JPS6270368A - Substituted 1-benzopyran-2-yl-propanoic acid - Google Patents

Abstract

(57) [Abstract] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention]

The present invention provides compounds of the formula A (wherein R represents a hydrogen atom or a methyl group, and when B represents a hydrogen atom, the compound is in the form of a monohydrate) and their pharmacological effects. Regarding the addition salts that are acceptable for. Compounds of formula A of the present invention are leukotrienes D, (L'
Novel compounds of the formula Useful in the preparation of acceptable addition salts: OOH [wherein Z Fia) -(CR2)n-; 'b)
-(OH2)p-eH= or a) -co-(O
H2), - (in each formula, n is an integer of 1 to 3; p is 0 to
4 is an integer: q is an integer from 0 to 4; p+q is equal to or less than 6: r is an integer from 1 to 5: 8 is an integer from 0 to 4 t is an integer from 0 to 4; and W is an integer from 1 to 6) and: m
must be an integer from 2 to 6: Y is a) -Hz b) =H2# or (ri-O
H: with the proviso that a double bond in the 3-4 position can be present only if Y is H: R1 and R2 are each the same or different and are alkyl having 1 to 6 carbon atoms: R3 is a) hydrogen or alkyl having 1 to 6 carbon atoms; b)
-cooH; or C) (CHz)zcOOR5, where t is an integer from 0 to 2 and R5 is alkyl having 1 to 6 carbon atoms; and R4 is a) hydrogen; b ) -CO2H; C) -
CO2R6 in which B6 is alkyl having 1 to 6 carbon atoms; or d) -OH]. L'I is a product of the 5-lipoxygenase pathway and is the main active component of the slow-reacting substance of anaphylaxis (5R8-A) in humans and guinea pigs [
Lewis et al., Naturs USA, 293:
pp. 103-108 (1981)]. It is a potent bronchoconstrictor released during allergenic reactions. Because antihistamines are ineffective in managing asthma, 5R8
-A is believed to mediate bronchoconstriction resulting from allergic challenge. 5R8-A is also a potent inducer of vascular permeability and may also be involved in other inflammatory conditions such as rheumatoid arthritis (Gax
ler J, et al. J, C11n, Kncjocri
nol. Metab, 43: 686-688 (197
6 years)]. General information AppHtOn etc. J, MQ (1, Chem, 2
Q, pp. 371-379 (1977) describes 1S chromone-2-carboxylic acid compounds that are 8R8-A agonists. In particular, sodium 7-[3-(4-acetyl-6-hydroxy-2-f lobylphenoxy)-2-
HyProxyproboxy]-4-okine-8-propyl-
4B-1-benzot-lane-2-carpoxyle) (F
PL 55712) is considered to be the first reported specific agonist of 5R8-A and LTD4. Acid form salts of these compounds include sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, ammonia, trialkylamines, dialkylamines, monoalkylamines, dibasic amino acids, sodium acetate, potassium benzoate, It can be produced by neutralization with appropriate amounts of inorganic or organic bases such as triethanolamine and similar bases. LT8 produces bronchoconstriction when administered to humans and guinea pigs. This bronchoconstriction has two components: a) L
It has a direct stimulation of respiratory smooth muscle by TD4 and b) an indirect component due to the release of thromboxane A2 and subsequent production of contraction of respiratory smooth muscle. The compounds of the invention antagonize this direct factor. Compounds of the invention are tested in vivo as follows. Adult male fasted Partly guinea pigs weighing 300-350 I are pretreated with biliramine and indomethacin to inhibit the bronchoconstrictor effect of endogenous histamine and the synthesis of thromboxane A2, respectively. The compound of the present invention is LTD4200
Administer intravascularly or intragastrically before administering 0 units intravascularly. Intratracheal pressure is monitored pre- and post-administration of LTD in animals anesthetized with bendoparbital and connected to a veterinarian. Compounds that antagonize the direct component of LTD4 on respiratory smooth muscle inhibit the increase in intratracheal inspiratory pressure (P or = 0.05) caused by LTI). Use FPT, 55712 as a control. Compounds of the invention can be administered in a number of dosage forms. A preferred method of administration is one in which the effect of the depressant is localized. For example, for asthma, the compounds can be inhaled using an aerosol or other suitable spray. For inflammatory conditions such as rheumatoid arthritis, the compound can be injected 11 times into the affected joint. The compounds can also be tablets, capsules, pills, powders,
can also be administered in oral unit dosage forms such as granules. These compounds can also be administered rectally or vaginally, such as in a lozenge. The stiff compounds can also be administered in the form of intraperitoneal, subcutaneous or intramuscular fecal drops, which are well known in the pharmaceutical arts. For the treatment of allergic skin conditions, the compounds of this invention can also be administered topically in the form of ointments, creams, gels, and the like. Regardless of the route of administration chosen, the compounds of the invention can be formulated into pharmaceutically acceptable dosage forms by conventional methods known in the leavening art. An efficacious, nontoxic amount of the compound is used for treatment. What is the dosage regimen for the compound of the present invention to inhibit CSLTI4? The choice will depend on a variety of factors including the medical condition and medical condition, the particular disease and its severity, the route of administration and the particular compound used. A skilled physician or veterinarian can readily determine the amount of this compound that will be effective in preventing or arresting the progression of the condition. -1 would be expected. At the beginning of administration, the physician or veterinarian may initially use a relatively low dose and then increase the dose until maximal response is obtained. Compounds of the invention are prepared by the general methods illustrated in Reaction Schemes A-E. A variety of compounds and intermediates can be readily transformed by methods known to those skilled in the art. example is,
Ester compounds can be hydrolyzed to the corresponding carboxylic acid compounds (salted according to Okobiso tl et al.), converted to the corresponding amide compounds by appropriate reaction with amines, and by reducing agents such as lithium boron hydride. Can be reduced to alcohol compounds. Of course, such products and intermediates can be interconverted as well. As illustrated in Figure A, the 2-hydroxyacetophenone of 2) readily reacts with the ketone of formula
fused ring compounds are provided. Ketones of formula (1) include ketoesters where Z is alkylene or alkenylene and R4 is alkoxycarbonyl. An example of this ↓ketoester is ethyl levulinate. Suitable condensation and cyclization conditions include heating the compound of formula II and the compound of formula II in toluene in the presence of a base such as pyrrolidine while removing water in an apparatus such as a Dean-Stark trap. This includes refluxing. The intermediate of formula 1 thus produced can be used in the reaction of diagram B without further purification or may be converted to the related intermediate of formula ↓ according to methods known to those skilled in the art. For example, hydrogenation over palladium on carbon reduces the formula X10 keto functionality to the corresponding dihydrobenzopyran (Y"") (2). Partial hydrogenation provides the corresponding hydroxyl compound (Y=H,OR). As illustrated in Figure B, compounds of Formula XIV can be alkylated under basic conditions to produce compounds of Formula XXI. Suitable reactants include dihaloalkanes such as 1,6-dibromopropane and the like. Preferred conditions include reaction in anhydrous dimethylformamide in the presence of anhydrous potassium carbonate. Intermediate XXI is typically purified by column chromatography on silica gel. When these intermediates are reacted with 2-hydroxyacetophenone of formula (1), the object compound of the present invention, formula XXI, is obtained. Preferred conditions include reaction in dry dimethylformamide in the presence of anhydrous potassium carbonate. Alternatively, the reaction can be carried out under phase transition conditions. Figure C illustrates the preparation of compound XXI using a variation of the method of Figure B. A 2-hydroxyacetophenone of Formula XXXII is reacted with a dihaloalkane as described above to form an intermediate of Formula XXXI. Formula ff, to Formula XII
By the same general method used to convert to the formula XX'X[
and a compound of formula XIV to produce the compound of interest of the present invention, formula xxi. The diagram illustrates another route for preparing some of the compounds of the invention. It is known from the literature that the benzopyrone of the formula XL() can be reduced to the compound of F2XLI by catalytic hydrogenation: in this case Y is; from 0 to (H, OB) ~
H2 and these can be further converted by methods known to those skilled in the art. For example, a hydroxyl compound (Y=H, OB) can be dehydrated to produce a benzopyran of formula XLI. This method involves conversion to mesylate derivatives followed by elimination under basic conditions to
It includes the generation of As another example, an ester compound (R4=eOO(alkyl)) can be reduced with an active metal hydride such as lithium boron hydride to form the formula XL
The corresponding alcohol compound of IV can be produced. Figure E also illustrates another route for making some of the compounds of the invention. Compounds of formula Ll, where R11 can be a protecting group that is removed in post-treatment,
or the final aromatic side chain already formed as generally described above) is first treated with a strong base in a non-reactive solvent. Preferred reactants include n-butyllithium in tetrahydrofuran. Upon alkylation, a compound of formula LH is obtained. Examples of alkylating agents include simple alkylno-rides or substituted alkyl halides such as iodoalkyl carboxylic esters, beta-unsaturated carboxylic esters (subject to conjugate addition), and many other reactants known to those skilled in the art. includes. Upon further transformation of the compound of Ll, other derivatives such as the free carboxylic acid of formula Ll can be generated. That is, this carboxylic acid can be generated upon hydrolysis of compound LII. Acylation under similar conditions to compound LIt provides a compound of formula LIV. Acylating agents include acyl or other activated acyl derivatives. Preferred reactants include substituted N
-Includes alkanoyl imidazole derivatives. Formula L■
The compounds can also be converted into other derivatives. For example, basic hydrolysis leads to decalcylated compounds of formula LVO. The invention will become more fully apparent from the following side. These examples are for illustrative purposes only and are not to be construed as limiting the invention in either spirit or scope. Many modifications, both to materials and methods, will be apparent to those skilled in the art from this description. In these examples, unless otherwise specified, temperatures are given in degrees Celsius ('O) and amounts of materials are given in milliliters. Example 1 Ethyl 3-(3,4-dihydro-7-hydroxy-2-
Methyl-4-oxo-8-propyl-2H-1-benzobylan-2-yl)propanoate 2,4-dihydroxy-3-propylacetophenone 58.0 N (0,299 mol) in 250 toluene. A solution of 29.51 u (0.36 mol) of pyrrolidine and pyrrolidine was heated to reflux for 6 hours using a Dean-Stark trap. After cooling the mixture, ethyl lepliné) 68
．． 2117 (0.48 mol) is added and the mixture is refluxed for 2 hours. Additional pyrrolidine 10Mt (0.12 mol)
ft and the mixture was refluxed overnight under a Deano-Stark trap. The reaction mixture is diluted with ethyl acetate and washed sequentially with water, 2M hydrochloric acid, water and prine. It is then dried over Mg5Od, filtered and evaporated to dryness. The residue was chromatographed on silica gel using 60 ethyl thiacetate/hexane as eluent to give 35.5 g of the title ester: melting point = 92-94 o. Estimated structure confirmed by iinmr and infrared spectroscopy. IR (eHc1!3): 1665.1730z
",,. Example 2 l-43-(3,4-dihydro-7-hydroxy-2-
Methyl-4-oxo-8-jRobiA・~2H-1-benzopyran-2-yl)-1-:#quinpropyl]bi'loridine From another chromatographic fraction of Example 1, the titled amino ￥3
0. ! i't: Melting point: 182-184. The predicted structure was confirmed by ITNMR and infrared spectroscopy, and by elemental analysis. IR (KBr): 1615.1675m". Elemental analysis: Regarding e2oHs+7NOt, Calculated value:
e 69.54; E 7.88: N 4.0
5 fruit 1ull rice: c 69.22; H7,93;
N 3.97 Example 6 3-(3,4-dihydro-7-hydroxy-2-methyl-4-okine-8-propyl-2FJ-1-penzohy'
Ran-2-yl) propanoic acid A mixture of 20.0 g (103 mmol) of 2,4-dihydroxy-6-propylacetophenone and 15.5 g (164 mmol) of methyl levulinate in 100 M1 dry toluene was added with .5id (approximately 260 mmol) is added via syringe. After stirring for 1 hour, the solution is heated on a steam bath for 4 periods and then cooled. Add toluene solution to water and 2
Wash with N Na0T1. Acidic solution t2,
Extract with dieglyether followed by saturated sodium bicarbonate. , the basic aqueous extraction solution is neutralized with diluted gold sulfuric acid, and extracted again with diethyl ether. After drying, the solution is evaporated and the resulting oil is crystallized to obtain the title compound 'f': melting point = 152.
~156. Elemental analysis: C16112oO5Vr, calculated value:
C65,74; R6,90 actual value: C65,24
; H6,86 Example 4 Methyl 3-(3,4-dihydro-7-hydroxy-2-
Methyl-4-okine-8-propyl-2H-1-benzobilan-2-yl)propanoate The title compound of Example 3 (4,39; 14.7 mmol)
, trimethyl meltformate 61, and sulfuric acid 1.4
The mixture of 1 is stirred at room temperature for 2 hours. Reaction mixture 'kN
Pour onto stirred ice/water and then extract with ethyl acetate. Washed with clear water and dried over magnesium sulfate,
Concentrate to an oil. The oil was chromatographed on silica gel to obtain 6.7 g of the title compound (Japanese Co., Ltd. 1-1) as a whole crystal; melting point: 101.5-102.5; the estimated structure was determined by nmr and infrared I checked the spectrum. Example 5 4-(3--7" lomozolooxy)-2-hydroxy-6-propylacetophenone 2,4-dihydroxy- in 250 ml of dichloromethane
3-propylacetophenone 50.0 g (257 milliliters), tetrazotylammonium hydrogen sulfate 87.4
g (257 mmol) and dibromopropane 52.2
2 N NILO in a mixture of Wt (approximately 514 mmol)
Add E 225711 (450 mmol). The mixture is then heated to reflux for about 60 minutes and cooled. After the reaction mixture has been concentrated under reduced pressure, the residue is triturated with diethyl ether, the ether solution is filtered and then concentrated to dryness. After purification by column chromatography on silica gel, the title compound is isolated and used in the next reaction without further confirmation. Example 6 Methyl 3-(7-1:3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4
-dihydro-2-methyl-4-oxo-8-propyl-
2H-1-benzo-ran-2-yl)-zolopanoate 1.9 g (6.2 mmol) of the ester product of Example 4, 2.2 g ( 6,8 mmol) and anhydrous charcoal 1 yen
A mixture of 1.8 g (13 mmol) of llJum is stirred at room temperature for 16 hours. The inorganic salts are filtered off and the dimethylformamide is evaporated under reduced pressure. The residue is dissolved in ethyl acetate 5 and additional inorganic salts are filtered off. The filtrate is evaporated and the residue is chromatographed on silica gel using 7qb ethyl acetate/toluene as eluent to give the title compound 2.5 fIk; mp near 6-74.5°. The predicted structure was confirmed by NTOR and infrared spectra and by elemental analysis. nmr (CDC13): δ (ppm) 0.8
9 (t, J = 7.5Hg. 6B, propyl CH3's) x 1.24 (t
, J = 7Bs. 3H, Ester CH! , ); 1.35 (a,
3I (, 2-methyl proton); 2.55 (s,
3B, acetyl CH3): 4.22 (t, J
= 6FIZ, 4Fl, 0CI-12'θ
): 6.42. 6.53, 7.54, 7.71 (-set d1 aromatic) IFI (CHC15): 1625.1675
．． 1760 mer-1 elemental analysis: For Cs1'fkoOe, calculated value: C68,87; E (7,46 Actual value: C69-12; El 7.44 Example 7 3- -6-hydroxy-
2-propylphenoxy)zoloboxy]-6,4-dihydro-2-methyl-4-oxo-8-brol-2H-
A solution of 0.511 (19.5 mmol) of lithium hydroxide in 10 ml of aqueous 1-benzobylan-2-yl)propanoic acid was mixed with 2.29 ml of the title compound of Example 6 in 2,511,117 ml of tetrahydrofuran and 20 ml of methanol.
3.9 mmol). After stirring the reaction mixture for 3 hours at room temperature, the solvent is evaporated and water is added to the residue. After extraction with a small amount of diethyl ether, the aqueous phase is acidified with dilute hydrochloric acid and left overnight in the cold. The solid material is peeled off, washed with water, and recrystallized from ethyl acetate/hexane to give the title compound 1.83,9'; melting point: 80-83°. Estimated structure is based on MR and infrared spectra. and elemental analysis. nmr (CDC13): disappearance of ester CH3 (compare with example 6) IP (KBr): 1625.1675.
1710.1730 art-' Elemental analysis: C31H
380B ・Calculated value for H2O: C66,16
: H7,40 actual measurement value: e 66.15; R7,
44 examples 8 1-(3-[7-(3-bromopropoxy)-6,4
-dihydro-2-methyl-4-oxo-8-propy/l
--2I-1-1-Benzobylan-2-yl]-1-oxoprobyl) pyrrolidine title compound (melting point: 103-104°) ft by the method of Example 6 to produce the amidopyrrolidine product of Example 2 and 1. 6
- Manufactured using dibromopropane as raw material. The predicted structure was confirmed by nmr and infrared spectra and by elemental analysis. IR (CHCf3): 1 625, 1 675
cm-1 elemental analysis: C23H32BrNO4V (it x i*: c 59.23;
H6,92: N 3.00 Actual value: c 59
．． 44: H6,96; N 2-84 Example 9 1-[3-(7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)solboxy]-3,4-
The title compound (dihydro-2-methyl-4-oxo-8-7''-2H-1-benzobilan-2-yl)-1-oxinzolobylpyrrolidine (melting point: 93-94.5) in Example 6 The method is prepared using the title compound of Example 8 and 2,4-dihydroxy-6-propylacetophenone as starting materials. The predicted structure was confirmed by tinmr and infrared spectra and by elemental analysis. Engineering R (CHCJ3) = 1625.1675 cyn-'
Elemental analysis: Calculated values for C34R45NO7:
c 70.44; n 7.82; N 2.42
Actual value: C70,32: R7,78; N 2.3
Example 5 10 Methyl 3-(3,4-dihydro-7-hydroxy-2-
4.1 g (13
-4 mmol) is hydrogenated for 21 hours using 4p81 and valadiram on carbon as catalyst at room temperature. The catalyst is filtered off and the filtrate is evaporated to dryness. The residue was chromatographed on silica gel using 20% ethyl acetate/hexane as eluent to give 1.8 g of the title compound.
Obtained as an oil. The estimated structure was confirmed by nmr and infrared spectra. nmr (CK C, j!3): δ (ppm) 0
．． 94 (t, , r = 7H2,3H. Propyl FE) 13); 1.23 (e, 3H,
2-methyl proton); 3.67 (s, 3t, ester CH3): 6.28 (d, J = 8H2, 1t
l, aromatic): 6.71 (a, J=8H2,
1B, aromatic) ■Han CHCf3): 1730 cm-1 Example 11 Methyl 3-[7-(3-bromopropoxy)-6゜4-
Dihydro-2-methyl-8-propyl-2B-1-benzobilan-2-yl]propanoate methylene chloride 12
1.7 g (5,51 mmol) of the title compound from Example 10 in 1, 1.11 LI of 1,3-dibromopropane? (
11 mmol) and 1.9 g (11 mmol) of tetrabutylammonium hydrogen sulphate are added 5.51 g of 2M sodium hydroxide solution. The reaction mixture is heated to reflux for 15 minutes, then cooled. The organic layer is separated, washed with prine, dried over sodium sulfate, filtered, and concentrated to dryness. The residue is chromatographed on silica gel using 10 ethyl thiacetate/hexane as eluent to give the title compound as 1.8 g of an oil. The predicted structure was confirmed by nmr and infrared spectra. nmr (CD CAS): δ(l1l)In)
4.02 Addition of CH2Br signal at (t, J = 6 Hz) (compare with Example 10) 11'tCOH 3)
: 1735CI! -”Example 12 Methyl 3-(7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4-
Dihydro-2-methyl-8-propyl-2,H-1-benzobilan-2-yl)propanoate The title compound (melting point = 56-55°) was prepared by the method of Example 6 to produce the product of Example 11 and 2. It is produced using 4-dihydroxy-6-propylacetophenone as the raw material. The estimated structure was determined by ntor and infrared spectra.
and confirmed by elemental analysis. IR(CHcc,,): 1625.1730cII
L" elemental analysis: Lie 1 on C31Fi4207, calculated value: C70,70; H[04 actual value: c70.59; H8,10 Example 16 3- (7-[3-(4-acetyl-3-hydrof '/-2-propylphenoxy)furophoxy]-3,
4-dihydro-2-methyl-8-f lobi-2H-1
-Benzobyran-2-yl)furopanoic acid The title compound is prepared by the method of Example 7 using the product of Example 12 as starting material, but by extracting the acidified aqueous layer with ethyl acetate. The organic layer was then washed with water and prine and washed with Mg80. Drying on top, filtration and evaporation to dryness gives the title compound as an oil. The predicted structure was confirmed by nmr and infrared spectra and by elemental analysis. Engineering a (KBr): 1620.1705.1735c
Ift-1 elemental analysis: For C30B400, calculated value: C70,29; H7,87 actual value: C69
,93; )17.77Example 14 3-(2-carboxy-3,4-dihydro-7-hydroxy-4-okine-8-7'glu-2H-1-benzobilan-2-yl)propanoic acid Title is prepared by the method of Example 10 using α-ketoglutaric acid as the starting material. The crude product is used without further purification. Instead of α-ketoglutarate, congeners such as 4-ketovinsphosphate (4-ketovinsulfate) can be substituted.
topinalieacid) can be used to generate homologues of the title compound. Example 15 Methyl 3-(3,4-dihydro-7-hydroxy-2-
Methoxycarbonyl-4-oxo-8-propyl-2B
-1-benzobyran-2-yl)propanoate methanol 250m7! and 5N sulfuric acid to a solution of 13.9% of the crude product of Example 14 in 251% of trimethyl orthopormate! Add V. The reaction mixture is stirred at room temperature for 12 hours, poured onto an ice/water mixture and then extracted with ethyl acetate. The organic layer is washed successively with water, 5T sodium bicarbonate solution, water and brine, dried over MgSO4, filtered and then evaporated to dryness. The residue is chromatographed on silica gel using 16 ethyl thiacetate/hegysan as eluent to give 6.1 g of the title compound. The estimated structure was confirmed by nmr and infrared spectra. nmr (CDcJ, 3): δ (ppm) 0.99
(t, tT = 6Hz. 3I4.Propyl eH3); 3.64.3.71
(a pair of 8°68, ester CH3' e ); 6
-45.7-56 (1 pair of d'B, aromatic) IR (CI (C13) = 1685.1740 cm - 1 Example 16 Methyl 3-(7-[3-(4-acetyl-3-hydroxy-2 -propylphenoxy)furopoxy]-3,4-
Dihydro-2-methoxycarbonyl-4-oxo-8-
Propyl-2H-1-benzobylan-2-yl)propanoate The title compound is prepared by the method of Example 2 using the product of Eli Example 11 as the starting material. Estimated structure is nm
R and infrared spectra have confirmed the nature and elemental analysis; homologues of the corresponding compounds where t is 1 or 2 can be used as substitutes. nmr (CD C7!3): δ (ppm) 0.88
．． 0.93 (1 pair of t. 6B, propyl CH3'8); 2-56 (s,
3H, Acetyl CB3): 3.61.3.68 (1
Pair B, 6F + ester CH3'8); 4.2
1 (t, J==7Hz, 4H. 0CH2'6): 6.69.6.55.7.56.7.
66 (1 set of d'B, aromatic) IR (011ci3): 1630.1685.17
40cm-1 elemental analysis: ('5zH4o0□. Calculated value: c 65-74; H6,90 actual value: C! 65.89: E 6.87 Example 17 3-(7-43-(4-acetyl -6-Hiroki-/-
2-7'ropylphenoxy)profoxy]-2-carboxy-6,4-dihydro-4-oxo-8-propyl-
2H-1-benzobylan-2-yl)propanoic acid, R20 The title compound (melting point near 6-79) is processed in the process of Example 7 and the product of Example 16 is used as the starting material, with the exception that 1
Produced using 0 equivalents of lithium hydroxide. The acidified aqueous layer is extracted with ethyl acetate, then washed with water and brine, then dried over MgSO4, filtered, and then evaporated to dryness to yield the title compound. The predicted structure was confirmed by nmr and infrared spectra and elemental analysis.
Disappearance of 8 (compare with example 16) IR (K, 13r): 1620.1680% 17
10-17406R-' Elemental analysis: CzoFlza
For OxoaHzO, calculated value: e 62.71
; H6,67 actual measurement value: C62,85; H6,64
Example 18 3-1.4-DihyP-low 7-hydroxy-2-methyl-
4-oxo-8-propyl-2H-1-benzopyran-
2-yl)propanamide dry tetrahydrofuran 50
2.1 g of phosphorus pentachloride (1.0 g; 3-4 mmol) of the title product of Example 3 in 1
0.2 mmol). Mix, after stirring the thing for 60 minutes 1 liquid ammonia about 21! / is added and the solution is allowed to warm to room temperature and stirred for an additional 60 minutes. Evaporate the solvent
Dissolve the residue in ethyl acetate. The organic layer was washed sequentially with saturated bicarbonate solution, water and prine, and
Dry 17 on g 804, filter and then concentrate to dryness. The crude product (melting point: 10 days to 115°) is not further purified. The predicted structure was supported by nmr and infrared spectra. IR (KBr): 1680 cyn-'Example 19 3-(7-[3-(4-acetyl-6-hydroxy-
2-! (ropylphenoxy)noropoxy]-3,4-dihydro-2-methyl-4-oxo-8-propyl-2H-
1-Benzopyran-2-yl 1-propanamide The title compound (melting point near 7-79) was processed into the process of Example 6 using the AmiP product of Example 18 as starting material, but after stirring at room temperature for 16 hours. The reaction mixture is further heated at 50° C. for 3 hours to make it. The estimated structure is nmR
and confirmed by infrared spectroscopy and by elemental analysis. IR (KBr): 1630.1675m-” Elemental analysis: Calculated value for C3oH39C)y: C6B
, 55; I'l 7.48; N2-66 actual value: C6B, 62; H7,81; N 2.49
Example 20 3-(3,4-dihydro-7-hydroxy-N.N,2-trimethyl-4-oxo-8-zorobi-2B
-1-Benzobylan-2-yl)propanamide and a solution of the title product of Example 6 (1,[l9: 3.4 mmol) in dry dimethylformamide 401 cooled to = 20° with 1-methylmorpholine. 3.37m (3,
4 mmol)t? , then a solution of 0.45 mA (3.4 mmol) of imptyl chlorformate in dimethylformamide 6 is added. The reaction mixture was heated to -60 for about 20
Stir for a minute, then bubble in gaseous dimethylamine for 2 minutes. After stirring for 20 minutes, the mixture is warmed to room temperature and stirred for a further 30 minutes. The solvent was evaporated and the residue was dissolved in ethyl acetate and saturated sodium bicarbonate solution,
Wash sequentially with water and syline, then dry over Mg5O. Filter and remove the solvent to give the title compound 0.
84,! / Obtain: Melting point: 108-110°. The estimated transverse system was confirmed by an NMR infrared spectrum. n1llr (CD Cl3): δ (ppm) 0.
97 (t, , T = 7 Hz. 3H, protether CE3) Sl, 39 (s, 3B, 2-methyl proton); 2.89.3.06 (1 pair of B
. 6)1, ti(CH3)2); 6.55.7.
52 (1 set of d′6° aromatic) IR (KBr): 1625.1985 cm″″1 example 21 3- (7-C3-(4-acetyl-6-hyroxy-
2-propylphenoxy)-furoboxy]-6,4-dihyFo-N,N,2-triy'-f-ru-4-oxo-
8-Propyl-2H-1-benzobylan-2-yl)propanamide Title compound (melt reaction: 126-128°) All prepared by the method of Example B using the amide product of Example 20 as the starting material. . The estimated structure was confirmed by nmr and infrared spectroscopy and elemental analysis. nmr (eDcj3) Niaryloxy! Additional signal for Roboxy proton (compare with Example 20) IR
(KBr): 1655.1685cm-'Elemental analysis: Calculated value for C3zHtsNOy: c 69
．． 41; H7,8; N2-6 Actual measurement value: C
69,06; H7,87; N 2.51 Example 22 3-(7-43-(4-acetyl-6-hydroxy-2
-propylphenoxy) soroboxy]-6,4-dihydro-2-methyl-4-oxo-8-propyl-2H-1
-benzobilan-2-yl) propanoic acid monopotassium salt 85 potassium hydroxide in methanol 251 0.139
(1.9 mmol) is added to a solution of 1.0 g (1.8 mmol) of the title compound of Example 7 in methanol 251R1. The solution is neutralized with a cation exchange resin in the sulfonic acid form, filtered and then evaporated to dryness. The residue is triturated with diethyl ether to give 0.7 g of the title compound. The predicted structure was confirmed by elemental analysis. Elemental analysis: Calculated value for CzoH370sK/2HtO: c 60.89; H6,81; K
6.61 actual measurement value: c 61.08: H6,71:
K 6.69 Example 23 3-(7-[6-(4-acetyl-3-hyproxy2
-propylphenoxy)70ropoxy]-3,4-dihyPrho2-methyl-4-okine-8-propyl-2H-
1-benzobylan-2-yl)propanoic acid tris(hydroxyethyl)ammonium salt 0.8 of the title compound of Example 7 in 2511 Lt of methanol
Add triethanolamine 0-2N (1-5 mmol) to a solution of 9 (1,5 mmol). The solvent was evaporated and the residue was triturated with ether to obtain a solid. Recrystallized from nee chill/hexane l-1 Title compound 0.6
．． ! i'(f-obtain; melting point: 84-85° Estimated structure is n
Confirmed by MR and infrared spectra and by elemental analysis. IR(CB(J3): 1620.1670.17
00.17 d Ocm-' Elemental analysis: Calculated value for C5eHssO11N:
C66,98; H7,91; N 2.07 Actual value: e 63.86; R8,01; N 1.98
Example 24 3-(7-[3-(4-acetyl-3-hydroxy-2
-propylphenoxy)propoxy]-6,4-dihydro-2-methyl-4-oxo-8-propyl-2H-1
-benzopyran-2-yl)propanoic acid, 5-amino-
5-Carboxypentanammonium salt The title compound (melting point: 125-127) was prepared by the method of Example 23, and 0.989 (1,8 mmol) of the title compound of Example 7 and 0.24 g (1,6 mmol) of DL-lysine were prepared. mmol)
ft is used as a raw material and manufactured. Estimated structure is nm
This was confirmed by an off-site spectrum and an elemental analysis. IR (KBr): 1635.1685 cm-1 Elemental analysis: Calculated values for C3aHs20xo/HzO: c 66.42; H7,84; N 4.
11 Actual value: e 63,43; E 7.79;
N 4.09 Example 25 Methyl 4-(7-(3-(4-acetyl-3-hydroxy2-propylphenoxy)furopoxy)-3.4-
DihyP-Rho 2-methyl-4-oxo-8-propyl-2
B-1-Benzopyran-2-yl)butanoate The title compound is prepared by the method of Examples 1 and 6 using riftyl 5-oxohexanoate as starting material. The estimated structure was confirmed by elemental analysis using nmr and infrared spectroscopy. IR (CHC10): 1625.1675.176
0cIL″″1-element analysis: Calculated value for ei2Et20s:

[Coro 9.29; H7,63 actual value:
e 68-80; H7-72 Example 26 4-(7-[:3-(4-acetyl-3-hyProxy-2-propylphenoxy)propoxy]-3,4-dihydro-2-methyl-4-oxo -8-propyl-2B-
1-Benzobylan-2-yl)butanoic acid The title compound (melting point: 106-108°) is prepared by the method of Example 7 using the title compound of Example 25 as starting material. The predicted structure was confirmed by nmr and infrared spectra and by elemental analysis. IR (CE C10): 1625.1675.
1710.1750cIL-1 Elemental analysis: C31! (For 4008, calculated value:
C68,87; H7,46 actual value: c 6B, 68
: H7-79 Example 27 Ethyl 3-(3,4-dihydro-7-hydroxy-8-
7'ropyru-2H-1-benzopyran-2-yl)propanoate Ethyl 3-(4-oxo-7-phenyl medoxy 8-propyl-4H-1-benzopyran-2 in acetic acid 401)
A solution of 2.0 g (5.1 mmol) of -yl)-2-propanoate is hydrogenated at 50 psi and 70% over a palladium-on-5 carbon catalyst. The catalyst is filtered off and the filtrate is evaporated to dryness to give 1.6 g of the title compound as an oil. The predicted structure was supported by nmr and infrared spectra. nmr (Cr) C10): δ (ppm) 0.9
5 (t, :r = 7Hz. 3B, 7'l: I building eR3); 1-27 (t*
J = 7Hz @3B, ester CH3); 3.9(
m, IH, 2-f roton); 4.13 ((1, J=7E
z, 2H, ester CB2): 6.29.6.69
(a pair of d, aromatic) DingR (aHaz3):
1 7 2 5cln” Example 28 Ethyl 3-1 nia-(3-bromopropoxy)-6,4
-dihydro-8-flovir-2H-1-benzopyran-
2-yl]propanoate The title compound is prepared by the method of Example 11 using the product of Example 27 as starting material. The predicted structure was supported by nmr and infrared spectra. n+r+r (CDCI 3 ): δ(1)I)m)
Additional signals (compare with example 27) containing 5.59 (t, J = 7 Hz, 2H. CH2Br) I
R(CH(J3) + 1725 cm-” Example 29 Ethyl, 5- (7-[3-(4-acetyl-6-hydroxy-2-propylphenoxy)propoxy] -5
'+ 4-dihydro-8-propyl-2H-1-benzopyran-2-yl) glopanoate Title compound (melting point: 68-70°) All examples The product of Example 28 was used as starting material 2 according to the method of and manufacture it. The deduced structure was confirmed by nmr and infrared spectra and by elemental analysis. nmr (CDCI3): δ (ppm) 0.89 (t
,,y = 7 Hz, 6H. Propyl CH3”) y 1.25 (t* J-
7Hz * 3 H + ester CH3); 2.27
(t, J=6H, 2H. "H2" H2, aH2), 2-54 (s t 5
H* Acetyl CH3)y3.9 (m, I H
,2-proto7); 6.39.6.42.6.7
8.7.54 (1 set of d's, aromatic) IR(C
HCjs): 1625.1725(m-"Elemental analysis"
For 31H4207, calculated value: C70,70;
King (8,04 actual value: C70,57; I-T
8.09 Example 60 3-(7-[3-(4-acetyl-6-hydroxy-2
-propylphenoxy)furoxy]-6,4-dihydro-8-propyl-2H-1-benzopyran-2-yl)propanoic acid Title compound (1 point: 109-110°)
is prepared by the method of Example 7 using the product of Example 29 as starting material. The deduced structure was confirmed by nmr and infrared spectra and by elemental analysis. nmr (CDCI, 3): Disappearance of ester proton (compared with Example 29) IR (KBr): 1655.17051-1 Elemental analysis: For 029H380, estimated value: c69.8
6; H7,68 actual measurement value: C69,85: H7,
6B Example 61 Ethyl 5-C6,4-Zohygel 7-(2-oxiranylmethoxy)-8-propyl-2H-1-benzobilan-2-yl]panoate The title compound was prepared by the method of Example 11. using 3.0 g (10.6 mmol) of the product of Example 27 and 1.3 ml of shrimp bromohydrin (15 mmol) as starting materials. Estimated structure is nm
Supported by r and infrared spectra. IR (CHCl, ): 1725 cln-1 Example 62 Ethyl 5-(7-C5-<4-7cetyl-6-hydroxy-2-propylphenoxy)-2-hydroxypropoxy)-3,41'hydro-8-propyl- 2H-1-
Benzopyran-2-yl)propanoate 2.9 g (8,6 mmol) of the title compound of Example 51 in dry dimethylformamide 60a and 2.4 g (8,6 mmol) of 2,4-dihydroxy-6-propylacetophenone, @ (
Triton B2#J is added to a solution of 12.5 mmol). The reaction mixture is heated to 110-120° for 48 hours, then cooled and evaporated to dryness. The crude product is chromatographed on a silica dal using 20% acetone/hexane as eluent to give 1.6 g of product as an oil. The predicted structure was supported by nmr and infrared spectra. nmr (CDCj3): δ (ppm) 0.91.0
．． 93' (1 pair of t. 6H, 7" lobil cn! 3's); 1.25 (t
, J = 7Hz. 5H, ester CH3); 2.56 (S-5Hz
, 7 cetyl CH3; 3.90 (m, I
H9CHOH);4.12(d-J-7Hz, 4'
H-0CH2' sL 6.40.6-45, 6.80
．． 7.56 (1 set of d's, aromatic) IR (CHCl
3): 1 625, 17250-1 Example 63 5-17-C5-<4-acetyl-6- and droxy-2
-propylphenoxy)-2-hydroxypropoxy”
J-5,4-Dihyr-8-propylene-2H-1-benzobilane-2-(propanoic acid) The title compound was prepared by the method of Example 7 using the ester product of Example 62 as the starting material. The deduced structure was confirmed by nmr and infrared spectra and by elemental analysis.nmr(CDCj, ): loss of ester proton (compare with example 62) IR(CHC73): 1625.17Q5cIn-
“Elemental analysis: c29”! Calculated value C67,68; H7,44 Actual value c67.03; H7,59 f! 134 Methyl 7-hydro4xy-4-oxo-8-propyl-4
H-1-Benzobyran-2-oate 2,4-dihydroxy-6-propylacetophenone in dry dimethylformamide 1-e 99.7,! i' (0,513 mol) and 72.7 g of dimethyl oxyplate (,0,7
7 mol) of sodium methoxylF in a solution of 97 g (1,
8 mmol) little by little. After stirring for 4 hours, add 1.8-e of acetic acid and continue stirring for 4 hours.
Continue for days. The reaction mixture is heated in a steam bath for 4 hours and evaporated to dryness. Add water to the residue and heat the mixture. The solid matter was collected by filtration and recrystallized from 4 ethanol.
Produces 89.8 g of the title compound; mp = 222-2
24°. The predicted structure was supported by nmr and infrared spectra. TR(KBr): 1650.1745Cb Example 65 Methyl 7-1:5-(4-acetyl-6-hydroxy-
2-7'ropylphenoxy)furboxy]-4-oxo8-fropyru-4H-1-benzopyran-2-oni~
The title compound was prepared by the method of Example 6 with all of the product starting materials of Example 64 and 1. Manufactured using Estimated structure is I″1mr
and confirmed by infrared spectrum. , nmr (CDC, / 3): δ (ppm) 0
．． 89, skin 96 (1 pair of t. t5H, propyl CH3's), 2-55 ("
, 3'-■, acetyl CI (3); 2.62.2.
88 (1 pair, 4°ocs2'S): 6.98
(s, IHC=CI(); 6.42, /, 0
0.7.54.8.00 (1 set of d's, aromatic)■
u(cncl,): 1 6 5 D , 1
745 (1777-1 Example 66 Methyl 7-[3-(4-acetyl-6-hydroxy-2
-propylphenoxy)propoxy]-6,4-zohyro8-propyl-2H-1-benzopyran-2-oate All the title compounds 9 by the method of Example 27 Product of Example 65 50
．． "# (61,9 mmol) is prepared using all starting materials and I-. The deduced structure is supported by nmr and infrared spectra. mr+r (CDCt3): alkenyl prff
) disappearance; δ (ppm) 4.41 (t, =
Addition of 2-proton to T=5 H2) (compare with Example 65) rR(c■(C10): 1610.1620.176
0, 1750 (1) Punishment example 67 7-46-C5-hydroxy-4-(1-hydroxyethyl)-2-propylphenoxy]furopoxy J-3,
4-Dihydro 0-8-propyl-2H-1-benzobylan-2-ylmethanol H A solution of 2.8 g (0.13 mol) of lithium boron hydride in 500 ml of tetrahydrofuran is added to tetrahydrofuran Example 66 in Lofuran 2007111 The title compound of 25.
0.9 (51.6 mmol). The reaction mixture is stirred at room temperature for 2 hours and then heated to reflux for 1 hour. After the mixture has cooled, excess borohydride reagent is added with water and then decomposed by adding a small amount of dilute hydrochloric acid. The reaction mixture was diluted with total ethyl acetate, washed with sodium bicarbonate solution, water and then washed with MgSO
4, filtered [7] and then evaporated to dryness. The residue is chromatographed on silica sol using 40% ethyl hexate/hexane as eluent to give the title compound 16.5y as a solid oil. The predicted structure was supported by nmr and infrared spectra. nmr(CDCl2): ,:c-ste#disappearance of CH3;
Acetyl/I/ CH3 δ (ppm) 1.55 (a
, J=7EIz): Change to 4.96 (q, J
-6Hz, 1H, Methyl-〇HO-) Additional signal (compare with Example 66) IR(CH(Jz): No carbonyl band appears between 1600 and 1800α-1. Example 58 7- (5-[ 4-(1-hydroxyethyl)-3-(
phenylmethoxy)-2-propylphenoxy]solboxy)-6,4-dihydro-8-furopyru2H-
1-Benzobylan-21lumethanol OH The title compound is prepared by the general procedure of Example 11 using the product of Example 67 and benzyl chloride as starting materials. The predicted structure was supported by nmr and infrared spectra. IR (CHCI,): 160 D and 1800 (Ml
-'b No carbonyl band appears nmr (CDC13): Additional aromatic proton (Example 67
Example 69 7-15-C4-acetyl-6-(phenylmethoxy)
-2-7'ropylphenoxy]furophoxy)-5,4-
Dihydro-8-propyl-2H-1-benzobilane-2
18 g (162 mmol) of manganese dioxide are added to a solution of 8.9 g (16.2 mmol) of the title compound of Example 68 in 150 ml of methylene chloride. The reaction mixture is stirred at room temperature for 12 hours and then filtered. Removal of the solvent gives 6.9 g of the title compound: mp 286-85°. The predicted structure was supported by nmr and infrared spectra. IR (CHC73): 1665 cm-'nmr (
CDCj3): δ (ppm) 2.55 (s, 3
Acetyl CH3 is reproduced in H) (Example 66.67.68
Compare with) Example 40 7- +3-1: 4-acetyl-6-(phenylmethoxy)-2-rrobylphenoxy]propoxy)-5,4
-dihydro-8-propyl-2H-1-benzobilane-
2-Carboxaldehyde A solution of 1.2 mJ (15,3 mmol) of oxolyl chloride in methylene chloride 60° was cooled to 70 ° and a solution of 1.9 mJ (26,6 mmol) of dimethyl sulfoxide in methylene chloride 9d. )
Add the solution. The mixture was stirred for 5 minutes and then 6.6 g (1
Add a solution of 2.1 mmol). After stirring for a further 15 minutes, 8.5 N (60.5 mmol) of triethylamine are added and the mixture is stirred at -70° for 5 minutes and warmed to room temperature. Add water and separate the layers. The organic layer is washed successively with dilute hydrochloric acid, 5% sodium bicarbonate solution, water, and brine, dried over Mg5Oj, and then filtered. Removal of the solvent gives the title compound 6.44y as a yellow oil. The predicted structure was supported by nmr and infrared spectra. nmr (CDCj3): δ (ppm) 9.76
(s, I HoCHO)r R(cHcj
3) Two 1665, 17.55 (hehe, -
Example 1 41 57C7-45-C4-acetyl-6-(phenylmethoxy)-2-propylphenoxy]propoxy)-5,
4-dihydro-8-propyl-2ET-1-benzobilan-2-yl]-2(g and Z ) -7' o pennitrile The title compound 6 of Example 40 in 150 M of benzene
．． 55 g (11,7 mmol) of cyanomethylenetrinoenylphosphorane in a solution of 4.04. ! i' (13,5
mmol). The reaction mixture is stirred for 12 hours at room temperature and then evaporated to dryness. The residue was chromatographed on silica gel using 20% ethyl acetate/hexane as eluent to obtain the cis isomer 1. ．． 5. ! I'1 trans y complex body skin 8 y and 53:47 cis/trans mixed 8- object 1.1 y to 14+. The predicted structure was supported by nmr and infrared spectra. nmr (CDC13) (cis NI'lE form): δ(
ppm) 5.44 (da, Jl −= 1
1) rz, J2 = 1.5 Hz,
I H, CHCN) (trans isomer) two δ (
ppnn) 5.69 (dd. , Tl = l (5Hz, , , T2 = 6 Hz
I H, CI ((:'N); 6.77 (dd, J
l -145Hz, J3 "" 4 NT
z, i H, I(C'-”?CCN)IR(
CHC#, S) (cis isomer) = 166 skin 2.21Q
tyn-” (trans isomer): 1665.223
0z-'Example 42 5- (7-C5-(4-acetyl-6-hydroxy-
2-Propy(3-rufemexy)propoxy]-6,4-dihydro-8-propyl-2H-i-benfe-fyn''
-2-1 l-2(7,)-Noropennitrile - 1.4 of the cis isomer product of Example 41 in Hanabi methylene 70d cooled to 78°,! ii' (2.4 mmol) of a 1 MM solution of ternary Ichhou chord in methylene chloride 9.7
mA<9-6 mmol) all added. After the addition is complete, pour the reaction mixture into an ice/water mixture and then add additional methylene chloride. Wash with several layers of gold water and brine, and
Dry with gSO, then filter. The solvent is removed, and the title liquid is converted into an oily substance. The estimated lecture was supported by nmr and infrared spectra KJ:'). nmr(CDCIJ:δ(I)L)m) 5-46 (
dd, Jl ”” 11 Hz. I H, CI ((:'N); 6-67 (dd, J
l ”” 11 Hz, ,J! 3-. 5.5Hz,
i H,H(nC-CN) ; disappearance of ester proton (compare with Example 41) r R(Icl, 3)2 1 6 2 5,
2 2 3 0 CWn-'Example 46 Lo-(7-C5-(4-·acetyl-6-hydroxy-2-zolobilphenogysi)propoxy2-6,4-dihydro-8-floby-2H-1 -benzobilan-2-yl)propanenitrile A solution of 1.6 g (5° 4 mmol) of the title compound of Q Example 42 in 271 ml of ethyl acetate and 5 ml of acetic acid was prepared over a 10% palladium on carbon catalyst at total atmospheric pressure and room temperature. Hydrogenate using The catalyst was filtered off and the filtrate was evaporated to dryness. The residue was eluted with silicavir 1-20% ethyl acetate/
Chromatography using gold hexane gives 1.3 g'fc of the title compound: mp: 89-89.5°.
. The predicted structure was confirmed by nmr and infrared spectra and by elemental analysis. nmr(CDCl2): disappearance of alkenyl proton (compare with example 41)
Elemental analysis: Calculated values for C29H3705N:
C72,62; H7,78; N 2.92 Actual measurement:
C72,92; H7,79; N 2.851+
IJ 44 Methyl 5-(7-C5-<4-acetyl-6-hydroxy-2-f lobylphenoxy)propoxy]-3,4-
Dihydro-4-oxo-8-propyl-2H-1-benzobylan-2-yl)propanoate Methyl 3-(7-IT3-(4-74=-F- Lou 6
-Hydroxy-2-propylphenoxy) Zorobogishi]
A bath solution of 1.9 g (3.6 mmol) of -4-oxo 8-f ropyru 3 H-7-be/zobin-2-yl 1-noropanoate was hydrogenated using a Raney nickel catalyst at room temperature and 2 pS. Add to the trend. The reaction mixture is filtered and evaporated to dryness. 4% crude raw material as eluent on silica gel
Chromatography using acetone/toluene yields 0.9 g of the title compound: mp = 1o1-101
．． 5°. The deduced structure was confirmed by nmr and infrared spectra and by elemental analysis. Engineering R (cHc13): 1625. 1675. 1
750cm-"Elemental analysis" Calculated value for C,0H1808: C68,42; H7,27 actual value: C
68,+0; H7,22 Example 45 Methyl 5-(7-C5-(4-acetyl-6-hydroxy-2-7'robylphenoxy)furoboxy)-,5
,4-dihydro-4-hydroxy-8-propyl-2H
1.0 g of the title alcohol compound are obtained from another chromatographic fraction of -1-benzobylan-2-yl)propanoate Example 44; melting point: 125-125.5°
. The deduced structure was confirmed by nmr and infrared spectra and by elemental analysis. IR (CHC73) 2 1 6 5 0. 1
7 65cm "Elemental analysis: Regarding C5oHtoOe, total n value: C68,16; H7,66 actual value:
C68,21; H7,60 Example 46 5-17-C5-<4-acetyl-6-hydroxy-2
-71'robylphenoxy)furoboxy]-6,4-dihyro4-oxo-8-propyl-2H-1-benzopyran-2-yl)propanoic acid Title compound (melting point: 149-150) Method 7 The ketone product of Example 44 is prepared by using it as a chemical substance. The deduced structure was confirmed by nmr and infrared spectra and by elemental analysis. IR (KBr): 1655. 1665. 172
About 5cm-"Elemental Analysis" C211H3608,
Calculated value: c 67.95; H7,07 actual value:
c 67.76; H7,LI 5 examples 47 Methyl 6-(7-C5-(4-7cetyl-6-hydroxy-2-propylphenoxy)propoxy2-8-f
Lobi-2H-1-benzobylan-2-yl)propanoate methanesulfonyl chloride in methylene chloride 5at)
A bath solution of 0.2 g (2.4 mmol) of triethylamine in methylene chloride 20Id and 0.7 mJ (5 mmol) of the hydroxy compound of Example 45 i, o g<2.
0 mmol) dropwise into the cooled (-20°) vinegar solution. The reaction mixture is cooled at -5° for 16 hours, then poured onto ice and extracted with diethyl ether. The organic layer is washed successively with 2M hydrochloric acid, 10% sodium bicarbonate solution and water, dried over MgSO4 and then filtered. Removal of the solvent gives 0.6 g of the title compound as an oil. The estimated structure was confirmed by nmr and infrared spectra. nmr(C'DCj3) :δ(pI)m) 6-64
(s, 6H, ester CH3)s 4.8 (
, m, I H92-po);5.5 (dd,
Jl = 10 Hz, I H* 6-proton); 6
．． 75 (dd, Jl-10Hz1.I H94-7°
Roton) IR (CHC73): 1605. 162
5. 1745C1n-'Example 48 5-(7-[5-(4-acetyl-6-hydroxy-2-propylphenoxy)furopoxy]-8-propyl-2H-1-benzopyran-2-yl)propanoic acid Title compound (Melting point: 6 (J~.62°) gold side 7. Produced using the product gold raw material of Example 47 by the method of Gold side 7. The deduced structure was confirmed by nmr and infrared spectroscopy and by elemental analysis. 1.3 nmr (CDCl 3 ): δ (ppm) 5.5
8 (dd, , r, = 10 H3゜J2=3Hz
, I H, 3-7″D ton); 6.37 (dd
. J1'-" 1 0 I(z, , T!S"" 1-
5 Hz, lH,4-proton); Disappearance of ester CI■3 IR (KBr): 1605.1625.1725゜1730c1n-"Elemental analysis" For 29HT607, calculated value 2C70
, 14; H7,31 Actual value: C69,94; H7,11 Example 49 3.4-dihydro-7-hydroxy 2-methyl-4-
Okin-8-propyl-2H-2-benz)4-ran-
2-carboxyarte" human pyrrolidine in 125 ml of toluene containing 15.5 ml of 2,4-dihyde was mixed with Roxy 5-f loby-acetophenone 3 Ll, Og, and the water was removed using a Dean star trap. Heat to reflux.Vilpaldehyde zomedylacetal2.
After adding 9.2171 ffl to the cooled (~00) solution, the mixture is heated to reflux while removing more water. After 5 hours, a further 5.2 ml of pyrrolidine is added and the mixture is refluxed for a further 18 hours. The reaction mixture was cooled, concentrated, and then taken up in ethyl acetate. The resulting solution is washed sequentially with water, 1N hydrochloric acid, and brine, dried over magnesium sulfate, filtered, and concentrated to dryness. The residue was taken up in ethyl acetate/hexane, filtered through silica sol, concentrated and washed into an oily column of silica gel. The shrine is made by comatography. The intermediate acetal derivative of the title compound is yellow 1. ! Obtained as a +j shape (13.75'). This product is used without further elaboration in the preparation of the title compound. [Analytically pure material (melting point: 146
~148°) is recrystallized from ethyl acetate/hexane. Intermediate acetal compound in 20 mj of acetic acid containing 10 ml of 10% sulfuric acid 2. [J y solution ft 5 at 80°
Heat for an hour. The mixture was taken up in ethyl acetate and washed with water, aqueous sodium bicarbonate and brine, then #
Dry over magnesium chloride, filter, and concentrate. The title compound obtained as an oil (1.7 g) is used in the next reaction without further purification. The predicted structure was supported by nmr and infrared spectra. nmr (CDCIJ: δ (ppm) 0.99.1.
55.2.70 (je my t+ 7H, 7'
C53 (st3H+ methyl); 2.88 (q, 2H, jRCH2); 6.52
, 7-62 (1 pair of d-5 examiners &); 9.60 (
s, I H, CHO) IR (CHCIJ: 1
740,1 67 bcyn"Example 5U2R-(5,4S-dimethyl-5R-phenyl-2f
(-oxazolidinyl)-3,4-dihydro-7-hydroxy-2-methyl-8-propyl-2H-i-benzobylan-4-one 20.0 g of the title compound of Example 49 in 150 g of benzene and an excess of M A solution of 1-ephedrine is heated to reflux while removing water and gold using a Dean-Stark trap. Reflux for 4 hours, then filter the solution through silica sol and add 5% ethyl acetate/'
Wash with xane and concentrate and dry under reduced pressure. Column chromatography using ethyl acetate/hexane on silica gel yields 1.1 g of the title compound, which is recycled to obtain the least polar compound;
Melting point = 196-197°. Structure determination was confirmed by X# crystallography. [α), = −2,1° (1.1129% in acetone)
. Example 51 2S-(3,4,R-dimethyl-58-phenyl-
PpI
point I = 196 to 198°] in Example 49 by the method of Example 50.
of the title compound and an excess of d-ephedrine. The optical rotation of the title compound was opposite to that of the title compound of Example 50. [α]ゎ-+1.6° (1.Rho 4% in acetone). Example 52 6.4-dihydro-7-hydroxy-2-methyl-4-
Oxo-8-propyl-2H-1-benzobilane-2R
- Carboxaldehyde To 441 g of the title compound of Example 50 dissolved in 150 ml of methanol
wex) -50 (H+ form) 12g and water 50ml
Add. After 2.5 hours at 50°, the mixture was filtered and
The filtrate is concentrated under reduced pressure to obtain 1.2 g of the title compound. A second crop of product is obtained by suspending the recovered exchange resin in 90 g of aqueous methanol, adding an additional 4 g of Dopex-50, heating at 60° for 6 hours, filtering, and then concentrating to dryness. A total of 2.4 g of aldehyde product is delivered. This (R)-aldehyde is further f#
Use in the next reaction without breaking. Example 56 3.4-dihydro-7-hydroxy-2-methyl-4-
Oxo-8-propyl-2H-1-benzobilane-28
- Carboxaldehyde Title Compound <6. '051 is prepared by the method of Example 52 using 5.0 g of the title compound of Example 51. This (S)-aldehyde is used in the next reaction without further loading. Example 54 Ethyl 6-C5,4-dihydro-7-hydroxy-2R
-Methyl-4-oxo-8-propyl-,2'H,-
1.2 g of the (R)-aldehyde product of Example 52 and 1.8 g of (carboethoxymethylene)triphenylphosphorane.
Leave the solution in g for about 7 hours. The solution is filtered through silica gel and the filtrate is concentrated to dryness. The residue is then chromatographed on silica gel using 1.8 ethyl thiacetate/hexane as eluent. The title compound (the cis-isomer) is obtained from the initial chromatographic fraction; mp = 104-106°. Example 55 Ethyl 5-(3,4-dihydro-7-hydroxy-2
R-Methyl-4-oxo-8-propyl-2H-1-benzobilan-2-yl)-2(E-hoopropenoate U The trans isomer is obtained from the later chromatographic fractions of Example 54; melting point: 111.5-112 -5°. The predicted structure was supported by nmr spectrum, optical rotation and elemental analysis. nmr (CDCJ3): δ (ppm) 6-0 [
J (d, J= 1 6H7). 6.95 (cl, J=16H7,) A・Ke=
Lupu'roton〔α〕ゎ-+129-0' (CHCf
Z Medium (K, 906%) Elemental Analysis'C1eH2205・
'/21120, it J Todoroi [value 2 C6
6.9 6; H7, [J2 actual value: C6
7, [Ja; n6.95 Example 56 Ethyl 3-(3,71-dihydro-7-hydroxy-2
8-Methyl-4-oxo-8-propyl-2H-i-benzopyran-2-yl) -2(Z)-propenoate The title compound (-f rope b1 cis isomer: melting point = 109
~110°) to the method of Example 54 with 3.05 g of the (S)-aldehyde product of Example 53 and 4.
7. ! 9. Estimated structure? This was supported by optical rotation and elemental analysis. (α), = -185,8° (CIIC!!05 (J,
771%) Example 57 Ethyl 3-(S,4-dihydro-7-hydroxy-28
-Methyl-4-sxiso-8-propyl-2H-1-benzobilan-2-yl)-2)-butropenoate All trans isomers from the fJa chromatography fraction of Example 56; melting point: 11 [], b~ 111.5°0J
Supported by optical rotation and elemental analysis! did. [α']ra = -125,7° (1 in CHC73
．． 0 15%) Elemental analysis' C1eH2205
Regarding, total initial 1*: c67.91; H6,97 actual value: C67,67; H6,98 Example 58 Ethyl 5-17-C5-<4-acetyl-6-hydroxy-2-f lobilphenoxy) 7" roboxy '3-5
．． 4-zohydro-2R-methyl-4-oxo-8-7°
robi-2H-1-benzobilan-2-yl) -2(
R:)-propenoate dimethylformamide 6Qm
The title compound 1.1 of Example 55 in A &, the title compound 1.1 of Example 5. A mixture of tJ, 9 and 0.91 g of powdered potassium carbonate was stirred overnight in a vacuum. The reaction mixture was diluted with ethyl acetate, filtered, washed successively with diluted ammonium chloride and brine, filtered, and then concentrated under hot water pressure to give an oil. Complete column chromatography on silica gel with 7% ethyl acetate/toluene yields 1.2 g of the title compound: mp: 155.5-1
36.5°. The predicted structure was supported by optical rotation and elemental analysis. [α]ゎ-+91.8° (1.0 in CHCt3 [3
1]%) Elemental analysis: Cq2H<o (for Ja, i
x 1 shift: C69, b 4;
H7,30 actual value: C69,52; H7,25 example 5
9 Ethyl 6-(7-C5-<4-acetyl-6-hydroxy-2-propylphenogysi)solboxy:]-3,4
-dihydro-28-methyl-4-oxo-8-propyl-2H-1-penzopyran-2-yl J-2(E)-propenoate Title compound (melting point = 164-.165°
) is prepared by the method of Example 58 using the title compound of Example 57. The predicted structure was supported by optical rotation and elemental analysis. [α), = -87,3° (c'gct! 1.002 in 3
%) Elemental analysis: Calculated value for C32H4008:
c 69.54; H7,50 actual value: C69,
57; H6,96 Example 60 5-(7-C5-<4-acetyl-6-hydroxy-2
-propylphenoxy)propoxy]-6,4-dihydro-2R-methyl-4-oxo-8-propyl-2H-
Example 7
Using the general method of
15:1 toluene/ethyl acetate/acetic acid) to give 0.67 g of pure solid, prepared from 1.05 g of the ester product of Example 58. The predicted structure was supported by optical rotation and elemental analysis. [α], = +93.3° (1.0 in CHcj3 [1
1%) Elemental analysis: For C3oHs60a, calculated value: C68,68; H6,92 actual value: C68,6
2; H6,76 Example 61 3-(7-[3-(4-acetyl-6-hydroxy-2
-propylphenoxy)propoxy]-6,4-dihydro-28-methyl-4-oxo-8-propyl-2H-
The title compound (melting point: 179-181°) was prepared by the method of Example 60 using the ester product i, tg of Example 59. do. The predicted structure was supported by optical rotation and elemental analysis. [α), = -90,8° (1.0.02% in CHCjF
) Elemental analysis: 'For C3oHs60a, calculated value: C68,68; H6,92 actual value: C68,6
0; H6,79 Example 62 Ethyl 6- (7-(6-(4-acetyl-6-hydroxy-2-propylphenoxy)propoxy)-3,4
-dihydro-28-methyl-4-oxo-8-propyl-2H-1-benzobilan-2-yl) -2(Z)-
The propenoate title compound (melting point: 98-99°) is prepared by the method of Example 58 using the title fraction of Example 56. The predicted structure was supported by optical rotation and elemental analysis. [α], :=-118,8° (1.013 in CHCtS
%) Elemental analysis' Calculated value for C32H400B:
C69,54; a7.50 Actual value: C69,65; H7,60 Example 66 N-[67(7-rJ6'-(4-acetyl-6-hydroxy-2-propylphenoxy)furboxy]-5,
4-dihydro-2-methyl-4-oxo-8-propyl-2H-1-penzobilacy2-yl)-zolopanoyl'II-L-7'loline methyl ester The title compound was prepared from dimethylamine by the method of Examples 20 and 21. Produced using L-proline methyl ester instead of. Confirmed by 1 mm cell structure nmr spectrum and elemental analysis. nmr (CDC13): δ (ppm) 1,55
(s, 6H,2-methyl proton); 2-55
(s, 5H, acetyl CH,); 3-71 (s,
3H, ester CHI); 6.42°6.55.
7.56.7.72 (1 set of d, aromatic) elemental analysis:
For CzaH<tNOo, calculated value: c 67.
80; H7,43; N 2.20 actual value 2c 6
7.68; H7,70; N 2.15 Example 64 N-C5-(7-L: 5-<4-acetyl-6-hydro
xy-2-propylphenoxy) soroboxy'1-3.
4-Zohydro-2-methyl-4-oxo-8-probyl-2n-1-benzobilan-2-1-7'lovanoyl) -L-y'lolin The title compound was prepared according to the method of Example 7. , prepared using the title compound of Example 65, substituting sodium hydroxide for lithium hydroxide. The deduced structure was also confirmed by elemental analysis. Elemental Analysis” About 35H45NO9/N20, it
s value: C65,55; H7,,58; N 2.1
8 Actual measurements: C65,76; H7,44; N1.89
Example 65 N-1:3- +7-[6-(4-acety, Fi/-3
-Hydroxy-2-7'' Robilf J-noxy]7° Roboxy)-5,4-dihydro-2-methyl-4-okino8-FD Lobil-2-1-benzobilan-2-yl)propanoyl] Lucosine ethyl ester title compound (melting point: 1o1-102°) prepared by the methods of Gold Sides 20 and 21 using sarcosine ethyl ester in place of dimethylamine. Estimated structure nm
Confirmed by r spectrum and by elemental analysis. nmr (CDCJ3): δ (ppm) 2.15 (
s, 3 H, N -CHI) y l, 55 (S
, 3H,7 cetyl CHJ; 5. D7(S,
2H,N-CH,-co); 6.50 (overlapping d. aromatic); 7.57. 7.72 (d pair, aromatic) elemental analysis: 03. H,, 1st calculation shift for NO9: C67,18; H7,57; N
2.2 4 actual measurements: C67,12; H7,55;
N 2.19 Example 66 N-[3174:3-(4-acedel-6-hydroxy-2-propylphenoxy)propoxy)-3,4-dihydro-2-methyl-4-oxo-8-propyl-2H
-1-benzobylan-2-yl)propanoyl]sarcosine is prepared by the method of Example 7 using all of the title product of Example 65. The predicted structure is supported by elemental analysis. Elemental analysis: For C33H, 3NO, ・V2H20, ii1 value: C65,35; H7-51; N
2-31 actual measurement value: C65,10; H7,40;
N 1.98 Example 67 Methyl 7-Hydroxy 6.4-dihydro-8-propyl-2H-1-benzobylan-2-oate The title compound (melting point: 51-56°) was converted to the title product of Example 64 (6, 6 g; 25 mm!7 mol), using the general method of Example 27 but using 1 as the chromatographic eluent.
Prepared using 5% ethyl acetate-hexane. The predicted structure was supported by nmr, infrared and ultraviolet spectra, and elemental analysis. nmr (CDC13): δ (ppm) 0.95 (
t, 5) (, propyl CHsL 5-77 (s
, 6H, ester CH3); 4.75(t, iH
, 2-proton) ; 6.36.6.72 (a pair of d
-'s, aromatic) Engineering R (cHclz): 1740. 176 QcI
n”UV (methanol): λmax284nm (C1
830) Elemental analysis' For C14H1804, calculated value: c 67.18; H7,25 actual value: C6
7,11J; H7,42 Example 68 Methyl 7-phenyl medoxy 5,4-dihydro-8-
7'Lobi-2H-1-benzobilane-2-oate The title compound was prepared as an oil from the title product of Example 67 (5,25,!i'; 21 mmol) and benzyl bromide by the general method of Example 6. [Manufacture. The deduced structure was supported by nmr, infrared and ultraviolet spectra and by elemental analysis. nmr (CDCl2): δ (ppm) 5.05,
7.58 with an additional signal for the benzyl proton (
Compare with Example 67) 1 liter CHCl3)' 1755. 17
55m-1UV (methanol) 2λmax 276
mm (C1862). 284 nm (C1966) Elemental analysis: Calculated value for C21H2404: C7
4,09; H7,11 actual measurement value: C74,11; H
7,06 Example 69 Methyl 2-(7-phenylmedoxy5,4-dihydro-2-methoxycarbonyl-8-propyl-2H-1-
Benzobylan-2-yl)-1-cyclopropylcarboxylate cooled (-10°) anhydrous tetrahydrofuran 600M
To a solution of 0.77 ml of diisopropylamine (<ca. 5.5 mmol) in 2.5 M n-butyllithium in tetrahydrofuran is added under an argon atmosphere. The solution was further cooled to -70° and 1.7 g (5
(mmol) slowly while stirring. After 1 hour, a bath solution of 0.87 g (approximately 6.6 mmol) of methyl 4-bromocrotonate in tetrahydrofuran 10711 is slowly added. The reaction mixture is warmed to about 0° and then cooled with dilute hydrochloric acid. The mixture was poured into 150 ml of diethyl ether, washed successively with water, saturated sodium carbonate and prine,
It is then dried over magnesium sulfate, filtered and concentrated under reduced pressure to give an oil. V loading by commercial performance liquid chromatography gives the title compound as an oil. The product crystallizes slowly: mp 282-84°. The deduced structure is supported by nmr, infrared and ultraviolet spectra and by elemental analysis. nmr(CDC13)-:δ(ppm) 0.94 (
t, 5H, propyl CH3); 5-66. 5
．． 68 (1 pair of 5v6H, x stell "H3'"):
5.02 (s, 2H, benzyl CH2);6.
5-7.4 (Aromatic) IR (CHCI3): 1720 n” UV (methanol): λmeLX276f1m (Sh: g 187
5) t' 284 nm (C1964) Elemental analysis: Calculated value for C+aH3o06: C71,2
1; H6,90 actual value: C70,41; H6,88 Example 70 Methyl 2-(7-hydroxyloxy6.4-dihydro-2-
Methoxycarbonyl-6-)urobi-2H-1-benzobilane-soyl)-1-cyclopropylcarboxylate Title compound (550m9) Gold side 69 Title product 6
From 99+119 (1.6 mmol), iR is prepared using the general method of Example 27 but using ethanol as the hydrogenation component M solvent. The putative structure is supported by nmr spectra. nmr (CDCl 13): Disappearance of benzyl signal (compare with Example 69) Example 71 Methyl 2-C7-<5-bromopropoxy-6°4-
2-methoxycarbonyl-8-propyl-2
Title product of H-1-pen-dopyran-2-yl-1-cyclopropylcarboxylate Example 71 658rn
g (1,7 mmol), 1,6-dibromopro7g5
．． 18 g (25,7 mmol), sodium iodide 11
2m9C0.75 mmol) and anhydrous potassium carbonate 4
A mixture of 80 μm (6.5 mmol) is heated under reflux for 6 days in 75 ml of methyl ethyl ketone in the presence of 6-person molecular sieves. After filtering off the insoluble material, the mixture is concentrated under reduced pressure to form an oil (44). Purification by centrifugal thick layer chromatography affords the title compound 4701nQ as an oil. This product is purified as follows without further purification. Used in the reaction. Example 72 Methyl 2-(7-[3-(4-acetyl-6-hydroxy-2-propylphenoxy)propoxy)-3,4-
dihiro 2-methoxycarbonyl-8-propyl-2
H-1-benzobylan-2-yl)-1-cyclopropylcarboxylate Title compound (209) Using the general method of Example 71 the title product of Example 71 (4701'l&;0.90 mmol) and 2,4-dihydroxy-6-progylacetophenone. The predicted structure is supported by elemental analysis. Elemental analysis: For Cs5H420p, calculated value: C
68,02;) T7.26 actual value: C67,44;
H7, 18 Example 76 2-(7-45-(4-acetyl-6-hydroxy-2
-flobylphenoxy)prophoxy]-6,4-dihydro-2-carboxy-8-7゜lobyl-2H-1-benzobylan-2-yl)-1-cyclopropylcarboxylic acid Title compound (melting point: 168-140 °) Using the method of Example 7 from the title product of gold side 72, but loading total 73:2
Supported by centrifugal thick-layer chromatographic Ti nmr spectra using 5:2 hexane-ethyl acetate-acetic acid as eluent and by elemental analysis. nmr (CDCz3): δ (ppm) 0.88,
0.90 (1 pair of t. (5H, Propyl C'z'S) s 1.14 (m,
I H, cyclopropyl terminal to carbonyl
C'H); 2, mouth 0 (m, IH, cyclozolovir-CH
-Coo-); 2.24 (t, 2H, cyclopropyl CH2); 2-56 (S, 3 Hl acetyl CH,,); 6.6-7.5 (Aromatic) elemental analysis'CIH3809・'/ For 2H20, calculated values:
C64,01; H7,11 actual value: C64,26
; H6, 71 Example 74 Ethyl 4-'(' 7-phenyl medoxy5.4-
dihydro-2-methoxycarbonyl-8-propyl-2
H-1-benzobylan-2-yl)-4-oxobutanoate The title compound (6.0 g) was prepared using the general procedure of Example 69, but the reaction was quenched with 0.5N sodium bisulfate and the chromatographic N-
<5-ethoxycarbonylzopanoyl)-imidazole and the title compound of Example 68 above (5.1 g; 15
Mi! 7 mol). The estimated structure is r+mr,
Supported by infrared and ultraviolet spectra and by elemental analysis. nmr (CDCl 3 ): δ (ppm) 0.9
9 (t, 6H, propyl cH3): 1.23 (t
, 5. H, ethyl aH3), 6.71 (Sv
6Hv methyl ester (JJ3); 4.10 (q
. 2H, ethyl CH2); 5.01 (s, 2
H, benzyl CH2); 6.5-7.4 (aromatic)
IR(CH(j3): 1 725. 1 745
Cm-”UV (methanol)λI11ax279n
m(Sh:ε2027). 284nm (!2085) Fluorine analysis” Calculated value based on C27H3207:
C'69.21; H6,89 actual measurement jlfi: C
69,64; H6,94 Example 75 Ethyl 4-(7-C5-C4-acetyl-6-hydroxy-2-propylphenoxy)furopoxy)-3,,4
-dihydro-2-methoxycarbonyl-8-propyl-
2H-1-Benzobylan-2-yl)-4-oxobutanoate The title compound (1,6,1) was prepared from the title product of Example 74 in Examples 70.71 (but without chromatography) and 72 (but 6 Purification is by performance liquid chromatography using 20% ethyl acetate-hexane followed by centrifugal thick layer chromatography using 20% dioxane-hexane. The estimated structure of 5° is nmr
, infrared and ultraviolet spectroscopy), and elemental analysis. nmr (CD, C)3): δ (ppm) 0.90. ,
0.95 (1 pair of t. 6H, propyl “H3”)s, 1.25 (t*
3H-ethyl CI (3); 2-55 (s,
Acetyl CH3); 6.69 (s. 6, H, methyl ester CH3): 6.3-7.4
(Aromatic)IR(CHCls)+ 1.62.5. 1
730,1751]cIn-"UV (methanol)2λmax 286Hm, (gl, 769'0) Elemental analysis: Calculated value for Cq4Ht40to: C
'66.65; H7, 24 actual value: c 66.
62; H7, 31 Example 76 4- +7-[,5-(4-acetyl-6-hydroxy-2-propylphenoxy)furboxy]-6,4-dihydro-2-carboxy-8-propyl-2H-1- Benzobylan-2-yl)-4-oxobutanoic acid The title compound (melting point: 100-102°) is prepared from 1.1 g (1.8 mmol) of the title product of Example 75 using the method of Example 7, but with The reaction is allowed to proceed for 4 hours and the reaction mixture is acidified using sodium bitfate to prepare. Isomorphic product (7) obtained by concentrating and drying the ethyl acetate extract
00m9) is analytically pure. The estimated structure is nmr
, supported by infrared and ultraviolet spectra, and elemental analysis. na+r (C'DC73) Disappearance of ester and ethyl ester protons: δ (ppm) 4.46 (d
d, I H) addition of 2-zolotone (compare with Example 75) IR (CHC73): 1660. 1715. 1
7b IJt'm-'ov (methanol): Tag 1
aX284nm (6186θIJ) element molecule r:
Regarding CzoHs80e, calculation im: c
6 8.4 2; H7, 27 actual suppression] 1st shift:
C! 6 8.1 2; H7, 26 figure
A Figure B IV XI1 Figure C ■I XXN+ Figure D R2 y AJ-JV Figure E R1) B y, IV LM LV

Claims (1)

[Claims] Formulas include mathematical formulas, chemical formulas, tables, etc. (In the formula, R represents a hydrogen atom or a methyl group, but if R represents a hydrogen atom, the compound is in the form of a monohydrate. ) and its pharmacologically acceptable addition salts.