JPS5973576A - Piperidinylcyclopentanolheptanoate - Google Patents

Abstract

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

Description

[Detailed Description of the Invention] Engineering/Doberoki 7 Dobrostaglandin G, , Th
and H2 as well as tro/hoki f 7 A, are reactive metabolites of natural arachito/acid in human platelets. These substances are effective not only as flocculants, but also as constrictors of vascular and bronchial smooth muscle.

Therefore, substances that antagonize the effects of these substances are quite useful as human medicines.

Endo exhibits peroxide and thromboquinane antagonism, and thus new compounds have been discovered that are useful in the treatment of asthma and cardiovascular diseases.

This compound is [IFL-(1α(Z), 2β.

3β, 5α]]-(i)-7-(5-((1,1'-biphenyl)-4-yl]methoxy]-3-hydroxy 2
-(i-H:U')Nyl)cyclopentyl]=4-heptenoic acid hydrochloride (hereinafter referred to as "Compound A").

The invention particularly relates to pharmaceutical compositions containing Compound A, li-, and one or more pharmaceutical carriers.

Amino acids, which are the parent compounds of compounds, are also known as other H-nocyclo acids and esters, as described in British Patent Specification 1.
1F No. 2097397A. Compounds have a wide variety of uses, both in their formulation and pharmaceutical use, in general as compared to these compounds, and in particular as compared to their parent amino acids and other salts or solvates thereof. It is beneficial in several ways. Therefore, for example,
Compound A is prepared and can be easily isolated from the reaction mixture. It is also obtained in highly pure crystalline form. This is a desirable property for pharmaceutical formulations.

Compound A causes platelet aggregation and manifests bronchial stenosis.

To determine the inhibitory effect on platelet aggregation, compounds are administered orally to fasted guinea pigs with a suitable vehicle.

platelet rich plasma
a) was prepared from each individual, and.

The agglomeration properties for the concentration range of colladan were determined by Born's method (Nature, 194, 927-929 (1999).
The colladan concentration effect curve for each plasma sample measured according to 62)) was calculated, and the result (5
) The effect is expressed as the shift of the curve after treatment with the compound.

Compound A as a bronchial stenotic agent (1):
1a-((α, 4α, 5βtZ), 6α(1E.

38")
) is determined by measuring the effect of Compound A on the dose-response curve of anaesthetized guinea pigs.

Therefore, Compound A is useful in the treatment of asthma.

It is also used in renal dialysis and is useful as an inhibitor of platelet aggregation and thrombosis. In addition, the compound can be used to treat arteriosclerosis, gamma-theroma arteriosclerosis, and peripheral vascular disease.

Cerebrovascular disease (e.g. momentary ischemic attack, stroke attack) pulmonary artery embolism, diabetic retinopathy, postoperative thrombosis, angina, ←
It is useful for the treatment, prevention and treatment of obstructive vasculopathy such as cardiomyopathic infarction and cardiomyopathic infarction. The compound may be suitable for use with one or more pharmaceutical carriers.1. + It can be formulated into a dosage form by a conventional method. (6) For oral administration, the pharmaceutical composition is prepared in a conventional manner, eg, as a single tablet, together with possible excipients.

It can take the form of capsules, powders, solutions, or tablets.

The compound can be administered by temporary bolus injection for parenteral administration.
It can also be formulated into a continuous infusion drug. Formulations for injection may also be presented in unit dosage form, such as in vials with added preservatives.

For administration by inhalation, the compound may be administered in pressurized packaging (aerosol) i
or administered by spraying from a nebulizer, -! The powder composition is easily administered in the form of a cartridge that can be inhaled with the aid of a suitable device. In the case of pressurized sprays (aerosols), the unit dose needle can be defined by being fitted with a pulp that releases only a predetermined amount.

When used as an antithrombotic agent, the compound may be administered in doses of 2 to 4 times a day, e.g. 0.05 to 5 doses per kg of body weight.
Oral administration is preferred.

The compound is similarly used in the treatment of asthma.

1 to 4 doses per day at a dose of 0.05 to 5 cm per 1 kg of body weight
It can be administered orally twice. But please,
Administer by inhalation 1 to 4 times a day at a dosage within the range of 0.03 to 30 mno. The compounds of the invention can also be used in combination with other anti-asthmatic drugs.

Therefore, unit dosage formulations typically contain between 6.5 and 35
Contains 0 Da. Of course, the exact dosage depends on the patient's age, health and condition.

Platelet aggregation inhibitory effect Compound A was administered to fasted guinea pigs (1% Na).
0.3 Iv1kg administered as HCOs solution t-'v
The platelet-rich serum of each individual was adjusted and the aggregation was carried out to a colladan concentration range of (0.2tt9/ml-20tt') IR1).

Born 1 (Natt+re, 194, 927~
929 (1962>). Compound A is 2.
This resulted in a shift of the curve of more than 5 times.

toxicity Compound A is nontoxic at therapeutically significant doses of 1.

For example, if Compound A is administered to dogs at 1/kp (
It did not produce any adverse effects.

A preferred method for preparing Compound A is described below. The compound can be prepared by treating the parent amino acid or a suitable ester (eg, trityl ester) with hydrogen chloride or hydrochloric acid. Organic solvents for parent amino acids (e.g., ether, ethyl acetate, CH, CI,
or dimethoxyethane) solution with hydrogen chloride, for example,
The desired salt is prepared by addition at a temperature ranging from 0°C to room temperature.

The invention will now be illustrated by examples.

In the description of the following examples, unless otherwise specified, the temperature unit is 1°C; TLC means thin i chromatography using 8IO7; FfR means ether: FiAFi ethyl acetate THF means tetrahydrofuran; η゛DIRAL means diisodacylaluminum hydride; Clondgelafy was carried out using silica dal (9); "dried" means Mg80. "Hyflo" is a filter aid.

The preparation of intermediate 1 is disclosed in GB 2075503A. - Intermediate 1 (IR-(exo, endo))-(-)-2-promo 3-hydroxybicyclo(3,2,0)hebutane-6-
The preparation of intermediates 2 and 6 is described in British Patent Specification No. 20973.
No. 97A.

Intermediate 2 (IB-(1α(Z), 2β, 3β, 5α]-(+)~
Methyl 7-[5((1,1'-biphenyl)-4-yl]methoxy]-3-hydroxy-2-(1-piperidinyl)cycloR-ethyl)]-4-hebutenoate intermediate 5 (lB- (1α, 2β, 3α, 5α))−5=[(1,
1'-Biphenyl)-4-yl]methoxyclopentane γcetaldehyde Intermediate 4 A solution of Intermediate 3 (13, Og) in toluene (39 ml) was dissolved in potassium t-butoxide (5,96 g) in toluene Cs (2 ml). Add dropwise to suspension1. fc,. Methoxymethyltriphenylphosphonium chloride (15,5'5g)
was added and the mixture was stirred overnight (18 hours). Add 2N hydrochloric acid (52d).

The mixture was heated at 40° C. for 30 minutes with stirring.

To the solid, Co3(13,!i') was added, the organic phase was separated, washed with water (52 ml) and dried azeotropically, and a toluene solution of intermediate 4 (115 tnl
) got f. A portion of this solution (8,81!Il)
Elution with a mixture of eBA/methanol (9:1) and purification by clontgelafing gave 0.5514 fc of the title compound in the form of two foams.

TLC: Rf2 0.15 (gA/methanol, 4:1 mixture) Intermediate 5
198m/)F? and in THF (52rnl) solution.

3-(carboxypropyl)triphenylphosphonium bromide (41,14,9) was added under a nitrogen atmosphere. After 1.5 hours, a solution of Intermediate 4 (24.5 g) in toluene (220 ml) was added and the mixture was stirred for 6 hours. Add water (1251n/) (2,
Shake this mixture vigorously and.

Separated into two phases. The aqueous phase was dissolved in toluene (2x225ml
) and discard the toluene phase).

Acidified to pH 7.5 with 2N hydrochloric acid and.

Extract with CHzClt (2X 225 ml)*.

Combine the C1l and C71'2 extracts, dry this,
The title compound (2), which is a gummy base, is then evaporated.
4,47,9) were obtained.

CH of conobase C93my), C1l, (1.5ml
) The solution was treated with an excess of ethereal hydrogen chloride. The solvent was removed and the remaining oil was triturated with gR (5 m/). The resulting solid was filtered, washed with ER, and dried to yield the title compound (82 da)'e. m, p
, 152.5-136°C (softened at 128°C) Intermediate 6 The base (5,88,!9) of Intermediate 5 and trif-chloride ('4.4j9) were converted to CH2c4 (24m')
Triethylamine (
2,49d) was added. This mixture was stirred for 60 minutes.

Then water (6011 Ll) was added and further CH2
C6° (30 mA') was added. Separate the organic phase.

Evaporated in vacuo. The residue was converted to CH2C6, (6Qmj
! ) to obtain 1013.9 of an oil. D.A.
This oil was chromatographed on alumina (50[]g) using as eluent to give the title compound (5,1
4g) was obtained. TLC (A40.): Rf=0
．． 52 (EA/methanol, 49:1 mixture) Intermediate 7 Intermediate 6 (6,47,!9) CH, C4 (65 mA!
) triethylamine (9,17m
A') was added at 2°C, followed by the addition of pyridine/so3 complex (5,75,!il')(Ddi)tylxru*+si)'
(65ml) solution was added. The obtained solution is
Stirred for 2 hours at 5°C and quenched by dropwise addition of ice water (6511/). The reaction mixture was extracted with diethyl ether (2X65+114) and the extract was mixed with water (651R1), 1M citric acid (4X
10 m/) and water (10 ml). Na28
After drying at 0.04 ml, the solvent was evaporated to give 5.911 ml of the title compound in the form of a 9 foam. IIL(CHBrs): 1
740cIIL' Example 1 Intermediate 2 (10,58II) was dissolved in 740P ethanol (6
0111> and 5N' NaOH (30M) at 20°C for 16 hours. Add this solution to water (400m)
The solution was diluted with 1 and then extracted with ER (2 x 150 mA).The aqueous phase was adjusted to 6 with 2N HCA.

It was then extracted with CH2Cl2 (5X2Q (1 ml)). The extracts were combined and evaporated to yield 945 g of 2 foam.

The majority of this foam (9,59) was converted into CH2Cl2 (
5Dyn1) and then treated with an excess of hydrogen chloride in ethanol. Evaporate in vacuum.

The residue was triturated with ER (4×7511/) to give 9281 of the title compound in powder form. The sample was crystallized from an EA/methanol mixture to give a product with m, p of 124-126°C.

(a) Rate = + 65.1° (CHC/,) Example 2 2.6-di-t-butyl-4-methylphenol (2,
DIBAL (5.5i1 as a 1.M hexane solution) was added dropwise to a stirred solution of 9,li+) in CH2Cl2 (15p) at 0-2<0>C. Add this solution to -5~θ℃
The mixture was stirred for 1 hour and then cooled to -20°C. A solution of intermediate 7 (1.3 g) in CH2Cl2 (13 m/) was added at -18 to -20<0>C. The reaction mixture was stirred at this temperature for 2.5 hours and then treated with IN hydrochloric acid (20 m/mL).
) was added dropwise and the mixture was stirred at room temperature for 60 minutes. Divide into two phases, and the aqueous phase is CfhC12 (101171
) was extracted. The organic extracts were combined, washed with brine, dried over Na2804, and evaporated to give a yellow gum. This product was triturated with diethyl ether to obtain a pale yellow powder t0.689. Recrystallization from EA/methanol gave the product m, p, 128-130°C.

(a)'7,=+-66,5°(CHCj's) Formulation Example In the following formulation, "ELP, C"' means the British Official Formulary, and "B, P,'" means the British Pharmacopoeia.

Tablets These can be manufactured by direct compression or wet granulation. Although direct compression is the preferred method, it may not be suitable in all cases (17). This is because direct compression methods depend on the dosage level and physical properties of the active ingredient.

Human, direct compression method Compound A 100.00 Microcrystalline cellulose (B, P, C,) 298.00
Magnesium stearate 2.00 Compound A was sieved through a 250 m sieve, mixed with other ingredients,
And 10. Compress with 01/ξ inches.

Tablets with different strengths vary compression weight.

And, it can be manufactured by using a suitable notch.

B. Wet granulation method 401 Ingredients Formulation # (my/tablet)
Compound A' 100.00 Lactose (B, P, ) 238.00 Starch (B, p, ) 40.00
Compressed weight: No. 400.001 Compound A is sieved through a 250 m' sieve and blended with lactose, starch and pregelatinized starch.

This mixed powder is moistened with purified water to produce granules.

Dry, sieve, and blend with magnesium stearate. The lubricated granules are compressed into tablets as described above for direct compression formulations. The tablets may be coated with a suitable coating material (eg methylcellulose, hydroxypropyl methylcellulose) by conventional techniques. Alternatively, the tablets may be sugar-coated.

Capsule Compound A 100.00*5T
A-'RX 1500 99.00 Magnesium stearate (B, P, )
1.00 Filled weight: 200. QQ〃y *Co1orcorn Ltd, (Orl ing
ton, Kent.

sold in Finland). Starch Compound A in directly compressible form is sieved through a 250 m-6 sieve and.

Combine with other ingredients. This mixture is filled into /162 hard gelatin capsules using a suitable filling machine. Capsules with other dosages vary in fill weight.

And, if necessary, it can be manufactured by varying the size of the capsule.

Inhalation cartridge Compound A (fine powder) 3. [)0 Lactose (B, P, ) Compound A is micronized to fine powder size in a fluid energy mill and then blended with conventional tablet lactose in a high energy mixer. This powder mixture is filled into 7165 hard gelatin capsules on a suitable capsule filling machine.

The contents of the cartridge are administered by using a powder inhaler.

Compound A (fine powder) 0.500 1
2071ip olein es (B, P,) 0
．． 050 12 Datrichlorofluoromethane (B, P,) 22,25 5.34
fl dichlorodifluoromethane (B, P,) 6a90
14.62. ! i' Micronize Compound A to a fine powder size range in a fluid energy mill.

Oleic acid is mixed with trichlorofluoromethane at a temperature of 10-15°C and finely powdered Compound A is mixed into this solution in a high shear mixer. A predetermined amount of this suspension was filled into four sol cans made of aluminum.

The can is fitted with a suitable metering valve for discharging a metered dose of 85 I of the suspension, and dichlorodifluoromethane is discharged into the can through this valve.

Syrup Compound A 100.00 Sugar (
B, P, ) 2750.00 Glycerin so o, o.

Total volume: 5.00 ml Dissolve the active ingredient, 1 buffer, 9 flavors, 9 colors and preservatives in a small amount of water and add the glycerin. Heat the remaining water to 80°C and dissolve the sugar in it and cool.

Combine the two solutions, adjust volume, and mix. The resulting syrup is filtered and clarified.

Ingredients Compound A
50 I〃9 Distilled water for injection (B,
P,) Appropriate total amount = 5d chloride) Lamb or other suitable substance may be added to make the solution isotonic. Further, by using a dilute acid or alkali, or by adding a suitable buffer salt, the value of the solution can be adjusted to a value that provides the maximum stability of the active ingredient. The solution is prepared, clarified, and lightened into appropriately sized ampoules and sealed by melting the glass. The injection solution is sterilized by heating in an autoclave through any of the available cycles. Alternatively, this solution is patented by Patent Applicant Gractu Group Limited Patent Attorney Masahiro Matsui (23) Continued from page 1 Priority Claim 0 October 28, 1982 [Sir] United Kingdom (GB) 8230771 0 Inventor Peter Barrett, United Kingdom, Hertfordshire, Royston, Passingbourne, Walnut, Tory Clowes 46 0 Inventor, Christopher John Wallis, Newmarket Road, Noons, Royston, Hertfordshire, United Kingdom Furii (no address) 68 (24) −

Claims (1)

[Claims] 1, (1a-(1α(Z), 2β, 3β, 5α)], -
(+1l-(s-(((1,i'-biphenyl)-4-
yl]methoxy]-3-hydroxy-2-(1-hyharidinyl)-cycloethyl]-4-heptenoic acid hydrochloride 2, consisting of treating the parent compound amino acid with hydrogen chloride or hydrochloric acid (IR, (1α(Z), 2β. 3β, 5α]]-...-7-[5-[((1,1'-biphenyl)-4-yl]methoxy]-3-hydroxy-2
A method for producing -(1-piperidinyl)-cyclopentyl]-4-heptenoic acid hydrochloride. 3, (1a-(1α(Z), 2β, 3β, 5α)]
-(t)-7-(5-(((1,t'-biphenyl)-
4. Pharmaceutical composition containing 4-yl]methoxy]-3-hydroxy-2-(1-hyheridinyl)-cycloninthyl)-4-heptenoic acid hydrochloride and one or more pharmaceutical carriers, 4. Claims 3. The composition according to item 3. Tablets, capsules, powders, solutions, syrups. A free composition in the form of an ampoule or a spray. 5. The composition according to claim 3 or 4, which comprises (1a-[1α(Z), 2β, 3β. 5α]]-(t)-7-[5-[( , 1'biphenyl)-4-yl]methoxy]-3-hydroxy-2-(
A composition in unit dosage form containing 1-piva'J)nyl)-cyclopentyl]-4-heptenoic acid hydrochloride ff1e3.5-350η. 6.% The composition according to claim 5. Tablets, capsules 1+ containing about 100 da of the compound as claimed in claim 1 are in the form of syrup or contain about 501 n of the compound as claimed in claim 1.
9 or in the form of an inhalation cartridge containing about 31 ny of the compound as claimed in claim 1. A composition in the form of a propellant adapted to release the compound at about 0, s1v. 2. The composition according to any one of claims 3 to 6, which further contains other anti-asthma systems.