2 + methoxyphenyl) -1-piperazinyl / propylamine. The crude base was purified by chromatography on silica gel eluting with chloroform: 5 N methanolic ammonia (100: 1) using conventional methods. converted to the hydrochloride. The product was crystallized from acetone. Melting point

195-198 ° C.

Example /117///2./'-·/ ./·''+//

7- {3- [4- (2-methoxyphenyl) -1-piperaziryl] -propylcarba; moyl} -2-benzoyl-3-ethyl-benzo (b) furan

This compound was obtained in Example 86 using Intermediate CIII instead of 8-carboxy-4-oxo-2-phenyl-4H-benzopyran-8-carboxylic acid. Reaction run7 / 777 185 7 / \ '' '7> ./.' 7 '· ta 4; hours at ambient temperature. The product crystallized from ethanol.'Melt.t. 165-166 ° C.

Example 118 ;: 5 / j // ⁷ 7; 7 /// 77 ;; ⁷ ^ 7; ^^ ⁷ './ <. '7.7 /./:. ⁷ 7/7 ^ 7c7

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

The title compound is obtained in Example 86 using CVI Intermediate instead of 4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic acid. The reaction was carried out for 20 hours at room temperature. The base was purified by crystallization from ethanol (m.p. 164166 ° C).

Example 119

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

A mixture of 6.2 g of methyl 3-propionyl salicylate and 5.8 g of nicotinoyl chloride hydrochloride in 18 ml of anhydrous o pyridine was stirred for 2 hours and heated to 100 ° C under nitrogen. Thereafter, 16 ml of triethylamine was added and heated at the same temperature for 1 hour. The reaction mixture was cooled to room temperature, poured into 600 mL of water, and the precipitate was collected under pressure and washed with water to give 5.4 g of methyl 2-hydroxy-3- (2-nicotinoyl) propionyl benzoate which was used in the next step without purification.

3.4 g of this intermediate were dissolved in 15 ml of acetic acid ii in 1 ml of 37% hydrochloric acid and heated at 100 ° C for 1.5 hours. The mixture was cooled to room temperature, poured into 150 mL of water and extracted with ethyl acetate. The organic phase was washed with 5% aqueous sodium bicarbonate followed by. water, dried over sodium sulfate and evaporated in vacuo to give 1.3 g of crude methyl 3-: methyl-4-oxo-2- (3-pyridyl) -4H-1-benzopyran-8-carboxylate.

1 g of the above ester was dissolved in 9 ml of methanol and 15 'ml of 1,4-dioxane and slowly combined with 1.7 ml of 10 N sodium hydroxide, maintaining the temperature at 20-25 ° C. The reaction was carried out at 50 ° C for 1 hour, after which the reaction mixture was poured into 150 ml of water and extracted with ethyl acetate. The aqueous layer was acidified with 1N hydrochloric acid.

The precipitate was collected under pressure to give 0.6 g of 3-methyl-4-oxo-2- (3-pyridyl) -4H-1-benzopyran-8-carboxylic acid which was used in the next step without purification.

The title compound was obtained in Example 86 using the above Intermediate instead of 4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic acid and reaction for 2 hours at room temperature.

The base was purified by chromatography on silica gel eluting with chloroform-methanol (98: 2), followed by crystallization from acetone to give 0.1.5 g. (mp 134.5137 ° C).

Example 120

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

1 g 59 Example compound and .0.32. g of 4-dimethylaminopyridine was dissolved in 10 ml of dichloromethane and slowly combined with 0.15 ml of acetyl chloride while maintaining the temperature at 8-10 ° C.

The reaction mixture was refluxed for 2 hours at room temperature, then the reaction mixture was poured into 70 ml of water and extracted with dichloromethane.

187 • 5% aqueous sodium hydrocarbonate followed by water, dried over anhydrous sodium sulfate and evaporated in vacuo. '

5 · The crude base was purified by chromatography on silica gel eluting with ethyl acetate-methanol (9: 1) followed by crystallization. from ethanol to give 0.74 g of the title compound (m.p. 120-123 ° C).

Example 121 '

3-Methyl-8- {3- [4- (2-methylaminocarbonyloxyphenyl) -1-piperazinyl] -propylcarbamoyl) -4-oxo-2-phenyl-4H-1-benzopyran *, c. ,,, ·· .. ..

g '59 Example compound and 1.8 ml of methyl isocyanate were dissolved in 30 ml of dry N, N-dimethylformamide and stirred at room temperature for 24 hours. The mixture was diluted with water, stirred for 2 hours and then filtered under pressure. The crude product was purified by chromatography on silica gel eluting with chloroform: 5 N ammonia in methanol (100: 3).

The title compound was crystallized from ethanol, m.p. 132-135 ° C.

Example 122

6-Acetoxy-8- {3- [4- (2-methoxyphenyl) -1-piperazinyl / propylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, stirred at 0 ° C. C 1 g 91 mg of acetyl chloride was added dropwise over a period of 5 minutes to a solution of the compound of the Example and 0.32 ml of triethylamine in 36 ml of chloroform. The reaction mixture was stirred at the same temperature for two hours, diluted with dichloromethane and water; organic layer separated, washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. The precipitate was crystallized from acetonitrile, yielding 0.8 g of the title compound, m.p. 148-149 ° C.

Example 123 (R.S.) -2,3-Dihydro-4-hydroxy-8- {3- [4- (2-methoxyphenyl) -1-piperazinyl / propylcarbamoyl} -4 H -1-benzopyran methanesulfonate

The title compound was obtained in Example 17 from Example 87 instead of Example 1;

The reaction mixture was diluted with water and stirred for 15 minutes; followed by extraction. ethyl acetate. Usual product / crude product obtained which was purified by chromatography on silica gel. eluting with dichloromethane: methanol (95: 5). The collected fractions were evaporated in vacuo to give a pure base which was converted to methanesulfonate and crystallized from acetonitrile (m.p.

. 172-175 ° C).

Example 124 '

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

2.22 g of Example 113, 0.56 g of Renee-Nickel in 96 ml of ethanol and 4.8 ml of acetic acid were hydrogenated in a Parr apparatus (pH ₂ = 1 atm) at room temperature. .

30 '

The reaction mixture was shaken for 6 hours, then the catalyst was filtered off, the filtrate was basified with 3N sodium hydroxide and diluted with water. The reaction mixture was stored for 2 days, after which the precipitated compound was collected under pressure, washed with water, suctioned and recrystallized from ethyl acetate.

189 '' -A · / ·,., ...

. acetate, followed by ethanol to give 1.5 g (mp 192194 ° C). \ '' Α '· ΑΛ. \ ¢¢ /

Example 125 · s: y · .. v ·.; · / Y / .'y · J, '; /. i3i> .y ·, <α · _; '

2- (4-Acetylamino-phenyl) -8- {3- [4- (2-methoxy-phenyl) -1-piperazinyl] -piperazinone} -3-methyl-4H-1 ben z opi r ana s

The compound above. obtained 36. By way of example, 10 'using the compound obtained in Example 124 instead of 33

Sample compound.

It was purified and crystallized from 95% ethanol (m.p. 207-209 ° C).

'

Example 126

2- (4-Hydroxyphenyl) -8- {3- / 4- (2-methoxyphenyl) -1-piperazinyl / propylcarbamoyl) -3-methyl-4H-1-benzopyran dihydrochloride monohydrate

The title compound was obtained in Example 86 using the CVII Intermediate in place of 4-oxo-2-phenyl-25H-1-benzopyran-8-carboxylic acid in a reaction at room temperature for -14 hours in the presence of a co-solvent of phosphoramide.

Excluded. the diethylphosphonyl ester of the title compound was hydrolyzed with alkali and then neutralized with dilute hydrochloric acid. The crude product was extracted with chloroform and the organic layer was washed with water and; evaporated. in a vacuum. The salt was obtained by adding ethanolic HCl to a base acetone solution, evaporated to dryness and washed with acetone (m.p. 193-205 ° C).

190

Example 127

8- (3- / 4- (2-methoxyphenyl) -1-piperazinyl / -propylcarbamoyl} -2-f 4-enyl, N N ₄ -triokso _{1Z-4H-l-benzopyran} in mono \ 5 hydrate.

0.8 g of 107 and 15 ml of acetic acid are combined with. 0.32 mL of 30% hydrogen peroxide and stirred at 50 ° C for 3 h. 0.48 ml of 30% hydrogen peroxide (3 x 0.16 ml portions, hourly / heating for 2 hours) was then added to the mixture.

The mixture was cooled, poured into 240 mL of water, neutralized with 5% aqueous sodium bicarbonate at pH 7 and extracted with chloroform. The organic layer was washed with water, dried. anhydrous sodium sulfate and evaporated in vacuo to give 0.18 g of the title compound which crystallized from acetonitrile, m.p. 172-175 ° C.

Example 128

7- {3- / 4- (2-methoxyphenyl) -1-piperazinyl / propylcarbamoyl) -2-phenylbenzo [b] furan ',

The title compound was obtained in Example 86 using 2-phenylbenzo / b / furan-7-carboxylic acid (EP 306, 226 (1989)) in place of 4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic acid and / 1.5 hours at room temperature ·

It is crystallized from carbon tetrachloride (m.p.

r y? yd / 'y.j ·., .. \

y '.-J' 191. Example 129

- {3 - [4- (2-hydroxy-oxy-1-yl) -1 -piperazinyl] -1-methyl-1-sulfamoyl} -3-methyl-4-oxo- 2-phenyl-4H-1-benzopyran

? 5r Methanesulfonate y y ·, 2.29 g of VIII Intermediate was added portionwise to 1.5 g of CI Intermediate and at 0 ° C. 0.95 triethylamine in 30 ml of chloroform solution.

10 '

The reaction mixture was further stirred at room temperature for 2 hours, diluted with dichloromethane, water and 0.5 N sodium hydroxide. The organic layer was washed with water, dried over sodium sulfate and evaporated to dryness in vacuo.

The residue was purified by chromatography on silica gel eluting with ethyl acetate - methanol (96: 4). The dead fractions were evaporated in vacuo to give the pure title compound as a base. This was converted to the methanesulfonate salt in the usual manner, which crystallized from ethyl acetate to give 2.75 g, m.p. 135-141 ° C (dec).

Example 130

8- {3- / 4- (2-Methoxyphenyl) -1-piperazinyl / butyl-N-methylsulfamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methanesulfonate

The title compound was obtained in Example 129 using CVIII Intermediate instead of CI Intermediate. /

The title compound was crystallized from acetonitrile (m.p. 173-175 ° C).

192. PHARMACOLOGICAL INFORMATION

Methodology

Sprague Dawley rat males / Crl: CD * BR) 200-300g, Albino Swiss mouse / Crl :: CD-H (ICR) BR / 20-30g, Beagle dog males (10-12 kg), . obtained from Charles River, Italy and Nossan (Correzzna, Milan, Italy), respectively. The animals were free to use food and water and forcibly kept in the light-dark cycle at 22-24 ° C during the experimental days.

Omus Toxicity '15 - Synthesized-Compounds for Swiss Mice • Intraperitoneally and orally followed by acute toxicity of these compounds. Four logarithmic doses of the test compounds were dissolved or suspended in 0.5% methylcellulose and 10 ml / kg in groups of four mice / dose. Mortality was determined after 7 days. Analytical data: LD ₅₀ values and their confidence limits were calculated by Weil (Biometrics, 13, 249, 1952). method.

Receptor Relationships Research

- / 3H / prazosin bond (α ₁ receptors)

Rat / cerebral cortex is homogenized

50 volumes of original wet weight in icy 50 m M

In Tris-HCl buffer, pH / 7.4. The homogenates were centrifuged at 48,000 x g for 10 minutes and the peas were twice

·. / Resuspended in _(the same volume of ice-cold buffer, centrifuged and resuspended two more times. The final pellets obtained two Seal resuspended in the same volume of buffer and incubated according to the conditions reported in the table below.

Preliminary studies of receptor binding, as well as experimental data in dogs described below, determine the compounds of the invention. cp -blockers, i.e.: present in the class of widely used antihypertensive and anti 5.j- -BHP agents. Watch e.g. Frishman, • K.H. et al., Medical Clinics of N. America, 72, 427,

-. 1988 and the directions cited therein.

- / 3H / 8-OH-DPAT bond (5HT _1A · receptors):

/ 10 \\ // λ // 7 ^ / 7 - // 7 '/;/.'/.//..y/':'///;./'/y. /// '/? /.; //' // 7 ^: /; '' - r: '^;' ^: 7' // :: ^; 7 ^;

Homogenized rat hippocampi in 50 volumes of original wet weight ice-cold 50 nM Tris-HCl, pH

7.4. The homogenates were centrifuged at 48,000 x g for 10 minutes, and the peas were suspended twice in the same volume of ice buffer, kept in a thermostat at 37 ° C for 10 minutes, centrifuged, and resuspended twice. The resulting peas were twice suspended in the same volume of buffer and maintained in a thermostat below the conditions described in the table. The following receptor binding assays are useful for determining compounds of the present invention as 5HT _1A receptor ligands. As described above, compounds containing 5HT _iA ligands exhibit anchio7 lithium 7 / and / antidepressant efficacy in animals. and humans (Hamon, M. et al., Ann, NY Acad. Sci., 600, ': 114, 1990; Traber J. et al., TIPS, 8, 437, 1987) 77

194

Receptor Relationships Research

Receptor / Ligand / ++ 'Conditions'' /, </ 1 adrenergic / H / · 5-HT _1A prazosin serotonergic / H / 8-OH-DPAT / nM / ligand 0, 35 1.0 preparation (n.m.p) -. 1 ml 1 ml 10 mg / ml 10 mg / ml incubation buffer * Tris HCl Tris CH1 50 mM 50 mM ' pH 7.4 pH 7.4 nonspecific connection prazosin 5-HT 2µΜ 10µΜ incubation 25 ° C 25 ° C 30 min 30 min

n.m.p = dirty membrane preparation *. = with 1% ascorbic acid and ΙΟμΜ pargyline

After some time removed, from the thermostat (see table), it was rapidly filtered through Whatman GF / B filters using a Brandel cell harvester. The filters were washed twice with 15 ml of ice buffer (see table). The remaining radioactivity in the filters was determined by calculating the fluorescence of the liquid. Non-specific relationship (totaling 1030%) was evaluated by adding high concentrations of specific substitutes (see table). All compounds were initially tested at a concentration of 1 χ 10 ^-6 M and, at significant substitution activity, a full competition curve (up to 10 ¹¹ M) was obtained. All examples were repeated three times.

Competitive curves were analyzed all the time (IC ₅₀ values / Estimation) by a logical equation adapted to the non-linear curve / De Lean et al. (Am. J. Physiol. 235, E97,

1978) using the ALLFIT program (publicly known from the National Institutes of Health (N.I.H.) in Bethesda, Maryland, USA) as recorded in the IBM PK. j

f 195 \,, K * -caused contractions of the bladder rhyme in rats

The whole bladder of rats was removed and immediately placed in b / d Krebs solution heated to · 37 ° C. From the bladder dome 5. Cut the lumbosacral muscle (20-30 mm in length, 1-2;

mm wide). Each iris was placed in a 10 ml organ bath and connected to a isometric strain gauge (DY-1 Basile, Comerio, Varese, Italy) at a constant load of 1 g. Contractions recorded

Basile 7070 polygraph. After 60 minutes equilibration, the bars were exposed to 80 mM KCl (final concentration). This caused rapid phase contractions followed by deceleration and continuous reinforcement. When the tonic contraction was stable, the strips were washed and then ^- 30 minutes caused a new contraction. After two or more of the reproducible reactions recorded, a single concentration of test drug was added to the bath and a new contraction was induced after 30 minutes. The 'concentration' of each test drug was determined in experimental groups consisting of at least two preparations taken from different animals. IC ₅₀ values for inhibition of antagonist-induced contractions were estimated by linear regression analysis.

Effects on canine urethral contraction and blood pressure

Experimental kit Imagawa et al. (J. Pharmacol. Methods, 22, 103-111, 1989), with substantial modifications: Aduit male hounds, weighing 8 to 0 kg, anesthetized with pentobarbital sodium (30 mg (kg iv and 2 mg / kg / h iv), intubated and involuntarily ventilated with room air.Systemic Blood Pressure (BP) is regulated by the introduction of a PE catheter;

'. - / · 'btl

Anesthetic is infused by injecting into the extra left. femoral vein needle. Noradrenaline (NA) injection into

. the artery is done by inserting a PE catheter into the inferior abdominal aorta through the right external iliac artery. As a result of this procedure, the NA was selectively distributed in the lower urinary tract and the nearest urethra was exposed through the middle abdominal wall incision. Two ureters were introduced to prevent bladder filling and urine was removed. Urinary duct pressure 'set by inserting into the bladder Micro-type catheter (6F) through the external urethral duct and removing when the pressure transducer is inserted into the prostatic urethra. interactions with the bladder. The catheter is protected by placing another bandage around the Micro-type catheter near the outer urethral lumen. * The stabilization period was followed by a surgical procedure (30 min) in which arterial and prostatic urethral pressure were continuously controlled as baseline NA for 10 min. at intervals. ¹ dose of NA is selected to produce at least 100% increase in urethral pressure. Test compounds are administered "by magnification: iv, at intervals of 15-20 minutes between administrations. NA injections are repeated approximately after each test compound has been administered.

Dose response curves are based on the percentage inhibition of urinary (NA) increase in test compounds and the percentage drop in blood pressure. Diastolic blood pressure ED ₂₅ (dose causing 25% reduction) and ID ₅₀ (dose causing 50% NA - induced urethral depression) were evaluated by linear regression analysis.

Results //''.'/à· '> \'

The compounds obtained in the Examples were analyzed as described above and the results are given in the tables below, taken together

197 • Standards used with comparison results. Compounds with 'receptor affinity (IC ₅₀ values) of less than about 500 nM are generally considered to have' good affinity. The first order includes those compounds with IC ₅₀ values less than 100 nM. .

15 '

198

Table 1; to. to

The compound i - Peceptoric connection Acute mouse toxicity _; to K ⁺ stimulation of the bladder of the rat 1 bladder, - j An example IC50 (nM) (mg / kg) (μΜ) /.//j No. 5HT _la i .p. // p.o. Phase susitrau-1 kimai- -j To Tonic i ⁴ / Ssoj / I 346 1732 I ⁵ 20th ./19///7/: 621 > 3000 1 ⁶ 107 1000 233 8 ⁷ 86 7.15.5 / 7 / j 384 1915 '· 8th 66. 111 > 500 1915 11th 29th 9th 247 297 2.9 3.0 13th 68 229 > 10C0 > 3000 10.0 10.0 14th 61 6th 140 559 ' ^15th 8th 131 306 496 16th 220 1050 345 778 1.6 2.2 17th 59 910 299 ' 608 8.8 · 3.8 18th 270 > 1000 457 3000 19th 165 340 > 1000 > 3000 20th 169 ...... 85 297 59.4 2.7 2.5 21st 17th 33 297 566 22nd 117 48 > 500 > 200.0 S ²⁴ 690 212 > 1000 > 3000 26th 270 > 1000 > 500 > 2000 27th 23rd 124 399 > 3000 1.0 0.8 S ²⁸ 120 96 203 1127 I ^29th 86 ..... 45 730 > 3000 10.0 -10.0 To 32 119 46th 301 > 2000 10.0 > 10 I ³³ 17th 38 399 > 2000 10.0 10.0 1 ³⁴ 30th /34:./ > 500 2.8 3.6 8 ³⁵ 15th 8 '' '' Ch'J ' 329 959 j 36 18th 54 i J / · ' > 500 > 2000 J ³⁷ 32 77 J // > 500 > 2000 To 38 20th 344 > 500 > 2000

Continuation of the table ki that fox

199

Table 1 (cont'd)

Compound ' Receptonic / connection Mouseworm 7 / toxicity / / / ' Stimulation of the bladderK ^{+ in} rats An example / ^IC ™ /// / (nM) ^^ 50 //; 7 (mg / kg) '1 ^ 50 // (μΜ) No. ' ^α ι // 5-HT _lt i -P · /// '' P-o././//· ' Phase whirling // · // '/ Kim ^J Tonic 39 90 170 > 1000 > 3000 40 75 83 140 349 0 / .5 .//////'/ Z 0.9 41 43 '' 53 '///./ · 399 2241 317 /// 7,. // 1.4 42 111 /.3/977//7./-// ./453//// 2163 'ΙΌΐΌ /'////./; 10.0 43 166 > 1000 44 685 201 34 / 7-:.: // 399 /ο/δ/'/Ζ//./// 0.5 45 15th 106 / 323 / '/' '/ 1727 46th 86 ///// 23rd 47 36 '//' // / 23 // 7/7 / 330./'/// 1047 -2- / 7: //// 77 // 5.2 48 104 / 5 / /: // //// 500, // 1914 49 152 · / ’/ · ./’/ /.3/////: 432 > 2000 50 39 300 211. - 299 51 22nd 84 > 500 > 2000 52 8 9 2 l //// i? i · ./././ · 224 53 7th / 41 /////: / '12? 7 /// .1020 54 35 143 ///.//. 106 421 55 291 > 1000 128. > 2000 7 '/ ·' 7 '·' ... 7 · '·'. ' 56 25 //// · / · -748 of > 500 57 69. > 1000 500 > 2000 58 > 1000 126 2 58. 7 // / 508, 7 '53, ////. '5./'//// 3. '' '/. 7 /' // > 500 278 60 /.//.././ / 25/1 / '45' 203 / / '329 ///' '' 61 // ''. 36. '// ii /// 315; / '/' / 592 // · '/ 62 252 278 ¹²⁸ 344 / 63 / '//// , 194 / 99 309 479 64 J 40 ' 11 ·· / '65 '·. 113 26th 66 57 ..// 56 601

Continuation of table in next sheet

Table 1 (continued).

Compound] * Receptor communication, -. / Acute Mice / Toxicity, * Rat urinated '/, ... j bladder K ⁺ / licking roe deer An example (nM) : LD _5Q / 7 / (mg / kg) ^ C ./:/</'/ /: (^ /, ////: No. : <l /// f ; 5,. / P // 7 / p. o. , ', .- / / Phase .source ΚΧίΠαΧ • Tone / -6-7 / - / 7-: /// - / :: / / 4: //// 7 4 I /, j 508 1868 / · ' 68 -, //// .29 13/7 : 69 16 // - <Τ / 77 '/ 344 .-- 7 / / 7Ό7 /// - 7 / 7-. /53<//.7.'7 / 85 7 /// > 500 18.68 .71 - // 5 ·· 10.8 69 72- 145 111 479 > 2000 73 6th 89 202 /46.2/,,/--, 74 178 482 .- / -. · /., / i. '- · /' 75 147 15th 78 18th 116 ^: / 7. '- · Γ 79 77 141 > 500 ' > 2000 80 28th 162 81 13th 81 θ.3 30th 5 84 5 2 85 16th 14th ///. . ·, / .-, 86 48 20th 87 119 107 237 /> 500 / / 88 216 11 - / 77 93:, 7 ^v: '7 / 7'f j 47 38 ^'94  39 // 77 / 56 //, // ', '9857 ^: //7'.'7 103 52 ///// 99 44 5 7 // 102 56 18th - / '--7 --- 104 9,7,7,7. 55. '/ 7 107 37 / '/ 16th 110 /: To Flavoksa-? j it 26 7 * »1000 15th »1000 385 808 13- 13 J

201Table 2 /

Effects on canine urethral contraction and blood pressure

Compound Example No. Urethral ED ₅₀ (gg / kg) DBP ed ₂₅ (gg / kg) DBP / urethra ratio • 5 37.0 1074 29.0 13th 16.0 215 13.4 ^17th 10.0 6.2 o; 6 * • 21 6.6 127 - 19.2 27th ^? 3.2 9.8 3.1 * ⁴ p 11.0 152 13.8 41 57.0 745 13.1 42 ' 31.0 404 13.0 * 45 16.4 186 11.3 - 47 35.0 530 15.1 Parazosin Terflavoxate 3.6 > 1000g 6.6 6060 1.8 *

Urethral active dose, 50% inhibition of noradrenaline-induced urethral contraction

DBP? active dose with a 25% reduction in diastolic blood pressure

DBP / urethra active dose ratio {selectivity index) * non-selective: real effects on both urethra and DBP.

Effective quantities ⁷

The following amounts are indicative of effective oral, parenteral, or intravenous dose limits, expressed in mg / kg body weight / day, in the following .20 cases:

(a) Obstructive Lower Urinary Tract Disorders: Overall 0.001 - 20

202

In the first row ; G, 053 '1

Best ** '·, 0.3 (b) As ant.ih.ipertph.ikai:

Overall 0, Q1 - 20

In the first row 0.1 - 5

Best ** 1 (c) Anchiolytics-antidepressants:. Overall 0.01 - 20

In the first row 0.05 - 5

Most ** 0.5 (d> Urethral spasmolytics

Overall 0.01 First order 0.02 Best ** 2? ///; - / 2h / - 10j * Best dosages for oral dosing, Intervening doses should be 10-100 times lower.

The group of patients in need of treatment with the proposed compounds and compositions also includes people with one or more symptoms of depression (Harrison's Principles of Internal Medicine, XII Ed., McGraw-Hill, Ine., P.2124) or people, / who experience symptoms of anxiety (Harrison ⁷ s, supra, pp.2131-2134).

Dosages for selective use, ie doses that are 30. ': Aktyvids; / žeimitinįam urinary tract with no significant effect on blood pressure depends kpnkretąus // Use of a compound 7beL.''' B ^^ ba £>? -., / IM _jkėtiirių; ..the selective-compound ED _5o may be administered without substantial effect on s

for blood pressure. ^λ Further / Improvements · <and .dose 35 settings are possible based on routine experiments.

203. The active compounds of the invention may be administered orally, for example, in an inert diluent or nutrient carrier, or may be enclosed in gelatin capsules or compressed into tablets. When appointing.

therapeutically orally active. The compounds of the invention can be combined with an inert filler and used in the form of tablets, pastels, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like. The formulations should contain at least 0.5% of the active compound, but the amount of active ingredient may vary depending on the form and may comprise 5% to 70% of the unit weight, respectively. The amount of active compound in such compositions is such that a suitable dosage will be obtained, irrespective of the fact that the desired dosage may be obtained in various dosage forms. Suitable compositions and preparations of the invention are formulated so that the oral dosage unit form contains between 1.0 and 300 milligrams of active compound. . ·>

Tablets, peas, capsules, pastels and the like may also have the following ingredients, for example: a binder such as Microcrystalline cellulose, gum or gelatin gum: a starch or bacterial filler, a disintegrating agent such as alginic acid, Primogel, gr and so on; an ointment such as magnesium stearate or Sterotex; a slippery material such as colloidal silica; a sweetening agent such as sucrose or saccharin or a flavoring. the agent, as mentioned above, has a salicylated or eliminated aroma. When doses. the unit is contained in a capsule and may be included with the above materials. liquid carrier, fatty oil. Other dosage unit forms may contain other various substances that alter. the physical form of the dosage unit, such as coatings. So pills or peas can. be coated with sugar, shellac, or other participating coating agents. Along with the active compounds, ΒΒ b /.--b 'sweetening agent syrup can' contain sucrose in some preservatives, dyes, colorings and flavorings. When preparing these various compositions, the material must be clean and used in non-toxic amounts.

For parenteral therapeutic administration, the active compounds of the invention may be in solution or. in suspension. These preparations should contain at least 0.1% of the active compound, but may range from 0.5% to about 30% by weight. the amount of the compound in such compositions is such that a suitable dosage can be obtained. Suitable compositions and preparations of the present invention are prepared so that the parenteral dosage unit contains from 0.2 to 100 milligrams of active compound. The solutions and suspensions may contain the following components: a sterile diluent, such as water for injections, saline, fixed oils, polyethylene glycols, glycerol, propylene glycols or other synthetic solvents;

antibacterial agents such as benzyl alcohol or methyl para-aminobenzoic acid; antioxidants such as ascorbic acid or sodium bisulfite; cyanating agents such as ethylenodiaminotetracetic acid; buffers, e.g. acetate; citrates or phosphates and tonicity regulating agents such as sodium chloride or dextrose.

Parenteral multiple dose vials may be made of glass or plastic.

Claims (7)

DEFINITION OF INVENTION A compound having the general formula I wherein - - - - corresponds to single or double connection; X represents an oxygen or sulfur atom or an imino, 'alkylimino, sulfinyl arsulfonyl group; W · represents a valence bond or a carbonyl, thiocarbonyl. a methylene or hydroxymethylene group; R ₂ represents a hydrogen atom or a group alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, substituted heterocyclyl or aroyl; the above substituted groups being substituted with 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 ₃ / represents a hydrogen atom or an alkyl, hydroxyalkyl, alkoxyalkyl, aralkoxyalkyl, phenyl, hydroxy, alkoxy, alkoxy or aralkoxy group; R ₆ represents a hydrogen or halogen atom or a nitro, R ₇ 5; -, γ / amino / alkylamino, / dialkylamino, acylamino, alkylsulfonylamine; cyano hydroxy. a1oxy or alkyl group; represents a hydrogen atom or an alkoxy group; . corresponding to one of the following groups, / each shown as /./ such that // the left end joins the hetero-bicyclic ring and its right side joins the group Z :. (Yl) -CO .- ///, /: (Y2) .-COO-, (Y3) -CONH-, 7 /, // (Y4) -CON (CH ₃ ) -, (Y5) -CON (OH) -, (Y6) : / - CH (OH} - / / - / (Y7) -CH (OAlkyl) -y (Y8) / -CH = CH-, y ////: (Y9) (Y10) fVT T v /. -H = CH-COO-, // -CHCH-CONH-, Vi r x t (Y12) ' IM- _r -CH ₂ -,. {¥ 13), -Ci ^ COO-, · (Y147 ': -CHiCONH-, (Y15) -CH ₂ NH-, ' (Y16) -CH ₂ N (CH ₃ ) ~, (Y17) ; 7CH ₂ N (C0CH ₃ ) (Y18) -CH ₂ N (CONH ₂ ) (Y19) L7CH ₂ NHCO-, · / (Y20) -CH ₂ N (CH ₃ ) CO-, (Y21) 7-CH ₂ NH-CONH-, (Y22) (Y23) -ch ₂ nhso ₂ -, -CH ₂ 0-, 7 (Y24) -CH ₂ S-, (Y25) -ch ₂ so-, (Y2Q. / -CH ₂ SO _2, ". (Y27) -ch ₂ sq ₂ nh ~, 207 (Υ28) (Y29) (Y30) (Y32) (Y33) (Y34) (Y35) (Y36) (Y37) (Y38) (Y39) (Y40) (Y41) (Y42) (Y43) (Y45) ( Y46) -CH ₂ SO ₂ N (CH ₃ ) -NH-, -N (CH ₃ ) -. -N (COCH ₃ ) -, -N (CONH ₂ ) ~, -NHCO-, ' -N (CH ₃ ) CO-, -NH-CONH-, -NHSO ₂ -, · -o-, -s-, -so-, · -so ₂ nh-, -SO ₂ N (CH ₃ ) -, -CONHO-, -CON (COCH ₃ ) -CSNH-, (Y48) (Y49) (Y47) -CON (Οι-to h j -, 30 B represents a linear or said alkyl chain having from 1 to 6 carbon atoms and having one hydroxy substituent selected; and corresponds to one of the following groups: (Bi.) R ~~ \ '£ - ^Λ —- 4 .., 208 J / wherein Q represents a methylene or ethylene group and A represents a yien of the following groups: (Al). a phenyl group substituted with one or more halogen atoms and / or one or more alkyl, alkoxy or hydroxy groups; (A2) 2 - a pyrimidinyl group, and (A3) a group of the general formula y in which - is - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - enti ή h c k ung t'į to (B2) // j / yy> ^, wherein each of Ll and L ₂ · independently represents a hydrogen atom, a phenyl, 4 - fluorobenzoyl or 2-oxo-benzimidazolyl gru25 Pe or a group of the general formula (CH ₂ ) -Ο-Ά, where n is 0,1 or 2 and A is denoted in this definition, provided that Lj and L _{2 are} both taken together 209 which visit the following ki e kvienas it from ₀ and R _is in offline pendent i: represents a hydrogen atom or Jąlkiltio aralkoxy group, R ₁₂ represents a hydrogen atom or an alkyl group on the 2 or 3 -N-CH wherein R ₁₂ is as defined in this point, and R ₁₃ is a hydrogen atom or an alkoxy group, wherein R ₁₂ is as defined herein, or a prodrug, an enapthiomeric diastereoisomer, an N-oxide, or a pharmaceutically acceptable salt thereof. · - 2. A compound according to claim 1, characterized in that it contains X W R ₂ ^R 3 ^r 6 R 1 is double: linked, corresponds to an oxygen atom, corresponds to a carbonyl group, corresponds to a phenyl group, corresponds to a methyl group, corresponds to a hydrogen atom and corresponds to a hydrogen atom. Compound according to claims 1 and 2, characterized in that Y represents one of the groups Y2, Y3, Y37, Y40 or Y41. 5 4. The compound according to any of against this existing points, b e siskirian t i s that when Z corresponds to a trimethylene or tetramethylene group 5. Compound according to any of against this existing 10th points, b e siskirian t i s that that B corresponds to one of the groups Ey or B ₃ . 6. Compound by 'any of against this existing. points,. b e siskirian t i s that that B 15 y corresponds to 4- {2 -methoxyphenyl) -1-piperazinyl group. 7. Compound according to any of against, this,, existing points, bes exclusive that k .ad Y, Z is B together corresponds to the 3- / 4- (2-methoxyphenyl) -1-piperazinyl / 20-propylcarbamoyl group. 8. Any of the following: · 8- {2- [4- (2-methoxyphenyl) -1-piperazinyl] -1-oxoethyl} -325 methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {2- [4- (2-Methylphenyl) -1-piperazinyl] -1-oxoethyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran. 8- (2- (4-ethoxyphenyl) -1-piperazinyl / -1-oxoethyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -1-oxopropyl} 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, - {8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propoxycarbonyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, · 35 8- {2- (4- (2-methoxyphenyl) -1-piperazinyl) -1. ethoxycarbonyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, ²¹¹ 8- {3- / 4- (2-chlorophenyl) -l-piperazinyl / propoks'ikarbonil) -3-methyl-4-oxo-2-phenyl-4H benzopyran _t, 8- [3- (4-Phenyl-1-piperazinyl) -propoxycarbonyl] -3-methyl-5,4-oxo-2-phenyl-4H-1-benzopyran, 8- {3- [4- (2-methoxyphenyl) -] 1-piperazinyl (propoxycarbonyl) -3-methyl-4-oxo-2-; phenyl-4H-1-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -2-methyl-2-10 propoxycarbonyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, *, 8- {3- / 4- (2-methoxyphenyl) -1-piperazinyl / propylcarbamoyl) -3-methyl-4-oxo-2-phenyl-4H-1 'benzopyran,' 15 '8- {2- / 4- (2-methoxyphenyl) -1-piperazinyl / ethylcarbamoyl) 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {3- [3- (2-methoxyphenoxy) ethylamino] propylcarbamoyl} 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran. 8- [3- (4-phenyl-1-piperazinyl) -propylcarbamoyl] -3-methyl-2 4-oxo-2-phenyl-4H-1-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- {1-hydroxy-2- [4- (2-methylphenyl) -1-piperazinyl] ethyl} 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran ,, 8- {1-Hydroxy-2- / 4- (2-ethoxyphenyl) -1-piperazinyl / ethyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran • { 1-hydroxy-3- [4- (2-methoxyphenyl) -1-piperazinyl / propyl] -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {1-hydroxy-4- [4- (2-methoxyphenyl) -1-piperazinyl / butyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {1-Ethoxy-2- (4- (2-methoxyphenyl) -1-piperazinyl / ethyl) 35 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 21.2 · 8- {N-Methyl-2- [4- (2-methoxyphenyl) -1-piperazinyl] ethylaminomethyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {N-acetyl-2- / 4- (2-methoxyphenyl) -1-piperazinyl / 5-ethylaminomethyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- [4- (2-methoxyphenyl) -1-piperazinylacetamidomethyl] -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {N-Methyl-N- [4- (2-methoxyphenyl) -1-piperazinyl] -acetamidomethyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {2- / 4- (2-methoxyphenyl) -1-piperazinyl / ethoxymethyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {2- / 2- (2-Ethoxyphenoxy) -ethylamino / -ethoxymethyl} -315 methyl-4-oxo-2-phenyl-4H-1-benzopyran, hydrochloride 8- {2- / 4- (2-methoxyphenyl) ) -1-piperazinyl / ethylthiomethyl} 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {2- / 4- (2-methoxyphenyl) -1-piperazinyl / ethylsulfinylmethyl} -3-methyl-4-oxo-2-phenyl-4H-120 benzopyran, 8- {2- / 4- (2-methoxyphenyl) -1-piperazinyl / ethylsulfonylmethyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {2- / 4- (2-methoxyphenyl) -1-piperazinyl / ethylamino} -325-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylamino} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {4- / 4- (2-methoxyphenyl) -1-piperazinyl-butylamino) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {N-Methyl-3- [4- (2-methoxyphenyl) -1-piperazinyl] -. propylamino} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, --- 8- {1 H -acetyl-3- [4- (2-methoxyphenyl) -1-piperazinyl / propylamino} -3-methyl-4-oxo-2-phenyl-4 H -1-benzopyrazine, 8 - {' 3- (4- (2-methoxyphenyl) -1-piperazinyl] -propionamido} 35 3-methyl-4-oxo-2-phenyl-1- 4 H -1-benzopyran, 8- {2- [4- (2-methoxyphenyl) -1-piperazinyl] -ethylureido) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 213 8- {2- / 4- (2-Methoxyphenyl) -piperazinyl-ethoxy} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propoxy} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {4- [4- ( 2-methoxyphenyl) -1-piperazinyl-butoxy) -3r · methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {5- / 4- (2-methoxyphenyl) -1-piperazinyl / pentyloxy} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {3- (4- (2-methoxyphenyl) -1-oxo-1-piperazinyl) - Propoxy) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {2- / 2- {2- _z- 6-dimethoxyphenoxy) -ethylamino / -ethoxy} -3-methyl-4-oxo- 2-phenyl-4H-1-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-1-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylsulfonyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {2- / 4- ( 2-methoxyphenyl) -1-piperazinyl / ethylsulfamoyl} 20 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {N-Methyl-2- [4- (2-methoxyphenyl) -1-piperazinyl / ethylsulfamoyl] -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {N-Carbamoyl-3- / 4- (2-methoxyphenyl) -1-piperazinyl / propylamino) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {4- / 4- (2-Methoxyphenyl) -1-piperazinyl / -1-oxobutyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran 8- {3- / 2- (1,4-Benzodioxanyl) methylamino / propylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {4- / 4- (2-methoxyphenyl) -1-piperazinyl / butyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 7 8- [3- (4-phenyl-1-piperadinyl) -propylcarbamoyl] -3-methyl- _? 4-oxo-2-phenyl-4H-benzopyran, - 7 8- [3- (4/4-Diphenyl-1-piperadinyl) -propylcarbamoyl] -3 " 35 Methyl-4-oxo-2-phenyl-4H-1-benzopyran / 8- (3- / 4- (4-fluorobenzoyl) -1-piperidinyl / propylcarbamoyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 214 - 8- {3- [4- (2-Oxo-1-benzimidazolinyl) -1-piperadinyl] -propylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, ' 8- {3- [4- (2-pyrimidinyl) -1-piperazinyl] -propylcarbamoyl} -3-ethyl-4-oxo-2-phenyl-4H-1-benzopyran, ' 5 '8- {3- [4- (2-Hydroxyphenyl) -1-piperazinyl] -propylcarba. moyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {4- / 4- (2-methoxyphenyl) -1-piperazinyl) butylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {3- / 4- (2-methoxyphenyl) -1-piperazinyl / -propyl10. sulfamoyl) -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, '8- {3- / N-methyl-2- (2-methoxyphenoxy) -ethylamino / -propyl-. carbamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {N-Methyl-3- [4- (2-methoxyphenyl) -1-piperazinyl) propionamido} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1H-piperazinyl] -propylcarbamoyl} -3-phenyl-4-oxo-4H-1'-benzopyran, 8- {3 - [(3,4-Dihydro-1-oxo-2H-naphthyl) -methylamino] -propylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {2 - [4- (2-methoxyphenyl) -1-piperazinyl] -ethoxycarbonyl20 methyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {4- [4- (2-methoxyphenyl) ) -1-piperazinyl / butylsulfamoyl} -3-methyl-4-oxo-phenyl-4H-1'-benzopyran, 8- {N- (2-tetrahydropyranyloxy) -3- (4-methoxyphenyl) -1-piperazinyl / -propylcarbamoyl} - 3-methyl-4-oxo-2-phenyl25 4H-1-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-135 benzopyran, 8- {4- / 4- (2-methoxyphenyl) -1-piperazinyl / butylsulfinyl} 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 215 8- (3- / 3- (2-methoxyphenoxy) -propylamino / propylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {3- / 2- (2-Methyl-thiophenoxy) -ethylamino} -propylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-1- - benzopyran, 8- {3- / 2- (2,6-Dimethoxyphenoxy) -ethylamino-propylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, (E) - ^ 8- ( 4- [4- (2-methoxyphenyl) -1-piperazinyl] -1-butenyl} .10 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-1-benzopyran, '1. 8- {N-acetyl-3- / 4- (2-methoxyphenyl) piperazinyl / propylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {2- [4- (2-methoxyphenyl) -1-piperazinyl] ethylsulfonyl} amino} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -1-propylthiocarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-1'-benzopyran,. /t'/.l / 8- {4- [4- (2-methoxyphenyl) -1-piperazinyl] -butylsulfonyl} 25 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3-hydroxymethyl-4-oxo-2-phenyl-4H-1-benzopyran, < 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -. Propylcarbamoyl} -4-oxo-2-phenyl-4H-1-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -1 '. propylcarbamoyl} -2,3-dihydro-4-oxo-4H-1-benzopyran, 8- (3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -4-oxo-4H-1-benzopyran , 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -6-bromo-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 2.16 8- {3- / 4- (2-Methoxyphenyl) -1-piperazinyl / propylcarbamoyl) -6-methoxy-3-methyl-4-oxo-2-phenyl-4H-1 benzopyran, ' 8- {3- / 4- (2-Methoxyphenyl) -1-piperazinyl} -1 ' 5-Propylcarbamoyl) -6-hydroxy-3-methyl-4-oxo-2-phenyl-4H. 1-benzopyran ,. , 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl / propylcarbamoyl] -3,6-dimethyl-; 4-oxo-2-phenyl-4H-1-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -7 ^; ·. / Λ j '//./ , ^; · 7'7, '7 / .j 22- j --λ ·;''' // 7. '· /? /; /' 2 - 7 · 7 ^;? · 7 ′ 27 27 27 2. 27 2. 2 · 2/2>>> 2 2 2 2 2 2 2 prop 2 2 2 2 2 2 2 2 2 2 2 prop prop prop prop prop prop prop prop prop prop prop prop prop prop prop prop prop prop 2 2 prop prop prop prop '' prop '''''''; 8- {3- / 4- (2-Methoxyphenyl) -1-piperazinyl / propylcarbamoyl) -6-amino-3-methyl-4-oxo-2-phenyl-4H-1115 benzopyran, ¹ 8- {3- [4- (2-methoxyphenyl) -1-piperaziryl] -propylcarbamoyl} -6-acetamido-3-methyl-4-oxo-2-phenyl-4H 1-benzopyran, 8- {3- / 4- (2-methoxyphenyl) -1-piperazinyl / 20-propylcarbamoyl) -6-ethylamino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {3- / 4- (2-methoxyphenyl) -1-piperazinyl / propylcarbamoyl) -6-dimethylamino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 25 8- {3- / 4- (2-methoxyphenyl) -l-piperazinyl / ¹ propylcarbamoyl) -7-methoxy-3-methyl-4-oxo-2-phenyl-4H-benzopyran, 8- {3- / 4- (2-methoxyphenyl) -1-piperazinyl / propylcarbamoyl) -3-methyl-4-oxo-2- (430 trifluoromethylphenyl) -4H-1-benzopyran, 8- {3- / 4- (2-methoxyphenyl) -1-piperazinyl / propylcarbamoyl) -2- (4-benzoylphenyl) -3-methyl-4-oxo-4 H -1-benz'opyran, - 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -. 35 propylcarbamoyl) -3-methyl-4-oxo-2- (4-phenoxyphenyl) -4H-benzopyran, inyl / 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-15-benzopyran, '8- {3- / 4- (2- methoxyphenyl) -1-piperazinyl / propylcarbamoyl} -2-cyclohexyl-3-methyl-4-oxo-4H-1-benzopyran, 8- {3- / 4- (2-methoxyphenyl) -1-piperazinyl / 10-propylcarbamoyl} -2- (2-yuryl) -3-methyl-'4-oxo-4H-1-benzopyran, 8- {3- / 4- (2-methoxyphenyl) -1-piperazinyl / propylcarbamoyl} -3-methyl-4-oxo-2-thienyl-4H-1 • benzopyran, ' ^λ: · ^: '; // · .! - ·, / '/ λ · / ·, // i' ” ⁷ ; ·. ··. · '7 7 ·:' 77 '/ //.<'·'·. '7/7 /' ·. 15 '8- {3- / 4- (2-methoxyphenyl) -1-piperazinyl / propylcarbamoyl} -4-oxo-2-phenyl-4H-1-benzothiopyran, (E) -8- {3- / 4- ( 2-methoxyphenyl) -1-piperazinyl / -propylcarbamoyl} -3-methyl-4- ⁱⁱ oxo-2- (2-styryl) -4H-first benzopyran,. 8- {3- / 4- (2-methoxyphenyl) -1-piperazinyl / propylcarbamoyl} -3-methyl-2- (4-methylphenyl) -4-oxo-4H-1-benzopyran, 8- {3- / 4- (2-methoxyphenyl) -1-piperazinyl / propylcarbamoyl} -2- (4-methoxyphenyl) -3-methyl-4-oxo-4H25 -1-benzopyran, 8- {3- / 4- (2-methoxyphenyl) -1-piperazinyl / propylcarbamoyl} -2- (4-fluorophenyl) -3-methyl-4-oxo-4H-1-benzopyran, 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -6-methanosulfonylamino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8- {3- / 4- (2-methoxyphenyl) -1-piperazinyl / propylcarbamoyl} -3-methyl-2- (4-nitrophenyl) -4-oxo-4H-1-benzopyran, // / 7/7 / //// / 7/7 c /// 7 '''·^; · // 7 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -7-propylcarbamoyl} -6-diethoxyphosphonyloxy-3-methyl-4-oxo. 2-phenyl-4H-l-benzopyran, '·· 218 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] propyl} carbamoyl} -3-methyl. 1-4-Oxo-2 -1-methyl-1- (4H-1-) 8- {N-methyl-3- [4- (2-methoxyphenyl) -1-piperazinyl] - + 5-propylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 7- {3- / 4- (2-methoxyphenyl) -1-piperazinyl / propylcarbamoyl} -2-benzoyl-3-ethyl-benzo / b / furan; 2- (4-Biphenylyl) -8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] propylcarbamoyl} -3-methyl-4-oxo-4H-1-benzopyran 8- {3- [4- (-2-Methoxyphenyl) -1-piperazinyl] propylcarbamoyl} -3-methyl-4-oxo-2- (3-pyridyl) -4H-1-benzopyran 8- {3- / 4- (2-Acetoxyphenyl) -1-piperazinyl} 15 Propylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran 3-methyl-8- {3- / 4- (2-Methylaminocarbonyloxyphenyl) -1-piperazinyl] -propylcarbamoyl} -4-oxo-2-phenyl-4H-1-benzopyran 6-Acetoxy-8- {3- [4- (2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (R, S) -2, 3-Dihydro-4-hydroxy-8- {3- / 4- (2-methoxyphenyl) -1-piperazinyl / propylcarbamoyl} -4H-1-benzopyran 25 Methanesulfonate 2- (4-Aminophenyl) -8- {3- / 4- (2-methoxyphenyl) -1-piperazinyl / propylcarbamoyl} -3-methyl-4-oxo-4H-1-benzopyran 2- (4-acetylaminophenyl) -8- {3- / 4- (2-methoxyphenyl) -1- + 30 piperazinyl / propylcarbamoyl} -3-methyl-4H-1-benzopyran +: [2- (4-hydroxyphenyl) -8- {3- [4- (2-methoxyphenyl) -1- ++ piperazinyl] propylcarbamoyl}. + -3-met i1-4H-1-benz opirano dihidroch1or ido ⁷ mbnoh IDR report 8- {3- / 4- (2-methoxyphenyl) -1-piperazinyl / 35 propylcarbamoyl} -2-phenyl-4, N ₇ , N ₄ ~ trioxo-4 H -1-benzopyran monohydrate. 219 r7- (3- / 4- (2-Methoxyphenyl) -1-piperazinyl / propylcarbamoyl) -2-phenylbenzene fburane. 8- {3- / 4- (2-Methoxyphenyl) -1-piperazinyl / propyl-N-methylsulfamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran 5 Methanesulfonate. 8- {3- [4- (2-methoxyphenyl) -1-piperazinyl / butyl] -N-methylsulfamoyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methanesulfonate; or a prodrug, an enantiomer, a diastereoisomer, an N 10 oxide 'or pharmaceutically. a suitable salt of such a compound. 9. A pharmaceutical composition comprising an active ingredient in admixture with a pharmaceutically acceptable diluent or carrier 15 - The ingredient is a compound according to any one of the preceding claims, or a prodrug, enantiomer, diastereo. an isomer, an N-oxide or a pharmaceutically acceptable salt thereof. ¹