JPH0680630A - Heterocyclic carboxylic acid and ester - Google Patents

Abstract

PURPOSE: To obtain the compounds useful as inhibitors of human platelet- enriched serum aggregation induced by adenosine diphosphate and collagen, particularly useful as oinhibitors of mammalian blood platelet aggregation.

CONSTITUTION: The compound of formula I (HET₁ is 3,4-diphenyl-1H-pyrol-1-yl, 1,6-dihydro-6-oxo-3,4-diphenyl-1-piridazynyl, 2,5-dioxo-3,4-diphenylimidazolin-1-yl, 4,5-diphenyl-2-thiazoyl or the like; n is 6 to 9; R is H, lower alkyl or alkali metal ion), e.g. 3,4-diphenyl-1H-pyrol-1-nonanoic acid, formula II (Het₂ is 4,5- diphenyl-2-tiazolyl, 3,4-diphenyl-1H-pirazol-1-yl, 1,5-diphenyl-1H-pirazol-3-yl or the like; R₁ is R), e.g. {3-[2-(4,5-diphenyl-2-thiazolyl)ethyl]phenoxy}acetate or the compound of formula III.

COPYRIGHT: (C)1994,JPO

Description

Detailed Description of the Invention

FIELD OF THE INVENTION The present invention relates generally to heterocyclic carbon compounds having drug and bioinfectivity and processes for their preparation. Particularly, the present invention relates to various heterocyclic derivatives characterized as an inhibitor of platelet aggregation.

[Prior art]

(1) Pyrrole Compound US Pat. No. 3,471,513 describes an antibacterial and ulcer-suppressing carboxylic acid having the following formula 16.

[Formula 16] U.S. Pat. No. 4,336,194 describes insecticidal carboxylic acid esters having the formula 17 below.

[Formula 17] U.S. Pat. No. 4,563,477 describes α- (N-pyrrolyl) derivative acids having antiplatelet-aggregating and analgesic activity having the formula 18 below.

[Formula 18] U.S. Pat. No. 4,694,018 has 5-lipooxydienase inhibitory substitution 1,5 having the following formula 19:
-Diphenyl-2-pyrrolepropionic acid is described.

[Formula 19] (2) Pyridazine Compounds US Pat. No. 2,712,542 has an analgesic, anticonvulsant, and sedative activity having the following formula 20:
(3-Pyridazonyl) acetic acid is described.

[Formula 20] U.S. Pat. No. 3,622,576 describes diphenylpyridazones having the following formula 21 having psychotropic and analgesic activity.

[Formula 21] U.S. Pat. No. 4,162,317 discloses 4,5-dihydro-3- (2H) having the formula 22 having muscle relaxing activity.
-Succinates of the pyridizones have been described.

[Formula 22] (3) Triazine Compounds US Pat. No. 4,167,566 describes 2-prenyl-3-oxo-5,6-diaryl-AS-triazines of the following formula 23 having antithrombotic properties.

[Formula 23] U.S. Pat. No. 4,318,911 describes 5,6-diaryl-1,2,4-triazines of formula 24 having antithrombotic activity.

[Formula 24] U.S. Pat. No. 4,511,566 describes 2-N-cycloalkylmethyl-3-oxo-5,6-diaryl-az-triazines of formula 25 having analgesic activity.

[Formula 25] U.S. Pat. No. 4,677,105 describes 2-alkoxycarbonylalkyl-3-oxo-5,6-diaryl-az-triazines of formula 26 below having non-inflammatory analgesic activity.

[Formula 26] US Pat. No. 4,851,411 describes 5-monoaryl-azu-triazin-3-ones of formula 28 having anxiolytic or antidepressant activity.

[Formula 27] (4) Pyrimidine Compounds US Pat. No. 4,486,443 describes hydantoins of the following formula 28 having antithrombotic activity.

[Formula 28] (5) Imidazolidine Compounds U.S. Pat. No. 3,965,114 describes imidazolidine derivatives of the following formula 29 having anticholinergic and anticonvulsant properties.

[Formula 29] U.S. Pat. No. 4,237,131 describes hydantoins of formula 30 having bronchodilator activity.

[Formula 30] U.S. Pat. No. 4,330,550 describes omega- (2-oxo-4-imidazolin-1-yl) alkanoic acids and esters of formula 31 having antithrombotic and analgesic properties.

[Formula 31] U.S. Pat. No. 4,709,042 describes 2-
A method for producing (1-hydroxyalkyl) -5,5-diphenyl-hydantoin is described.

[Formula 32] U.S. Pat. No. 4,797,493 describes UV absorbing imidazolines having the formula 33 below.

[Formula 33] (6) Tetrazole Compounds US Pat. No. 3,453,285 describes tetrazolyl alkanoic acids of the following formula 34 having anti-inflammatory properties.

[Formula 34] US Pat. No. 3,962,272 describes 1H-tetrazole-1-acetate esters of formula 35 and acids useful in the preparation of cephalosporins and penicillin antibiotics.

[Formula 35] U.S. Pat. No. 4,059,703 describes tetrazole compounds of formula 36 below having bactericidal activity.

[Formula 36] U.S. Pat. No. 4,652,671 describes a method for producing a dichloroisonitrilolocarboxylic acid ester of formula 37 below.

[Formula 37] (7) Thiazole Compounds US Pat. No. 3,506,679 describes 2,5- and 4,5-diaryl thiazolyl lower fatty acids having the following formula 38 having anti-inflammatory activity. However, R in the formula
³ is a straight or branched chain fatty acid radical having 2 to 6 carbon atoms.

[Formula 38] U.S. Pat. No. 3,538,107 discloses aryl-thiazolylacetic acid derivatives of formula 39 having anti-inflammatory, analgesic and antipyretic activity, such as alpha- [2- (4-chlorophenyl) thiazol-4-yl] propionic acid. Have been described.

[Formula 39] U.S. Pat. No. 3,661,920 describes thiazole derivatives of formula 40 having anti-inflammatory, analgesic and antipyretic activity.

[Formula 40] U.S. Pat. No. 3,821,237 describes thiazolylbenzoic acid compounds of the following formula 41 having fibrinolytic properties, platelet adhesion-reducing properties and antiulcer properties.

[Formula 41] U.S. Pat. No. 3,840,548 describes thiazolylbenzoic acid compounds of the following formula 42 having thrombolytic properties.

[Formula 42] U.S. Pat. No. 4,168,315 describes dianisyl thiazole compounds having the following formula 43 that reduce platelet adhesion and prevent platelet clumping.

[Formula 43] U.S. Pat. No. 4,659,726 describes 4,5-bis (4-methoxyphenyl) -2 (pyrrol-2-yl) thiazoles of the following formula 44 which have platelet aggregation inhibiting properties.

[Formula 44] U.S. Pat. No. 4,791,124 describes oxazole and thiazole compounds of formula 45 having insecticidal properties.

[Formula 45] (8) Imidazole compounds. U.S. Pat. No. 4,355,040 describes imidazole-5-acetic acid derivatives of the following formula 46 having pressor properties.

[Formula 46] U.S. Pat. No. 4,460,598 describes triphenylimidazolyloxyalkanoic acids of formula 47 below having antithrombotic properties.

[Formula 47] U.S. Pat. No. 4,668,794 describes imidazole acrolein analogs of formula 48 having blood cholesterol lowering properties.

[Formula 48] U.S. Pat. No. 4,686,231 describes 4,5-diaryl-2 (substituted) imidazoles of the following formula 49 having 5-lipooxydienase inhibitory properties.

[Formula 49] (9) Pyrazole Compounds US Pat. No. 3,704,241 describes 4-pyrazole acetic acid or ester of the following formula 50 having anti-inflammatory and analgesic properties.

[Formula 50] U.S. Pat. No. 4,042,706 describes pyrazole derivatives of formula 51 below having anti-inflammatory properties.

[Formula 51] U.S. Pat. No. 4,146,721 describes pyrazole-4-acetic acids of formula 52 having analgesic, anti-inflammatory and antipyretic properties.

[Formula 52] U.S. Pat. No. 4,495,195 describes 3 (5) -phenyl-substituted-5 (3) -pyrazole-carboxylic acids of formula 53 having xanthioxidase inhibitory properties.

[Formula 53] U.S. Pat. No. 4,613,610 discloses the following formula 5 which has cholesterol-biosynthesis inhibitory property of mevanololactone.
Four pyrazole analogs have been described.

[Formula 54] U.S. Pat. No. 4,826,868 describes 1,5-diaryl-3-substituted pyrazoles of formula 55 which block the activity of cyclooxydienase and nopooxydienase enzymes.

[Formula 55] US Pat. No. 3,853,404 describes 5-pyrazolylphenoxyacetic acids of the following formula 56 having diuretic activity.

[Formula 56] U.S. Pat. No. 4,870,095 describes 1H-pyrazole-1-alkanamids of formula 57 having antiarrhythmic activity.

[Formula 57]

[Problems to be Solved by the Invention] HET _1- (CH ₂ )
It is intended to provide _n CO ₂ R and heterocyclic carboxylic acids and esters represented by the following formula 5.

[Formula 5] In the above formula, HET ₁ , HET ₂ , R, R
₁ and n shall be defined later. These compounds are inhibitors of adenosine diphosphate and collagen-induced human platelet-enriched serum clumping and are particularly useful as inhibitors of mammalian blood platelet clumping. Another aspect of the invention is the use of an HET _1- (CH ₂ ) _n CO ₂ R (where R is hydrogen) as described above and an alkali metal salt of a carboxylic acid of formula 5 (where R ₁ is hydrogen) as described above. It also concerns. Another aspect relates to a pharmaceutical composition comprising the above compound in admixture with a pharmaceutically acceptable excipient. Yet another embodiment is a compound of HET _1- (CH ₂ ) _n CO ₂ R or an alkali metal salt thereof (when R is hydrogen) or a compound of the above formula 5 or an alkali metal salt thereof (R ₁
Is a hydrogen), and the method comprises the step of administering to a mammal in need thereof a therapeutically effective amount of H).

The present invention relates to HET _1- (C
H ₂₎ related inhibitors of mammalian blood platelet aggregates having _n CO ₂ R. However, n is 6 to 9, R is hydrogen, lower alkyl or an alkali metal ion, and HET ₁
Is a heterocyclic group selected from the group consisting of formula 1 below.

## STR00001 ## The present invention also relates to a compound of formula 5 below.

Wherein R ₁ is hydrogen, lower alkyl or an alkali metal ion, and the group —OCH ₂ CO ₂ R ₁ is a ring 3
HET ₂ is a heterocyclic group selected from the group consisting of Formula 6 below.

[Formula 6] "Lower alkyl" refers to a branched or unbranched saturated hydrocarbon containing 1-4 carbon atoms. In particular, methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl, and tertiary butyl are mentioned. "Lower alkanol" refers to an alcohol having 1 to 4 carbon atoms defined by lower alkyl.
"Alkali metal ion" refers to ions derived from alkali metals, most preferably sodium and potassium. According to the invention, said HET _1- (CH ₂ ) _n
The CO ₂ R compound can be obtained by the following method (a), (b) or (c). (A)

Hydrolyzing the compound of formula 2 or (b)

Esterifying the compound of formula 3 with a lower alkanol, or

[Formula 3] (c) HET ₁ -H (where HET ₁ is as defined above)

Alkylation with a compound of formula 4 Equation 58 below illustrates the above method.

[Formula 58] The compound of HET _1- (CH ₂ ) _n CO ₂ R is an intermediate alkyl ester HET _1- (CH ₂ ) _n CO ₂ which is obtained by esterifying HET ₁ -H with a lower alkanol of omega-halogenalkanoic acid as shown in formula 58. It can be produced by producing R ^a . Alkylation is carried out with sodium hydride, potassium hydride, potassium-t in a suitable solvent.
-Can be done with butoxide. Suitable solvents include tetrahydrofuran and dimethylformamide. Conditions will vary depending on the nature of the heterocycle (HET ₁ ) and the acidity of the substituted proton. Preferred alkylation conditions are dimethylformamide (D
Sodium hydride in MF) or DMF at 110 ° C
Use potassium carbonate in. If the alkylation results in a mixture of isomers, separation is easily achieved by chromatography on silica gel. Structural confirmation is made from consideration of ¹ H and ¹³ C NMR spectra. The HET ₁ -H used as starting material is synthesized by the methods reported in the chemical literature or by modifications thereof which are easy for the person skilled in the art. Ester (I ^a ) or HET <sub>1
- (CH 2) n CO 2</sub> R a is either the corresponding acid under the influence of aqueous alkaline or aqueous acid, depending on the sensitivity of the heterocyclic _{^{(I b) HET 1 - (}} CH 2) converted to _n CO ₂ R To be done. Alternatively, on the contrary, the acid (I ^b ) is obtained by converting the acid into HCl, H ₂ SO
It is conveniently softened to the corresponding ester (I ^a ) by heating in a lower alkanol in the presence of an inorganic acid such as ₄ . HET _1- (CH ₂ ) _n CO ₂ Alkali metal salt of carboxylic acid (R is an alkali metal ion)
(CH - HET ₁ is in a suitable solvent such as methanol
₂ ) prepared by dissolving the acid of _n CO ₂ R, adding a molar equivalent of an alkali base such as sodium methoxide, and precipitating the salt or removing the solvent. According to the present invention, the compound of formula 5 is (a)

Hydrolyzing the compound of formula 7 or (b)

A compound of formula 8 (HET ₂ is as defined above) is esterified or (c) HET ₂ -H (HET _2
2 is as defined above)

Alkylation with a compound of formula 9 or (d)

The compound of formula 10 is converted to BrCH ₂ CO ₂ R ₁ ^a (R ₁ ^a
Is lower alkyl) or (e)

Hydrolyzing the compound of formula 11). Expressions 59 to 62 are for explaining the above method more specifically.

[Formula 59]

[Formula 60]

[Equation 61]

[Formula 62] Formula 58 illustrates several different attempts at the synthesis of compounds containing an aryloxyacetic acid moiety. Direct alkylation of the heterocycle (1) with bromide (2) or with tosylate (TS) (3) derived from alcohol (5) can be performed with sodium hydride in DMF at room temperature or DMF at 110 ° C. Achieved with potassium carbonate in to yield ester (6). Alternatively, in some cases, the reaction of the heterocycle (1) with the alcohol (5) derived from the diol (4) is carried out in the presence of diethyl azodicarboxylate and triphenylphosphine to form the ester (6) Cause This reaction is Mitsunob
It is carried out under the mild conditions characteristic of the u reaction. Syn
See thesis 1, 28 (1981). The carboxylic acid (7) is obtained by alkaline hydrolysis of the ester (6). Formula 60 shows the synthesis of thiazole derivatives (12) and (13) in which the side chain of the aryloxy complex acid is carbon bonded. 2-by n-butyllithium
Metallization of methyl-4,5-diphenylthiazole (8) was carried out, followed by reaction with bromide (9) to produce silyl ether (10), which was prepared from tetra-n.
Deprotonated with butylammonium fluoride to give phenol (11). Phenol (11)
Is alkylated with methyl bromoacetate to give ether (12), which is hydrolyzed under aqueous alkaline conditions to give acid (13) Formula 61 is an imidazole derivative (wherein the aryloxyacetic acid side chain is bonded to carbon ( 19) and (20) are produced. The synthesis is performed in the same manner as in the case of Equation 60. However, the presence of active hydrogen in 2-methyl-4,5-diphenylimidazole (14) requires the introduction of a protecting group on one of the nitrogen atoms prior to metallation. Various protecting groups known to those skilled in the art can be used.
T. S. Manoharan et al. Org. Che
m. , 53, 1107-1110 (1988), the ethoxyethyl group being particularly preferred. It is cheap and easy to introduce. Heating 2-methyl-4,5-diphenylimidazole (14) with excess ethyl vinyl ether in a sealed vessel gives crystalline N- (1-ethoxyethyl) imidazole (15). Metallizing this imidazole (15) with n-butyllithium,
Then, it is reacted with bromide (9) to obtain silyl ether (16). Selective removal of the silyl protecting group is achieved by exposing the silyl ether (16) to tetra-n-butylammonium fluoride. The resulting phenol (17) is alkylated with methyl bromoacetate to give the ester (18), which is converted to the imidazole (19) by heating in methanol in the presence of concentrated sulfuric acid. This is hydrolyzed with aqueous alkali to obtain the acid (20). Formula 62 illustrates the preparation of pyrazoles (25) and (26). Alkylation of 1-benzoylacetone (21) with bromide (9) gives the diketone (22). The diketone (22) is reacted with phenylhydrazine to give the pyrazole (23). Removal of the silyl protecting group of pyrazole (23) with tetra-n-butylammonium fluoride followed by phenol (2
Alkylation of 4) gives the ester (25). Base-induced hydrolysis of the ester (25) gives the desired acid (2
6) is obtained. Alkali metal salt of carboxylic acid of formula 5 (R ₁
Is an alkali metal ion) is prepared by dissolving the acid of formula 5 in a suitable solvent such as methanol, adding a molar equivalent of an alkali base such as sodium methoxide, and precipitating the salt or removing the solvent. It [Pharmacological effect] As described above, HET _1- (CH ₂ ) _n C
O ₂ R and the compound of formula 5 have pharmaceutical properties that make them particularly useful as blood platelet agglomerates. Platelet clumping is considered to be one of the complex physiological mechanisms of thrombotic organisms in blood vessels. Thrombus formation is thrombotic vein, venous thrombosis, cerebral thrombosis, coronary thrombosis,
And a number of mammalian diseases including retinal thrombosis. Increased propensity for platelet aggregation is observed in childbirth, surgery such as coronary artery bypass surgery, organ transplantation, vascular surgery, heart disease surgery, arterial capsule, multiple capsule, intracranial tumor, thrombosis, and adiposity . A. Poplaw
shi, et al. J. Arteroscher
sis Research, 8, 721 (1968)
reference. The compound of the present invention having an antithrombotic effect is useful for preventing or treating the above-mentioned conditions including platelet aggregation and thrombosis. The compounds of the present invention are also considered to be potent antithrombotic agents due to their platelet aggregation inhibitory properties. The medical properties of the compounds of this invention may be demonstrated by routine in vitro and in vivo bioassays. [In vitro inhibition test for human platelet aggregation] Borm, C.I.
V. R. J. Physiol. , (London),
1962, 162, 67-68 agglomeration method Mustar
d, J. F. Et al. Lab. Clin. Med. 19
64, 64, 548-599 modified and used,
The in vitro activity of various compounds with respect to blocking adenosine diphosphate (ADP) and collagen-induced platelet aggregation was examined. The arm of a volunteer donor (human) is cleaned with 70% ethyl alcohol. 20 ml sterilized
20 ml of blood is withdrawn using a syringe and needle. Immediately transfer this blood to a test tube (3.8% to prevent aggregation)
(Including sodium citrate). 1 part sodium citrate is used for 9 parts blood. Platelet-rich serum (PKP) was separated from citrated (3.8%) human blood by centrifugation at 1000 rpm (140 xg) for 10 minutes. All prepared glassware of PRP was silicone treated. ADP or Evans, G., at a final concentration of 0.5 mcg / ml. , Et. al, J .; Ex
p. Mad. Aggregation was induced using 0.05 ml of a collagen suspension prepared by the method described in 1968, 128, 877-894. Various test compounds were dissolved in dimethyl sulfoxide (DMSO) and 5 mcl was added to platelet-rich serum to obtain the desired test concentration. A vehicle-only control study was performed and compared to aggregation induced in platelet-rich serum containing various concentrations of test compound. Dispensing response curves were obtained and inhibitory concentration (IC ₅₀ ) values were calculated. In this test, the IC ₅₀ value of dipyridamole, a clinically useful antithrombotic agent, was 512 mcg / ml against ADP,
245 mcg / ml for collagen. Results of 50% inhibition of ADP-induced aggregation were obtained for various compounds of the invention. The results are shown in Tables 1 and 2 below.

[Table 1]

[Table 2] When viewed as one group, HET _1- (CH ₂ ) _n CO ₂ R
And a compound of formula 5: HET ₂ —CH ₂ CH ₂ —
_{(C 6 H 4) -OCH 2} CO 2 Compound of R ₁ it is clear that a particularly potent blocking type ADP-induced aggregation of human platelets. Esters are generally less active than the original acid but are useful as in vivo precursors (because the ester is hydrolyzed in vivo to the corresponding acid. Formulations used in the therapeutic methods of the invention The amount will vary depending on the dosage form, the particular compound selected, the problem being tested, and the desired effect. Suitable effective dosages in animals are from 0.1 to 50 mg / kg body weight when orally administered, In the case of parenteral administration (subcutaneous, intramuscular, and intravenous injection), it is 0.05 to 10 mg / kg of body weight.The effective dose for humans is in the range of 1 to 100 mg, preferably 1 3 on a day
1 to 20 mg is administered once. According to normal clinical practice, the effective dosage is determined by administering substantially less than what is considered to be effective and then gradually increasing the dosage until the desired effect is achieved. It When the therapeutic method of the present invention is carried out, HET _1-
The compound of (CH ₂ ) _n CO ₂ R or a compound of formula 5 above or an alkali metal salt thereof is administered, preferably in combination with a pharmaceutically acceptable carrier. Suitable dosage forms for oral use are tablets, dispersible powders, capsules, syrups and drug solutions. Examples of predominant forms are solutions, suspensions, dispersions, emulsions and the like. 1 useful composition for oral administration
One or more conventional auxiliaries such as sweeteners, fragrances, colorants,
And a preservative. Tablets may contain the active ingredient in admixture with conventional pharmaceutically acceptable excipients. Such excipients include diluents such as calcium carbonate, sodium carbonate, lactose and talc; agents for granulation and disintegration such as starch and alginic acid; binders such as starch, gelatin and acacia; and lubricants such as magnesium stearate, stearic acid. , And talc; The tablets may be uncoated or they may be coated by well known techniques to provide for disintegration and absorption in gastrointestinal tissue for prolonged action. Similarly, suspensions, syrups and solutions are conventional excipients used in the manufacture of compositions, such as suspending agents (methylcellulose, tracagant and sodium alginate), wetting agents (lecithin, polyethylene stearate), and preservatives ( Ethyl-p-hydroxybenzoate and the like) may be included in admixture with the active ingredient.
The capsules may contain the active ingredient alone, or the active ingredient may be an inert solid diluent such as calcium carbonate,
It may be contained in combination with calcium phosphate, kaolin and the like. Injectable compositions can be formulated in a manner known in the art and can include suitable dispersants and suspending agents that are the same as or similar to those described above.

The following examples are for the purpose of illustrating the present invention more specifically, and should not be construed as limiting the present invention. Many variations are possible within the scope of the invention. In these examples, all temperatures are given in degrees Celsius. Melting point is Thomas-Hoover
Capillary melting point apparatus, and is displayed uncorrected. Proton magnetic resonance ( ¹ H-NMR) spectra are obtained by Bruher AM300, Bruker WM360.
Or recorded on a Varian Gemini 300 spectrometer. All spectra were measured in CDCl ₃ or DMSO-d ₆ unless otherwise noted, and chemical shifts are reported in Delta units in the lower field from the internal standard tetramethylsilane (TMS). The coupling constant between protons is reported in Hertz (Hz). The split patterns are named as follows: s, singlet (single child); d, tablet (doublet); t, triplet (triplet); q, quartet (quadruple); m,
Multiplet; br, broadpeak; and dd, doublet of doublet. Example 1 Methyl 3,4-diphenyl-1H pyrrole-
1-nonanoate

[Equation 63] Sodium hydride (50% dispersion in mineral oil 789 mg; 16
Was washed twice with hexane and DMF (40 ml)
Cover with. K. R. Kopecky et al. , Ca
n. J. Chem. , 54, 2645-2651 (19
76) 3,4-diphenylpyrrole (3 g,
13 mmol) was added and the mixture was stirred at room temperature until gas evolution ceased. Methyl-9-bromononanoate (3.
61 g, 14 mmol) was added and stirring was continued at room temperature.
After 15 minutes, the mixture was poured into a 1N hydrochloric acid solution and extracted with diethyl ether (3x). Combine the total extract with water (3
X), dried over sodium sulfate and concentrated in vacuo to give an oil. This was chromatographed on a column of silica gel. Melting with a (9: 1) mixture of hexane and diethyl ether gave 3,4-diphenyl-1H-nonanoate (3.70 g, 69%) as an oil. Analysis: C ₂₆ H ₃₁ NO _2: Calculated: C, 80.17; H,
8.02; N, 3.60. Found: C, 79.84;
H, 8.02; N, 3.36%. ¹ H-NMR (CDCl ₃ ) delta: 1.20 t
o 1.50 (8H, m), 1.60 (2H, m),
1.82 (2H, quintet, J = 7Hz), 2.
29 (2H, t, J = 8Hz), 3.64 (3H,
s), 3.87 (2H, t, J = 7Hz), 6.74
(2H, s), 7.20 to 7.60 (10H,
m). Example 2 3,4-diphenyl-1H-pyrrole-1-
Nonanoic acid

[Formula 64] A mixture of methyl 3,4-diphenyl-1H-pyrrole-1-nonanoate (2.50 g, 6.4 mmol), 5N sodium hydroxide solution (3.86 ml, 19 mmol) and methanol (50 ml) on a steam bath. Heated.
After 30 minutes, the solvent was evaporated, the residue diluted with 1N HCl solution and extracted with CH ₂ Cl ₂ . All extracts were dried over sodium sulphate, concentrated in vacuo and the residual oil chromatographed on a column of silica gel. Elute with a mixture of diethyl ether and hexane (3: 2) 3.
4-diphenyl-1H pyrrole-1-nonanoic acid (2.2
0 g, 91%) as an oil. Analysis: C ₂₅ H ₂₉ NO ₂ .0.7H ₂ O: Calculated value: C, 7
7.37; H, 7.90; N, 3.61; H 2 O, 3.
25. Found: C, 77.23; H, 7.52; N,
_{3.42; H 2 O, 0.43%} . ¹ H-NMR (CDCl ₃ ) delta: 1.42 (8
H, bs), 1.72 (2H, quintet, J = 7)
Hz), 1.89 (2H, quintet, J = 7H
z), 2.42 (2H, t, J = 7Hz), 3.92
(2H, t, J = 7 Hz), 6.83 (2H, s), a
nd 7.20 to 7.40 (10H, m). Example 3 Methyl 6-oxo-3,4-diphenyl-
1 (6H) Pyridazine nonanoate

[Formula 65] Sodium hydride (840 mg of a 60% dispersion in oil, 20
Was washed twice with hexane and DMF (25 ml)
Cover with P. Schmidt, et al. , H
elvetica Chim. Acta. , 37, 13
5,6-Diphenyl-3 (2H) -pyridazinone (4 g, 16 mmol) prepared by 4-140 (1954) was added. After gas evolution ceased, the mixture was stirred at room temperature for 30 minutes, after which 9-bromononanoate (4.45 g, 18 mmol) was added. Mix 11
A solution was obtained by heating at 0 ° C for a short time. It was then cooled and stirred at room temperature for 1 hour. The mixture was diluted with water and extracted with diethyl ether (3x). The total extracts were washed with water, dried over sodium sulfate and concentrated to give an oil. Methyl 6-oxo-3,4-diphenyl-1 (6H)-was chromatographed on a column of silica gel.
Pyridazine nonanoate (6.44 g, 95%) was obtained as an oil. _{Analysis: C 26 H 30 N 2 O} 3: Calculated: C, 74.61;
H, 7.22; N, 6.69. Found: C, 74.8.
9; H, 7.38; N, 7.23%. ¹ H-NMR (CDCl ₃ ) delta: 1.20 t
o 1.45 (8H, m), 1.56 (2H, quin
tet, J = 7 Hz), 1.85 (2H, quinte
t, J = 7 Hz), 2.23 (2H, t, J = 7.5H)
z), 3.59 (3H, s), 4.20 (2H, t, J
= 7 Hz), 6.88 (1H, s) and 7.00
to 7.40 (10H, m). Example 4 6-oxo-3,4-diphenyl-1 (6
H) -pyridazinenonanoic acid

[Formula 66] Methyl 6-oxo-3,4-diphenyl-1 (6H)
-Pyridazine nonanoate (6 g, 14 mmol), 5
A mixture of N NaOH solution (8.6 ml, 43 mmol) and methanol (100 ml) was heated to reflux on a steam bath. After 30 minutes, the mixture was concentrated, diluted with water and acidified to pH = 1 with a 2N HCl solution. The mixture was extracted with CH ₂ Cl ₂ , the total extracts were dried over sodium sulphate and gave an oil. This was left to crystallize. Recrystallization from a mixture of CH ₂ Cl ₂ and hexane gave 6-oxo-3,4-diphenyl-1 (6H)-.
Pyridazine nonanoic acid (3.92 g, 67%) was obtained. Melting point 100-103 [deg.] C. _{Analysis: C 25 H 28 N 2 O} 3: Calculated: C, 74.23;
H, 6.98; N, 6.93. Found: C, 74.2.
5; H, 7.13; N, 7.11%. ¹ H-NMR (CDCl ₃ ) delta: 1.20 t
o 1.50 (8H, m), 1.59 (2H, t),
1.87 (2H, quintet, J = 6.5Hz),
2.29 (2H, t, J = 7Hz), 4.24 (2H,
t, J = 7 Hz), 6.98 (1H, s), 7.00
to 7.40 (10H, m) and 9.83 (1
H, bs). Example 5 Methyl 6-oxo-3,4-diphenyl-
1 (6H) Pyridazinyl octanoate

[Formula 67] 5,6-Diphenyl-3 (2H) -pyridazone was reacted with methyl δ-bromooctanoate by the method of Example 3 to give the title compound as an oil. _{Analysis: C 25 H 28 N 2 O} 3: Calculated: C, 74.23;
H, 6.98; N, 6.93. Found: C, 74.2.
3; H, 7.27; N, 7.34%. Example 6 6-oxo-3,4-diphenyl-1 (6
H) -Pyridazinyl octanoic acid

[Formula 68] Methyl 6-oxo-3,4-diphenyl-1 (6H)
-Pyridazinyl octanoate was hydrolyzed by the method of Example 4 to give the title compound. Melting point 108-110
° C. Analysis: C ₂₄ H ₂₆ N ₂ O ₃ .0.2H ₂ O: Calculated value: C,
73.15; H, 6.76; N, 7.11; H 2 O,
0.91. Found: C, 73.20; H, 6.69;
_{N, 7.13; H 2 O,} 1.16. Example 7 Methyl 3-oxo-5,6-diphenyl-
1,2,4-triazine-2 (3H) -nonanoate

[Formula 69] 60% dispersion of sodium hydride (577 mg) in oil (1
4 mmol) was washed twice with hexane, and DMF (40 m
l) covered. M. Friedman, J .; Org. C
hem. 30 5,859-863 (1965) 5,6-diphenyl-1,2,4-triazole-
3 (2H) -one (3 g, 12 mmol) was added. After the gas evolution ceased, the mixture was stirred at room temperature for 15 minutes,
It was then poured into water and extracted with diethyl ether (3x). The combined extracts were washed with water (3x), dried over sodium sulphate and concentrated to give an oil. This was chromatographed on a column of silica gel. Methyl 3-oxo-5,6-diphenyl-1,2,4-triazine-2 (3H) -nonanoate (3.09 g, 61) was eluted by eluting with a mixture of diethyl ether and hexane (3: 2).
%). _{Analysis: C 25 H 29 N 3 O} 3: Calculated: C, 71.58;
H, 6.97; N, 10.02. Found: C, 71.5
9; H, 7.13; N, 10.06%. ¹ H-NMR (CDCl ₃ ) delta: 1.20 t
o 1.45 (8H, m), 1.58 (2H, quin
tet, J = 6 Hz), 1.90 (2H, quinte
t, J = 6 Hz), 2.26 (2H, t, J = 6H)
z), 3.63 (3H, s), 4.21 (2H, t, J
= 6 Hz) and 7.20 to 7.55 (10
H, m). Example 8 3-oxo-5,6-diphenyl-1,2,
4-triazine-2 (3H) -nonanoic acid

[Formula 70] Methyl 3-oxo-5,6-diphenyl-1,2,4
-Triazine-2 (3H) -nonanoate (1.90)
g, 4.5 mmol), 5N NaOH solution (2.72)
ml, 13 mmol) and methanol (130 ml) was heated on a steam bath for 30 minutes. The volatiles were removed in vacuo, the residue was diluted with water and dilute HCl solution was added until pH = 1. The mixture was extracted with CH ₂ Cl ₂ , the extract was dried over sodium sulfate and concentrated to give an oil. Chromatograph on a column of silica gel using diethyl ether as eluent to give 3-oxo-5,6-diphenyl-1,2,4-triazine-2 (1H) -nonanoic acid (1.50 g, 81 %) Was obtained. This was left to crystallize. Melting point 97-100 [deg.] C. _{Analysis: C 24 H 27 N 3 O} 3: Calculated: C, 71.09;
H, 6.71; N, 10.36. Found: C, 71.2
9; H, 6.97; N, 10.21%. ¹ H-NMR (CDCl ₃ ) delta: 1.20 t
o 1.50 (8H, m), 1.57 (2H, t, J =
7Hz), 1.88 (2H, quintet, J = 7H
z), 2.27 (2H, t, J = 7.5 Hz), 4.1
9 (2H, t, J = 7Hz), 7.20 to 7.6
0 (10H, m) and 10.89 (1H, bs). Example 9 Methyl 3-oxo-5,6-diphenyl-
1,2,4-triazine 2 (3H) -octanoate

[Formula 71] 5,6-diphenyl-1,2,4-triazole-3
(2H) one was reacted with methyl 8-bromooctanoate by the method of Example 7 to obtain the title compound as an oily substance. _{Analysis: C 24 H 27 N 3 O} 3: Calculated: C, 71.09;
H, 6.71; N, 10.36. Found: C, 71.0
5; H, 6.87; N, 10.41. Example 10 3-oxo-5,6-diphenyl-1,
2,4-triazine-2 (3H) -octanoic acid

[Formula 72] Methyl 3-oxo-5,6-diphenyl-1,2,4
-Triazine-2 (3H) -octanoate was used in Example 8
The title compound was obtained by hydrolysis according to the above method. Mp 111 to 113 ° C. _{Analysis: C 23 H 25 N 3 O} 3: Calculated: C, 70.57;
H, 6.44; N, 10.73. Found: C, 70.3
5; H, 6.72; N, 10.33. Example 11 Methyl 2-oxo-4,5-diphenyl-1 (2H) -pyrimidine nonanoate

[Formula 73] G. M. J. Coppola et al. Het. Chem. ，
4,5-Diphenyl-2 (1H) -pyrimidinone (6.00 g, 24 mmol) prepared by 16,545,554, methyl 9-bromononanoate (6.37 g,
25 mmol), potassium carbonate (4.00 g, 29 mmol), potassium iodide (catalytic amount), and DMF (12
0 ml) was stirred at 110 ° C. under a nitrogen atmosphere. After 30 minutes, the mixture was cooled, diluted with water and extracted 3 times with ethyl ether. Combine the total extract with water (3
X) washed, dried over sodium sulphate and the solvent evaporated. The residual oil was chromatographed on a column of silica gel with diethyl ether to give methyl 9- [4,5-diphenyl-2-pyrimidinyl) oxy] nonanoate (3.27 g, 32%) as an oil. Then elute further and methyl 2-oxo-4,5-
Diphenyl-1 (2H) -pyrimidine nonanoate (6.00 g, 59%) was obtained as an oil. _{Analysis: C 26 H 30 N 2 O} 3: Calculated: C, 74.61;
H, 7.22; N, 6.69. Found: C, 74.9.
4; H, 7.38; N, 6.89%. ¹ H-NMR (CDCl ₃ ) delta: 1.20 t
o 1.45 (8H, m), 1.56 (2H, quin
tet, J = 7 Hz), 1.81 (2H, quinte
t, J = 7 Hz), 2.24 (2H, t, J = 7H)
z), 3.60 (3H, s), 3.94 (2H, t, J
= 7 Hz), 6.95 to 7.45 (10 H, m)
and 7.61 (1H, s). Example 12 2-oxo-4,5-diphenyl-1 (2
H) -pyrimidine nonanoic acid

[Formula 74] Methyl 2-oxo-4,5-diphenyl-1 (2H)
A mixture of pyrimidine nonanoate (4.70 g, 11 mmol), 5N NaOH solution (7.40 ml, 36 mmol) and methanol (80 ml) at room temperature 75
Stir for 1 minute, then at reflux for 75 minutes, then
Cooled and concentrated. The residue was diluted with water and 2N HCl was added to pH2. The mixture was extracted with CH ₂ Cl ₂ , the extracts were combined, dried over sodium sulfate and the solvent removed to give an oil (crystallized). Diethyl ether and CH
Recrystallization from a mixture of ₂ Cl ₂ yielded 2-oxo-4,5
-Diphenyl-1 (2H) -pyrimidinenonanoic acid (3.
35 g, 73%). Melting point 120-123 ° C. _{Analysis: C 25 H 28 N 2 O} 3: Calculated: C, 74.23;
H, 6.98; N, 6.93. Found: C, 74.2.
2; H, 7.08; N, 6.61%. ¹ H-NMR (CDCl ₃ ) delta: 1.20 t
o 1.50 (8H, m), 1.56 (2H, bt),
1.80 (2H, bt), 2.27 (2H, t, J = 7
Hz), 3.94 (2H, t, J = 7Hz), 6.95
to 7.55 (10H, m); 7.65 (1H) a
nd 10.56 (1H, bs). Example 13 Methyl 2-oxo-4,5-diphenyl-1 (2H) -pyrimidine octanoate

[Formula 75] By the method of Example 11, 4,5-diphenyl-2 (1
H) -pyrimidinone was reacted with methyl 8-bromooctanoate to give the title compound. Melting point 80-83 [deg.] C. _{Analysis: C 25 H 28 N 2 O} 3: Calculated: C, 74.23;
H, 6.98; N, 6.93. Found: C, 74.6.
4; H, 7.21; N, 7.00. Example 14 2-oxo-4,5-diphenyl-1 (2
H) Pyrimidine octanoic acid

[Formula 76] Methyl 2-oxo-4,5-diphenyl-2 (1H)
Hydrolysis of -pyrimidinyl octanoate by the method of Example 12 gave the title compound. Melting point 121-123
℃ _{Analysis: C 24 H 26 N 2 O} 3: Calculated: C, 73.82;
H, 6.71; N, 7.17. Found: C, 73.4.
3; H, 6.83; N, 7.28. Example 15 Methyl 2,3-dioxo-3,4-diphenyl-1-imidazolidine nonanoate

[Formula 77] Diethylazodicarboxylate (1.39 g, 8 mmol) in THF (5 ml) was treated with methyl 9-hydroxynonanoate (1.50 g, 8 mmol), K.I. C. J
oshi, et al. J. Het. Chem. 1
3,165-1653 (1981) 3,4-diphenylimidazolidine-2,5-dione (2.02 g, 8 mmol) and triphenylphosphine (2.10,8 mmol) in THF (35 ml). Was added dropwise to a stirred solution consisting of. The mixture was stirred at room temperature for 72 hours, the THF was removed, the residue was triturated with a mixture of hexane and diethyl ether and chromatographed on a column of silica gel using a mixture of hexane and ethyl acetate (3: 2) as eluent. Graphed. Elution with methyl 2,5-dioxo-3,4-diphenyl-1-imidazolidine nonanoate (2.78)
g, 82%). Melting point 69-70 [deg.] C. _{Analysis: C 25 H 30 N 2 O} 4: Calculated: C, 71.07;
H, 7.16; N, 6.65. Found: C, 71.1
3; H, 7.19; N, 6.66%. ¹ H-NMR (CDCl ₃ ) delta: 1.20 t
o 1.40 (8H, m), 1.50 to 1.70
(4H, m), 2.25 (2H, t, J = 6Hz),
3.55 (2H, t, J = 6Hz), 3.61 (3H,
s), 5.41 (1H, s), 7.03 (1H, t, J
= 6.5 Hz), 7.10 to 7.40 (7H,
m) and 7.45 (2H, d, J = 6.5 Hz). Example 16 2,5-Dioxo-3,4-diphenyl-
1-imidazolidine nonanoic acid

[Formula 78] Methyl 2,5-dioxo-3,4-diphenyl-1-
A mixture of imidazolidine nonanoate (3.00 g, 7 mmol) and 6N HCl solution (30 ml) was heated at reflux temperature for 22 hours. The mixture is cooled and CH ₂ Cl ₂
The extract was washed with water and twice with saturated sodium chloride. After drying over sodium sulfate, the solvent was evaporated and the residue was chromatographed on a column of silica gel using a mixture of hexane and ethyl acetate (2: 1) as eluent. The eluent was recrystallized from a mixture of hexane, diethyl ether and CH ₂ Cl ₂ (6: 2: 2) to give 2,3-dioxo-3,4-diphenyl-1-imidazolidinenanonic acid (1.06 g, 36
%) Was given. Mp 111.5-112.5 ° C. _{Analysis: C 24 H 28 N 2 O} 4: Calculated: C, 70.57;
H, 6.91; N, 6.86. Found: C, 70.4
5; H, 7.05; N, 6.75%. ¹ H-NMR (CDCl ₃ ) delta: 1.20 t
o 1.40 (6H, m), 1.50 to 1.80
(4H, m), 2.14 (2H, t, J = 6Hz),
3.61 (2H, t, J = 6Hz), 5.42 (1H,
s), 7.09 (1H, t, J = 6Hz) and 7.
15 to 7.60 (9H, m). Example 17 Methyl 5- (diphenylmethyl) -2H
-Tetrazole-2-nonanoate

[Formula 79] 5- (diphenylmethyl) -1H-tetrazole (5 produced by the method of US Pat. No. 3,155,666)
g, 21 mmol), methyl 9-bromononanoate (5.84 g, 23 mmol), potassium carbonate (3.5
g, 25 mmol), potassium iodide (catalytic amount) and D
The mixture consisting of MF (75 ml) was stirred at 110 ° C. for 15 minutes. The mixture was cooled, diluted with water and extracted 3 times with diethyl ether. Wash the total extract 3 times with water,
Dry over sodium sulfate and concentrate in vacuo to give an oil. Chromatograph on a column of silica gel using a mixture of hexane and diethyl ether (1: 1) as eluent to give methyl 5- (diphenylmethyl)-.
2H-tetrazole-2-nonanoate (6.50 g,
75%). _{Analysis: C 24 H 30 N 4 O} 2: Calculated: C, 70.91;
H, 7.44; N, 13.78. Found: C, 71.0
0; H, 7.57; N, 14.24%. ¹ H-NMR (CDCl ₃ ) delta: 1.20 t
o 1.40 (8H, m), 1.59 (2H, quin
tet, J = 7 Hz), 1.96 (2H, quinte
t, J = 7 Hz), 2.28 (2H, t, J = 7.5H)
z), 3.64 (3H, s), 4.53 (2H, t, J
= 7 Hz), 5.81 (1H, s) and 7.10
to 7.50 (10H, m). Example 18 5- (Diphenylmethyl) -2H-tetrazole-1-nonanoic acid

[Formula 80] Methyl 5- (diphenylmethyl) -2H-tetrazole-1-nonanoate (5.00 g, 12 mmol),
A mixture of 5N NaOH solution (7.40 ml, 36 mmol) and methanol (100 ml) was heated to reflux temperature on a steam bath. After 20 minutes, the mixture was concentrated, diluted with water and 2N HCl solution and filtered to collect a white solid. Recrystallized from a mixture of CH ₂ Cl ₂ and hexane to give 5- (diphenylmethyl) -2H-tetrazole-1.
-Nonanoic acid (4.40 g, 90%) was obtained. Melting point 68-
70 ° C. _{Analysis: C 23 H 28 N 4 O} 2: Calculated: C, 70.38;
H, 7.19; N, 14.27. Found: C, 70.3
7; H, 7.24; N, 14.35%. ¹ H-NMR (CDCl ₃ ) delta: 1.28 (8
H, bs), 1.58 (2H, quintet, J =
6.5 Hz), 1.97 (2H, quintet, J =
6.5 Hz), 2.29 (2H, t, J = 7.5H
z), 4.55 (2H, t, J = 7Hz), 5.81
(1H, s), 7.15 to 7.40 (10H,
m) and 10.52 (1H, bs). Example 19 Methyl (3- [2- (4,5-diphenyl-2-thiazolyl) ethyl] phenoxy) acetate

[Formula 81] 3- [2- (4,5-diphenyl-2-thiazolyl)-
Ethyl] phenol (3.65 g, 10 mmol), methyl bromoacetate (1.72 g, 1.06 ml, 11
Mmol), potassium carbonate (1.69 g, 12 mmol) and acetonitrile (60 ml) were heated at reflux temperature for 90 minutes. The mixture was filtered and concentrated to give an oil. This was chromatographed on a column of silica gel. Hexane and diethyl ether (2:
Elution with a mixture of 1) methyl [3- [2- (4,5-
Diphenyl-2-thiazolyl) -ethyl] phenoxy]
Acetate (3.63 g, 82%) was obtained as an oil. _{Analysis: C 26 H 23 NO 3 S} : Calculated: C, 72.70;
H, 5.40; N, 3.26. Found: C, 73.1.
3; H, 5.50; N, 3.26%. ¹ H-NMR (CDCl ₃ ) delta: 3.10 t
o 3.20 (2H, m), 3.30 to 3.40
(2H, m), 3.78 (3H, s), 4.62 (2
H, s), 6.76 (1H, dd, J = 8Hz, J '=
2.5Hz), 6.16 (1H, d, J = 2.5H
z), 6.92 (1H, d, J = 8Hz), 7.15
to 7.40 (9H, m) and 7.50 to
7.60 (2H, m). Example 20 [3- [2- (4,5-Diphenyl-2thiazolyl) ethyl] phenoxy] acetic acid

[Formula 82] Methyl [3- [2- (4,5-diphenyl-2-thiazolyl) ethyl] phenoxyacetate (2.7 g, 6 mmol), 5N NaOH solution (3.77 ml, 18 mmol) and methanol (40 ml) were steamed. Heated to reflux on the bath. After 20 minutes, the mixture was cooled, removed with methanol and the residue diluted with water and 2N HCl solution. The precipitate was filtered, washed with water and dried in air.
By recrystallization from a mixture of CH ₂ Cl ₂ and hexane [3- [2- (4,5-diphenyl-2-thiazolyl)]
Ethyl] phenoxy] acetic acid (1.97 g, 75%) was obtained. Melting point 118-120 [deg.] C. _{Analysis: C 25 H 21 NO 3 S} · 0.1H 2 O: Calculated: C,
71.96; H, 5.13; N, 3.36; H 2 O,
0.43. Found: C, 71.69; H, 5.10;
_{N, 3.06; H 2 O 0.30} %. ¹ H-NMR (DMSO-d ⁶ ) delta: 3.06
(2H, t, J = 8Hz), 3.31 (2H, t, J =
8Hz), 4.62 (2H, s), 6.73 (1H,
d, J = 8 Hz), 6.90 (2H, bs), 7.19
(1H, t, J = 8Hz) and 7.25 to
7.60 (10H, m). Example 21 Methyl [3- [2- (4,5-diphenyl-1H-imidazol-2-yl) ethyl] phenoxy] acetate

[Formula 83] 3- [2- [1- (1-ethoxyethyl) -4,5-diphenyl-1H-imidazo-2-yl] ethyl] phenol (6.60 g, 16 mmol), methyl bromoacetate (2.69 g, 1) .66 ml, 18 mmol), potassium carbonate (2.65 g, 19 mmol), potassium iodide (catalytic amount) and acetonitrile (100 ml) were stirred at reflux temperature for 2.5 hours. The mixture is filtered, concentrated and the residual oil is methanol (120 ml).
I have been Concentrated sulfuric acid (6 drops) was added and the mixture was heated to reflux temperature. After 75 minutes concentrated sulfuric acid (3 drops) was added and the mixture was refluxed for an additional 3.75 hours. The methanol was evaporated, the residue diluted with water and saturated sodium carbonate solution and the mixture extracted with CH ₂ Cl ₂ . The combined extracts were dried over sodium sulphate and the solvent removed to leave an oil which left to crystallize for 40 hours. Triturate with diethyl ether and methyl [3- [2- (4,5
-Diphenyl-1H-imidazol-2yl] ethyl]
Phenoxy] acetate (5.15 g, 78%) was obtained. An analytical sample was prepared by recrystallizing the sample twice from a mixture of CH ₂ Cl ₂ , diethyl ether and hexane. Melting point 123-125 [deg.] C. _{Analysis: C 26 H 24 N 2 O} 3 · 0.8H 2 O: Calculated: C,
73.16; H, 6.05; N, 6.57; H 2 O,
3.38. Found: C, 73.00; H, 5.78;
_{N, 6.56; H 2 O 3.92} %. ¹ H-NMR (CDCl ₃ ) delta: 2.80 (4
H, bs), 3.71 (3H, s), 4.52 (2H,
s), 6.50 to 6.70 (3H, m), 6.9.
4 (1H, t, J = 7.5 Hz), 7.15 to
7.35 (8H, m), 7.40 to 7.45 (2
H, m) and 10.13 (1H, bs). Example 22 [3- [2- (4,5-diphenyl-1H
-Imidazol-2-yl) ethyl] phenoxyacetic acid

[Formula 84] [3- [2- (4,5-diphenyl-1H-imidazol-2-yl) ethyl] phenoxy] acetate (1.
20 g, 3 mmol), 5N NaOH solution (1.74)
ml, 9 mmol) and methanol (30 ml) were heated to reflux on a steam bath for 20 minutes. Remove the solvent, dilute the residue with water and adjust the pH with 2N HCl solution.
Acidified to = 1. The yellow solid was filtered and chromatographed on a column of silica gel using a mixture of chloroform and methanol (9: 1) as eluent, [3-
[2- (4,5-diphenyl-1H-imidazole-2
-Yl) ethyl] phenoxy] acetic acid (0.42 g, 36
%). Melting point 244-246 [deg.] C. Analysis: C ₂₅ H ₂₂ N ₂ O ₃ .H ₂ O: Calculated value: C, 72.
10; H, 5.81; N, 6.36; H 2 O, 4.3
3. Found: C, 72.01; H, 5.72; N, 6.
36; H ₂ O 1.07%. ¹ H-NMR (DMSO-d ⁶ ) delta: 3.03
(4H, bs), 4.63 (2H, s), 6.73 (1
H, d, J = 8 Hz), 6.80 to 6.90 (2
H, m), 7.20 (1H, t, J = 8 Hz) and
7.25 to 7.60 (10H, m). Example 23 Methyl [3- [2- (3,4-diphenyl-1H-pyrazol-1-yl) ethyl] phenoxy]
Acetate and methyl [3- [2- (4,5-diphenyl-1H-pyrazol-1-yl) ethyl] phenoxy] acetate

[Formula 85]

[Formula 86] Sodium hydride (50% dispersion in mineral oil 0.72 g, 1
(5 mmol) was washed twice with hexane, and DMF (10 m
Cover with l) and add 3,4-diphenyl-1H-pyrazole (2.99 g, 13 mmol). After the evolution of gas ceased, the mixture was stirred at 110 ° C. for 1 hour, cooled to room temperature and [3- [2-
[[(4-Methylphenyl) sulfonyl] oxy] ethyl] phenoxy] acetate (4.95 g, 12 mmol) was added. After stirring for 15 hours at room temperature, the mixture was poured into water and extracted with ethyl acetate. The total extracts were washed 3 times with water, once with saturated sodium chloride, dried over sodium sulphate and the solvent was evaporated. The residual oil was repeatedly chromatographed on silica gel using a mixture of hexane and ethyl acetate (4: 1) as eluent. Methyl [3-
[2- (3,4-diphenyl) -1H-pyrazole-1
-Yl] ethyl] phenoxy] acetate (1.71)
%, 30%). Analysis: C ₂₆ H ₂₄ N ₂ O ₃ .0.3H ₂ O: Calculated value: C,
74.73; H, 5.94; N, 6.71; H 2 O,
1.29. Found: C, 74.42; H, 6.07;
_{N, 6.55; H 2 O 0.65} %. ¹ H-NMR (CDCl ₃ ) delta: 3.21 (2
H, t, J = 7 Hz), 3.75 (3H, s), 4.3
6 (2H, t, J = 7Hz), 4.56 (2H, s),
6.60 to 6.80 (3H, m), 7.10 t
o 7.40 (10H, m) and 7.45 to
7.55 (2H, m). The more polar material w
as identified as methyl [3
-[2- (4,5-diphenyl-1 H- pyra
zol-1-yl) ethyl] phenoxy] ac
etate (0.66 g, 11%). _{Analysis: C 26 H 24 N 2 O} 3: Calculated: C, 75.71;
H, 5.87; N, 6.80. Found: C, 75.8.
4; H, 5.90; N, 6.71%. ¹ H-NMR (CDCl ₃ ) delta: 3.06 (2
H, t, J = 7 Hz), 3.75 (3H, s), 4.1
6 (2H, t, J = 7Hz), 4.48 (2H, s),
6.39 (1H, d, J = 1.5Hz), 6.56 (1
H, d, J = 7.5 Hz), 6.72 (1H, dd, J
= 7.5 Hz, J '= 1.5 Hz), 6.85 to
7.40 (11H, m) and 7.81 (1H,
s). Example 24 [3- [2- (3,4-diphenyl-1H
-Pyrazol-1-yl) ethyl] phenoxy] acetic acid

[Formula 87] Methyl [3- [2- (3,4-diphenyl-1H-pyrazol-1-yl) ethyl] phenoxy] acetate (1.70 g, 4 mmol), 3N NaOH solution (2.42 ml, 12 mmol) and methanol. (60
ml) was heated on a steam bath for 10 minutes.
The mixture was concentrated, diluted with water, brought to pH = 1 with dilute HCl solution and extracted with CH ₂ Cl ₂ . The total extract was washed with saturated sodium chloride solution, dried over sodium sulfate,
The solvent was evaporated. The residue was dissolved in CH ₂ Cl _2, and diluted with hexane [3- [2- (3,4-diphenyl) -
1H-pyrazol-1-yl] ethyl] phenoxyacetic acid (1.27 g, 77%) was obtained. Melting point 147.5-149 [deg.] C. Analysis: C ₂₅ H ₂₂ N ₂ O ₃ .0.15H ₂ O: Calculated value:
C, 74.86; H, 5.61; N, 6.98; H
₂ O, 0.67. Found: C, 74.55; H, 5.5.
_{7; N, 6.96; H 2} O, 0.43%. ¹ H-NMR (CDCl ₃ ) delta: 3.18 (2
H, t, J = 7.5 Hz), 4.39 (2H, t, J =
7.5 Hz), 4.57 (2H, s), 6.70 to
6.90 (3H, m), 7.10 to 7.40
(10H, m), 7.45 to 7.50 (2H,
m) and 7.60 (1H, bs). Example 25 [3- [2- (4,5-diphenyl-1H
-Pyrazol-1-yl) ethyl] phenoxy] acetic acid

[Formula 88] Methyl [3- [2- (4,5-diphenyl-1H-pyrazol-1-yl) ethyl] phenoxy] acetate (0.42 g, 1 mmol), 3N NaOH solution (1.0 ml, 3 mmol) and methanol. (30 ml)
The mixture consisting of was heated on a steam bath for 15 minutes and then evaporated in vacuo. The residue was diluted with water, added with 1N HCl solution until pH = 1 and the mixture was extracted with CH ₂ Cl ₂ .
The combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated in vacuo. CH the residue
_It was dissolved in ₂ Cl ₂ , diluted with hexane, and then [3- [2-
(4,5-Diphenyl-1H-pyrazol-1-yl)
Ethyl] phenoxy] acetic acid (0.28 g, 58%) was obtained. Mp one hundred thirty-three to one hundred and thirty-eight ° C. _{Analysis: C 25 H 22 N 2 O} 3: Calculated: C, 75.36;
H, 5.57; N, 7.04. Found: C, 75.2.
1; H, 5.48; N, 7.09%. ¹ H-NMR (CDCl ₃ ) delta: 2.99 (2
H, t, J = 7Hz), 4.21 (2H, t, J = 7H)
z), 4.57 (2H, s), 6.51 (1H, d, J
= 7.5 Hz), 6.57 (1 H, s), 6.78 (1
H, dd, J = 7.5 Hz, J ′ = 2 Hz), 6.95
to 7.45 (11H, m) and 7.85 (1
H, s). Example 26 Methyl [3- [2- (1,5-diphenyl-1H-pyrazol-3-yl) ethyl] phenoxy]
acetate

[Formula 89] [3- [2- (1,5-diphenyl-1H-pyrazol-3-yl) ethyl] phenol (4.50 g, 13 mmol), methyl bromoacetate (2.23 g, 1.
375 ml, 14.5 mmol), potassium carbonate (2.1
A mixture of 9 g, 16 mmol), potassium iodide (catalytic amount), and acetonitrile (80 ml) was stirred at reflux temperature for 3 hours. The mixture was filtered, concentrated and the residue chromatographed on a column of silica gel prepared in a mixture of hexane and diethyl ether (9: 1). Then elute with a mixture of hexane and diethyl ether (1: 1) to obtain methyl [3- [2- (1,5-diphenyl-1
H-pyrazol-3-yl) ethyl] phenoxy] acetate (4.83 g, 85%) was obtained as an oil. _{Analysis: C 26 H 24 N 2 O} 3: Calculated: C, 75.71;
H, 5.86; N, 6.79. Found: C, 75.4.
6; H, 6.13; N, 7.12%. ¹ H-NMR (CDCl ₃ ) delta: 3.04 (4
H, s), 3.77 (3H, s), 4.51 (2H,
s), 6.30 (1H, s), 6.75 (1H, d, J
= 7 Hz), 6.86 (1H, s), 6.93 (1H,
d, J = 7 Hz), and 7.10 to 7.40.
(11H, m). Example 27 [3- [2- (1,5-diphenyl-1H
-Pyrazol-3-yl) ethyl] phenoxy] acetic acid

[Formula 90] Methyl [3- [2- (1,5-diphenyl-1H-pyrazol-3-yl) ethyl] phenoxy] acetate (3.50 g, 8.5 mmol), 5N NaOH solution (5 ml, 25 mmol) and methanol. A mixture of (70 ml) was heated to reflux temperature on a steam bath for 15 minutes. The solvent was evaporated, the residue diluted with water and 2N HCl
Acidified to pH = 1. The white solid was filtered and recrystallized from a mixture of hexane and CH ₂ Cl ₂ [3- [2-
(1,5-diphenyl-1H-pyrazol-3-yl)
Ethyl] phenoxy] acetic acid (2.85 g, 84%) was obtained. Melting point 125-127 [deg.] C. Analysis C ₂₅ H ₂₂ N ₂ O ₃ .0.2H ₂ O: Calculated value: C, 7
4.69; H, 5.62; N, 6.97; H 2 O, 0.
90. Found: C, 74.68; H, 6.08; N,
_{6.87; H 2 O, 0.05%} . ¹ H-NMR (DMSO-d ⁶ ) delta: 2.95.
(4H, m), 4.65 (2H, s), 6.51 (1
H, s), 6.73 (1H, d, J = 7 Hz), 6.8
5 to 6.95 (2H, m), 7.15 to
7.25 (5H, m), 7.25 to 7.40 (6
H, m) and 12.65 (1H, bs). Example 28 Methyl [3- [2- (1,6-dihydro-
6-oxo-3,4-diphenyl-1-piperazinyl)
Ethyl] phenoxy] acetate

[Formula 91] Diethylazodicarboxylate (2.73 g, 2.5
0 ml, 16 mmol) was added to dry THF (75 ml) at 0 ° C.
5,6-diphenyl-3 (2H) -pyridazinone (3.00 g, 12 mmol), methyl [3- (2-hydroxyethyl) -phenoxy] acetate (2.80).
g, 13 mmol) and triphenylphosphine (4.12 g, 16 mmol) were added to a stirred solution. Remove the ice bath, stir the mixture at room temperature for 1.75 h,
Then the solvent was removed. The residue was chromatographed twice on a column of silica gel with a mixture of diethyl ether and hexane (7: 3) to give methyl [3- [2
-(1,6-Dihydro-6-oxo-3,4-diphenyl-1-pyridazinyl) ethyl] phenoxyacetate (5.12 g, 98%) was contaminated with 0.6 equivalents of 1,2-dicarboethoxyhydrazine. As a white foam. Analysis _{C 27 H 24 N 2 O 4} · 0.3H 2 O · 0.6C 6 H 12
N ₂ O _4: Calculated: C, 66.64; H, 5.82 ;
_{N, 8.13; H 2 O,} 0.98. Found: C, 66.
45; H, 5.60; N, 7.73; H 2 O, 0.42
%. ¹ H-NMR (CDCl ₃ ) delta: 1.24 (3
H, t, J = 7Hz), 4.49 (2H, t, J = 8H
z), 4.59 (1H, s), 6.77 (1H, dd,
J = 8Hz, J '= 2.5Hz), 8.83 (1H,
d, J = 2.5 Hz), 6.93 (1H, s), 6.9
3 (1H, m), 7.00 to 7.10 (4H,
m) and 7.15 to 7.40 (8H, m). Example 29 [3- [2- (1,6-dihydro-6-oxo-3,4-diphenyl-1-pyridazinyl) ethyl] phenoxyacetic acid

[Formula 92] Methyl [3- [2- (1,6-dihydro-6-oxo-
3,4-Diphenyl-1-pyridazinyl) ethyl] phenoxyacetate (4.60 g, 11 mmol), 5N
A mixture of the above NaOH solution (3.20 ml, 32 mmol) and methanol (90 ml) was heated to reflux temperature on a steam bath. After 25 minutes the methanol was evaporated, the residue diluted with water and acidified to pH = 1 with 2N HCl solution. The white solid was filtered and dissolved in CH ₂ Cl ₂ . Diethyl ether was added to add [3- [2- (1,6-dihydro-6-oxo-3,4-diphenyl) -1-pyridazinyl) ethyl] phenoxy] acetic acid hydrated dichloromethane solvate (2.60 g, 58). %). Melting point 165-16
7 ° C. _{Analysis: C 26 H 22 N 2 O} 4 · 0.1H 2 O · CH 2 C
l ₂ : calculated: C, 63.20; H, 4.76; N,
5.46; H ₂ O, 0.35. Found: C, 63.4.
1; H, 4.69; N, 5.44; H ₂ O, 0.14
%. ¹ H-NMR (DMSO-d ⁶ ) delta: 3.06
(2H, t, J = 7.5 Hz), 4.37 (2H, t,
J = 7.5 Hz), 4.62 (1H, s), 5.74
(2H, s), 6.65 to 6.90 (3H,
m), 6.94 (1H, s), 7.00 to 7.4
5 (11H, m) and 12.96 (1H, bs). Example 30 Methyl [3- [2- (2,3-dihydro-
3-oxo-5,6-diphenyl-1,2,4-triazin-2-yl) ethyl] phenoxy] acetate

[Formula 93] Diethylazodicarboxylate (2.72 g, 2.5
0 ml, 16 mmol) was added to dry THF (75 ml) at 0 ° C.
5,6-diphenyl-1,2,4-triazole-in
3 (2H) -one (3.00 g, 12 mmol), triphenylphosphine (4.11 g, 16 mmol) and methyl [3- (2-hydroxyethyl) phenoxy].
Add to a stirred solution of acetate (2.78 g, 13 mmol). The ice bath was removed and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated and the residue was chromatographed twice on a column of silica gel using a mixture of diethyl ether and hexane (7: 3) as eluent to give methyl [3
-[2- (2,3-Dihydro-3-oxo-5,6-diphenyl-1,2,4-triazin-2-yl) ethyl] phenoxy] acetate (6.40 g, 90%) as a yellow foam I got it as a thing. _{Analysis: C 26 H 23 N 3 O} 4 · 0.5H 2 O: Calculated: C,
69.33; H, 5.38; N, 9.33; H 2 O,
1.99. Found: C, 69.23; H, 5.19;
_{N, 9.56; H 2 O,} 0.15%. ¹ H-NMR (CDCl ₃ ) delta: 3.19 (2
H, t, J = 7.5 Hz), 3.72 (3H, s),
4.45 (2H, t, J = 7.5Hz), 4.56 (1
H, s), 6.70 to 6.80 (2H, m),
6.88 (1H, d, J = 7.5 Hz), 7.10 t
o 7.50 (11H, m). Example 31 [3- [2- (2,3-dihydro-3-oxo-5,6-diphenyl-1,2,4-triazine-
2-yl) ethyl] phenoxy] acetic acid

[Formula 94] Methyl [3- [2- (2,3-dihydro-3-oxo-
5,6-Diphenyl-1,2,4-triazin-2-yl) ethyl] phenoxy] acetate (4.00 g, 9
Mmol), 5N NaOH (3.70 ml, 18 mmol) and methanol (60 ml) were heated to reflux temperature on a steam bath. After 20 minutes the methanol was evaporated, the residue diluted with water and acidified with 2N HCl solution. The yellow solid was filtered and recrystallized from a mixture of hexane and CH ₂ Cl ₂ to give [3- [2- (2,3-dihydro-3-oxo-5,6-diphenyl-1,2,4-triazine- 2-yl) ethyl] phenoxy] acetic acid (2.
79 g, 72%). Melting point 179-182 [deg.] C. Analysis: C ₂₅ H ₂₁ N ₃ O ₄ .0.5H ₂ O: Calculated value: C,
68.80; H, 5.09; N, 9.63; H 2 O,
2.06. Found: C, 68.81; H, 4.79;
_{N, 8.64; H 2 O,} 0.51%. ¹ H-NMR (DMSO-d ⁶ ) delta: 3.10
(2H, t, J = 7.5 Hz), 4.36 (2H, t,
J = 7.5 Hz), 4.62 (2H, s), 6.70
to 6.95 (3H, m), 7.10 to 7.6
0 (11H, m) and 12.97 (1H, bs). Example 32 Methyl [3- [2- [5- (diphenylmethyl) -2H-tetrazol-2-yl) ethyl] phenoxy] acetate

[Formula 95] Diethylazodicarboxylate (0.96g, 5.5
Mmol) in dry THF (17
5- (diphenylmethyl) -2H-tetrazole (1.00 g, 4.2 mmol), methyl [3- (2
-Hydroxyethyl) -phenoxy] acetate (0.
98 g, 4.6 mmol) and triphenylphosphine (1.44 g, 5.5 mmol) were added to a stirred solution. The ice bath was removed, the mixture was stirred at room temperature for 1 hour and then the solvent was evaporated. The residue was chromatographed on a column of silica gel using a mixture of hexane and ethyl acetate to give methyl [3- [2- [5- (diphenylmethyl) -2H-tetrazol-2-yl] phenoxy] acetate ( 1.06 g, 58%) was obtained as a colorless oil. _{Analysis: C 25 H 24 N 4 O} 3: Calculated: C, 70.08;
H, 5.65; N, 13.08. Found: C, 70.0
3; H, 5.73; N, 12.66%. ¹ H-NMR (CDCl ₃ ) delta: 3.26 (2
H, t, J = 7.5 Hz), 3.78 (3H, s),
4.53 (2H, s), 4.79 (2H, t, J = 7.
5 Hz), 5.77 (1 H, s), 6.65 to
6.80 (3H, m) and 7.10 to 7.4
0 (11H, m). Example 33 [3- [2- [5-diphenylmethyl)-
2H-tetrazol-2-yl] ethyl] phenoxy]
Acetic acid

[Formula 96] Methyl [3- [2- [5- (diphenylmethyl) -2H
-Tetrazol-2-yl] ethyl] phenoxy] acetate (0.84 g, 2 mmol), 3N NaOH solution (2.00 ml, 6 mmol) and methanol (35
ml) was heated on a steam bath for 10 minutes. The methanol was evaporated, the residue diluted with water and acidified to pH = 1 with 1N HCl solution. The mixture was extracted 3 times with CH ₂ Cl ₂ and the combined extracts were washed with saturated sodium chloride solution and dried over sodium sulfate. The oil remaining after evaporation of the solvent was chromatographed on a column of silica gel using a mixture of chloroform and methanol (93: 7) as eluent, [3- [2- [5- (diphenylmethyl)- 2H
-Tetrazol-2-yl] ethyl] phenoxy] acetic acid (0.50 g, 61%) was obtained as a colorless oil. Analysis: C ₂₄ H ₂₂ N ₄ O ₃ .0.2H ₂ O: Calculated value: C,
68.96; H, 5.41; N, 13.41; H 2 O,
0.86. Found: C, 68.58; H, 5.42;
_{N, 13.05; H 2 O,} 0.54%. ¹ H-NMR (CDCl ₃ ) delta: 3.25 (2
H, t, J = 7.5 Hz), 4.54 (2H, s),
4.78 (2H, t, J = 7.5Hz), 5.80 (1
H, s), 6.60 to 6.85 (3H, m),
7.20 to 7.40 (11H, m) and 9.
62 (1H, bs). Example 34 Production of intermediate (34-1) 3- [2- (4,5-diphenyl-2-
Thiazolyl) ethyl] phenol

[Formula 97] N-Butyllithium (1.5 ml) in hexane (9.5 ml)
3 g, 24 mmol) was added dropwise to a stirred solution of 2-methyl-4,5-diphenylthiazole (5 g, 20 mmol) in dry THF (150 ml) kept at -78 ° C under a nitrogen atmosphere. After 25 minutes, [3- (bromomethyl) phenoxy] dimethyl (1,1) in THF (10 ml).
A solution of -dimethylethyl) silane (0.60 g, 22 mmol) was added dropwise and the mixture was stirred at -78 ° C for 10 minutes then warmed to room temperature. The reaction mixture was poured into saturated ammonium chloride solution and extracted with CH ₂ Cl ₂ , the extracts were combined, dried over sodium sulfate and concentrated in vacuo to give an oil. It was dissolved in THF (25 ml). A solution of tetra-n-butylammonium fluoride (6.77 g, 26 mmol) in THF (25.86 ml) was added, the mixture was stirred at room temperature for 30 minutes and then diluted with 1N HCl solution (100 ml). The mixture was extracted with CH ₂ Cl ₂ and all extracts were dried over sodium sulfate and concentrated to give an oil. Chromatograph on a column of silica gel using a mixture of hexane and diethyl ether (2: 1) as eluent 3- [2-
(4,5-Diphenyl-2-thiazolyl) -ethyl] phenol (4.13 g, 58%) was added to hexane and CH _2.
Obtained after recrystallization from a mixture of Cl ₂ . Melting point 166 ~
168 ° C. Analysis: C ₂₃ H ₁₉ NOS: Calculated: C, 77.28; H,
5.36; N, 3.92. Found: C, 77.22;
H, 5.46; N, 3.71%. ¹ H-NMR (CDCl ₃ ) delta: 3.04 t
o 3.14 (2H, m), 3.20 to 3.40
(2H, m), 5.89 (1H, s), 6.60 to
6.75 (2H, m), 6.80 to 6.90
(1H, m), 7.13 (1H, t, J = 8Hz),
7.20 to 7.45 (8H, m) and 7.5
0 to 8.00 (2H, m). (34-2) 1- (1-Ethoxyethyl) -2-methyl-4,5-diphenyl-1H-imidazole

[Formula 98] 2-Methyl-4,5-diphenylimidazole (3.0
0 g, 13 mmol), ethyl vinyl ether (9.2
A mixture of 3 g, 12.30 ml, 130 mmol) and hydroquinone (0.14 g, 1.2 mmol) was heated in a sealed vessel at 180 ° C for 17 hours. Excess ethyl vinyl ether was removed and the residue was chromatographed on a column of silica gel using a mixture of diethyl ether and hexane (3: 2) as eluent. 1- (1-ethoxyethyl) -2-methyl-4,5 by elution
-Diphenyl-1H-imidazole (2.68 g, 68
%). Melting point 87-89 [deg.] C. _{Analysis: C 20 H 22 N 2 O} : Calculated: C, 78.40; H,
7.24; N, 9.14. Found: C, 78.64.
H, 7.31; N, 9.56%. ¹ H-NMR (CDCl ₃ ) delta: 1.09 (3
H, t, J = 7Hz), 1.55 (3H, d, J = 6H
z), 2.62 (3H, s), 3.20 and 3.
35 (2H, m), 5.07 (1H, q, J = 6Hz)
and 7.00 to 7.50 (10H, m). (34-3) 3- [2- [1- (1-ethoxyethyl) 4,5-diphenyl-1H-imidazol-2-yl] ethyl] phenol

[Formula 99] N-Butyllithium (3.89 g, 61 mmol) in hexane (24.31 ml) was added under nitrogen atmosphere to -7.
1- (1-ethoxyethyl) -2-methyl-4,5-diphenyl-1 in dry THF (300 ml) kept at 8 ° C.
H-imidazole (15.50 g, 51 mmol) was added dropwise to a stirred solution. The mixture is stirred for 45 minutes,
[3- (bromomethyl) -phenoxy] dimethyl (1,
1-Dimethylethyl) silane (16.77 g, 50 mmol) was added dropwise. After 10 minutes, the mixture was poured into water, extracted into CH ₂ Cl ₂ , the extracts were combined and dried over sodium sulfate. Evaporation of the solvent left an oil which was dissolved in THF (75 ml) to give tetra-n-butylammonium fluoride (1 ml in THF (65 ml).
7.22 g, 66 mmol) was added. Solution at room temperature 3
Stirred for 0 minutes, evaporated the solvent and diluted the residue with water. Two
N HCl solution (20 ml drug) was added to pH = 5 and the mixture was extracted with CH ₂ Cl ₂ . The combined extracts were dried over sodium sulfate, concentrated in vacuo and the residue chromatographed on a column of silica gel. Elution with a mixture of diethyl ether and hexane (1: 1) 3- [2- [1-
(1-Ethoxyethyl) -4,5-diphenyl-1H-
Imidazol-2-yl] ethyl] -phenol (8.
18 g, 39%) was obtained after recrystallization from a mixture of CH ₂ Cl ₂ and hexane. Mp 165.5 to 167 ° C. _{Analysis: C 27 H 28 N 2 O} 2 · 0.4H 2 O: Calculated: C,
77.27; H, 6.92; N, 6.68; H 2 O,
1.72. Found: C, 77.31; H, 6.93;
_{N, 6.29; H 2 O,} 1.75%. ¹ H-NMR (CDCl ₃ ) delta: 0.99 (3
H, t, J = 7Hz), 1.45 (3H, d, J = 6H
z), 3.00 to 3.40 (6H, m), 5.0
5 (1H, q, J = 6Hz), 6.60 (1H, dd,
J = 7Hz, J '= 1.5Hz), 6.74 (2H,
m), 7.00 to 7.30 (4H, m), 7.3
0 to 7.45 (4H, m), 7.45 to
7.60 (3H, m) and 9.30 (1H, s). (34-4) 5- [3- [Dimethyl (1,1-dimethylethyl) -siloxy] phenyl] -1-phenyl-
1,3-pentanedione

[Formula 100] Sodium hydride (2.13 g of 50% dispersion in mineral oil,
(44 mmol) was washed twice with hexane and dried with THF.
Cover with (150 ml) and 1-benzoylacetone (6.0
0 g, 37 mmol) was added in small portions. The mixture was stirred under a nitrogen atmosphere at room temperature for 10 minutes to obtain a slurry, which was cooled to -20 ° C. N-Butyllithium (2.60 g, 40 mmol) in hexane (163.ml) was added dropwise to give a solution. The solution was stirred for 20 minutes and then [3- (bromomethyl) phenoxy] dimethyl (1,1-dimethylethyl) silane (11.17 g, 3
7 mmol) was added dropwise. After 15 minutes, the mixture was poured into saturated ammonium chloride and extracted with CH ₂ Cl ₂ . All extracts were dried over sodium sulfate, concentrated in vacuo and the residual oil chromatographed on a column of silica gel. 5- [3- [Dimethyl (1,1-dimethylethyl) siloxy] phenyl] -1-phenyl-1,3-eluting with a mixture of hexane and diethyl ether (9: 1).
Pentanedione (9.00 g, 63%) was obtained. (34-5) 3- [2- (1,5-diphenyl-1H
-Pyrazol-3-yl) ethyl] phenol

[Formula 101] 5- [3- [dimethyl (1,1-dimethylethyl) siloxy] phenyl] -1-phenyl-1,3-pentanedione (8.80 g, 23 mmol), phenylhydrazine (2.73 g, 2.50 ml, 25 ml), pyridine (3
ml) and methanol (70 ml) was stirred at room temperature. After 20 minutes, phenylhydrazine (0.3
ml) was added and stirring was continued for another 7 hours. Evaporate the solvent,
The residue was chromatographed on a column of silica gel using a mixture of hexane and diethyl ether (9: 1) as eluent to give 3- [2- [3-dimethyl (1,1-
Dimethylethyl) -siloxy] phenyl] -1- (diphenylmethyl) -5-phenyl-1H-pyrazole (1
0.27 g, 98%) was obtained. Part of it (9.20g,
20 mmol) was dissolved in THF (180 ml). Tetra-n-butylammonium fluoride (6.89
g, 26 mmol) in THF (26.34 ml) was added and the mixture was stirred at room temperature for 30 minutes. The solvent was evaporated and extracted with CH ₂ Cl ₂ . All extracts were dried over sodium sulfate and concentrated to give a white solid. Triturate this with diethyl ether, filter, and then 3- [2-
(1,5-diphenyl-1H-pyrazol-3-yl)
Ethyl] phenol (5.31 g, 77%) was obtained. The analytical sample recrystallized from ethanol has a melting point of 211-21.
Had 2 ° C. _{Analysis: C 23 H 20 N 2 O} : Calculated: C, 81.15; H,
5.92; N, 8.23 ;. Found: C, 80.90;
H, 6.24; N, 8.22%. ¹ H-NMR (DMSO-d ⁶ ) delta: 2.87.
(4H, bs), 3.35 (1H, s), 6.49 (1
H, s), 6.58 (1H, dd, J = 7Hz, J '=
1.5 Hz), 6.67 to 6.70 (2H,
m), 7.07 (1H, t, J = 7Hz), 7.10
to 7.30 (4H, m), and 7.30 to
7.50 (6H, m). HET ₂ is 4,5-diphenyl-1H-imidazole-
The compound of the present invention, which is a 2-yl heterocyclic group, is represented by Chemical formula 12.

Wherein R ₁ is hydrogen, lower alkyl or an alkali metal ion and is bonded to the group —OCH ₂ CO ₂ at the 3- or 4-position. The compound of formula 12 above is
(A)

Hydrolyzing the compound of formula 13 or (b)

Esterifying a compound of formula 14 or (c)
4,5-diphenyl-2-imidazole thiol

Obtained by a process which comprises alkylating with a compound of formula 15. The compound of formula 12 above is the above HE
T ₁ - (CH ₂₎ having the same pharmaceutical properties as the _n CO ₂ R, and the Equation 5. Example 3 which is an example of a compound of formula 12
In vitro human platelet aggregation inhibition test results for compounds 5 and 36 are shown in Table 3.

[Table 3] Example 35 Methyl [3-[(4,5-diphenyl-1
H-imidazol-2-yl) thio] methyl] phenoxy] acetate

[Formula 102] Sodium hydride (50% dispersion 684 mg, 14 mmol) was washed 3 times with hexane and covered with DMF (60 ml). 4,5-Diphenyl-1-imidazolethiol (3 g, 12 mmol) was added to give a yellow solution after hydrogen evolution ceased. Methyl (3-chloromethylphenoxy) acetate (2.68 g, 12.5 mmol) was added and the mixture was stirred at room temperature for 1.5 hours and then at 100 ° C for 0.5 hours. After cooling, the mixture was diluted with water and washed with diethyl ether (3 times). The total extract was washed with water (3 times), dried and concentrated in vacuo. The residual solid was recrystallized from a mixture of hexane and CH ₂ Cl ₂ [3-
[4,5-Diphenyl-1H-imidazol-2-yl) thio] methyl] phenoxy] -acetate (3.0
0 g, 58%). Melting point unclear. _{Analysis: C 25 H 22 N 2 O} 3 S: Calculated: C, 69.75;
H, 5.15; N, 6.51 ;. Found: C, 69.7.
9; H, 5.23; N, 6.24. ¹ H-NMR (CDCl ₃ ) delta: 3.72 (3
H, s), 4.13 (2H, s), 4.56 (2H,
s), 6.75 to 6.80 (3H, m), and
7.10 to 7.50 (12H, m). Example 36 [3-[[(4,5-diphenyl-1H-
Imidazol-2-yl) thio] methyl] phenoxy]
Acetic acid

[Formula 103] Methyl [3-[[4,5-diphenyl-1H-imidazol-2-yl) thio] methyl] phenoxy] acetate (2.00 g, 4.6 mmol), lithium hydroxide-
Hydrate (586 mg, 14 mmol), methanol (35
(ml) and water (10 ml) was stirred at room temperature for 2 hours. The solvent was evaporated, the residue diluted with water and 2N H 2
A Cl solution was added to bring the pH to 7. The white solid was filtered and recrystallized from aqueous DMF to give [3-[(4,5-diphenyl-1H-imidazol-2-yl) thio] methyl] phenoxy] acetic acid (1.33g, 69%). Melting point 2
33-235 ° C. _{Analysis: C 24 H 20 N 2 O} 3 S: Calculated: C, 69.21;
H, 4.84; N, 6.73 ;. Found: C, 69.4.
3; H, 4.92; N, 6.92. ¹ H-NMR (DMSO-d ⁶ ) delta: 4.34
(2H, s), 4.60 (2H, s), 6.77 (1
H, dd, J = 8 Hz, J '= 2 Hz), 6.90 t
o 7.00 (2H, m), 7.05 to 7.60
(12H) and 12.40 to 13.00 (1
H, bs).

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical display area A61K 31/50 9360-4C 31/505 9360-4C 31/53 9360-4C C07D 233/64 101 106 233/74 233/84 237/14 239/36 8615-4C 253/06 257/04 7433-4C 277/30 (31) Priority claim number 479561 (32) Priority date February 13, 1990 (33) Priority Claiming country United States (US) (31) Priority claim number 479464 (32) Priority date February 13, 1990 (33) Priority claiming country United States (US) (31) Priority claim number 479559 (32) Priority date February 13, 1990 (33) Priority claiming United States (US) (31) Priority claiming number 479560 (32) Priority date February 13, 1990 (33) Priority claiming United States (US) (31) Priority claim number 479506 (32) Priority date February 13, 1990 (33) Priority claiming United States (US) (31) Priority claiming number 540988 (32) Priority date June 20, 1990 (33) Priority claiming United States (US) (31) Priority claiming number 479505 ( 32) Priority date February 13, 1990 (33) Priority claiming countries United States (US)

Claims (39)

[Claims] 1. The formula 1 HET _1- (CH ₂ ) _n CO ₂ R (n is 6-9; R is hydrogen or lower alkyl or an alkali metal ion; and HET ₁ is a heterocycle selected from the group consisting of A compound of group (a), which comprises (a) By hydrolyzing the compound of (b) Esterified with a lower alkanol, or (c) HET ₁ -H (HET ₁ is as defined above) Alkylating with a compound of 2. The formula 5. (R ¹ is hydrogen, lower alkyl, or an alkali metal ion, and the group —OCH ₂ CO ₂ R ₁ is 3 or 4 of the ring.
Is bound to position HET ₂ is A heterocyclic group selected from the group consisting of: By hydrolyzing the compound of (b) (HET ₂ is as defined above) or (c) HET ₂ -H (HET ₂ is as defined above) Alkylation with a compound of formula (d) Is alkylated with BrCH ₂ CO ₂ R ₁ ^{a, where} R ₁ ^a is lower alkyl, or (e) Hydrolyzing the compound of claim 1. 3. The equation 12 (R ₁ is hydrogen, lower alkyl, or an alkali metal ion, and the group —OCH ₂ CO ₂ R ₁ is 3 or 4 of the ring.
A compound of formula (13), which is By hydrolyzing the compound of (b) Esterified compound of (c) or (c) 4,5-diphenyl-2-imidazole thiol Alkylating with a compound of 4. Methyl 3,4-diphenyl-1H-pyrrole-1-, which is a compound produced by the method of claim 1.
Nonanoate. 5. A compound produced by the method of claim 1, 3,4-diphenyl-1H-pyrrole-1-nonanoic acid. 6. A compound produced by the method of claim 1, methyl 6-oxo-3,4-diphenyl-1 (6).
H) -Pyridazine nonanoate. 7. Oxo-3,4-diphenyl-1 (6H) -pyridazinenonanoic acid, which is a compound produced by the method of claim 1. 8. A compound prepared by the method of claim 1, methyl 6-oxo-3,4-diphenyl-1 (6).
H) -Pyridazinyl octanoate. 9. 6-oxo-3,4-diphenyl-1 (6H) -pyridazinyloctanoic acid, which is a compound produced by the method of claim 1. 10. A compound produced by the method of claim 1, methyl 3-oxo-5,6-diphenyl-1,
2,4-triazine-2 (3H) -nonanoate. 11. A compound produced by the method of claim 1, which is 3-oxo-5,6-diphenyl-1,2,4-.
Triazine-2 (3H) -nonanoic acid. 12. A compound produced by the method of claim 1, methyl-3-oxo-5,6-diphenyl-1,
2,4-triazine-2 (3H) -octanoate. 13. A compound prepared by the method of claim 1, 3-oxo-5,6-diphenyl-1,2,4-.
Triazine-2 (3H) -octanoic acid. 14. Methyl 2-oxo-4,5-diphenyl-1 (2) which is a compound produced by the method of claim 1.
H) -Pyrimidine octanoate. 15. A compound prepared by the method of claim 1, 2-oxo-4,5-diphenyl-1 (2H)-.
Pyrimidine octanoic acid. 16. A compound produced by the method of claim 1, methyl 2-oxo-4,5-diphenyl-1 (2).
H) -Pyrimidine octanoate. 17. A compound produced by the method of claim 1, 2-oxo-4,5-diphenyl-1 (2H)-.
Pyrimidine octanoic acid. 18. A compound, methyl 2,5-dioxo-3,4-diphenyl-, produced by the method of claim 1.
1-Imidazolidine octanoate. 19. 2,5-Dioxo-3,4-diphenyl-1-imidazolidinenonanoic acid, which is a compound produced by the method of claim 1. 20. 5- (Diphenylmethyl) -2H-tetrazole-2-nonanoate, which is a compound produced by the method of claim 1. 21. 5- (Diphenylmethyl) -2H-tetrazole-1-nonanoic acid, which is a compound produced by the method of claim 1. 22. Methyl (3- [2- (4,5-diphenyl-2-, which is a compound produced by the method of claim 2.
Thiazolyl) -ethyl] phenoxy) acetate. 23. [3- [2-4,5-Diphenyl-2-thiazolyl) ethyl] phenoxyacetic acid, which is a compound produced by the method of claim 2. 24. Methyl [3- [2- (4,5-diphenyl-1H) which is a compound produced by the method of claim 2.
-Imidazol 2-yl) ethyl] phenoxy] acetate. 25. [3- [2- (4,5-Diphenyl-1H-imidazol-2-yl) -ethyl] phenoxyacetic acid, which is a compound produced by the method of claim 2. 26. Methyl [3- [2- (3,4-diphenyl-1H) which is a compound produced by the method of claim 2.
-Pyrazol-1-yl) ethyl] phenoxy] acetate. 27. Methyl [3- [2- (4,5-diphenyl-1H) which is a compound produced by the method of claim 2.
-Pyrazol-1-yl) ethyl] phenoxy] acetate. 28. [3- [2- (3,4-Diphenyl-1H-pyrazol-1-yl) ethyl] phenoxy] acetic acid, which is a compound produced by the method of claim 2. 29. [3- [2- (4,5-Diphenyl-1H-pyrazol-1-yl) -ethyl] phenoxy] acetic acid, which is a compound produced by the method of claim 2. 30. Methyl [3- [2- (1,5-diphenyl-1H) which is a compound produced by the method of claim 2.
-Pyrazol-3-yl) ethyl] phenoxy] acetate. 31. [3- [2- (1,5-Diphenyl-1H-pyrazol-3-yl) -ethyl] phenoxy] acetic acid, which is a compound produced by the method of claim 2. 32. Methyl [3- [2- (1,6-dihydro-6-oxo-3,4-diphenyl-1-pyridazinyl) ethyl] phenoxy] acetate which is a compound produced by the method of claim 2. 33. A compound produced by the method of claim 2 [3- [2- (1,6-dihydro-6-oxo-
3,4-diphenyl-1-pyridazinyl) ethyl] phenoxy] acetic acid. 34. Methyl [3- [2- (2,3-dihydro-3-oxo-5,6-diphenyl-1,2,4-triazine- which is a compound produced by the method of claim 2.
2-yl) ethyl] phenoxy] acetate. 35. A compound produced by the method of claim 2 [3- [2- (2,3-dihydro-3-oxo-
5,6-Diphenyl-1,2,4-triazin-2-yl) ethyl] phenyl] acetic acid. 36. Methyl [3- [2- [5- (diphenylmethyl)) which is a compound produced by the method of claim 2.
-2H-tetrazol-2-yl] ethyl] phenoxy] acetate. 37. A compound produced by the method of claim 2, which is [3- [2- [5- (diphenylmethyl) -2H].
-Tetrazol-2-yl] ethyl] phenoxy] acetic acid. 38. Methyl [3-[(4,5-diphenyl-1H-imidazol-2-yl) thio] methyl] phenoxy] acetate which is a compound produced by the method of claim 3. 39. [3-[[(4,5-Diphenyl-1H-imidazol-2-yl) -thio] methyl] phenoxy] acetic acid, which is a compound produced by the method of claim 3.