JPS6197283A - Piperidine derivative, manufacture and medicinal composition - 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 The present invention relates to piperidine derivatives, processes for their production and pharmaceutical compositions containing them.

[In the formula, A and Ar2 represent a phenyl group, a chenyl group, or a pyridinyl group, which may be individually substituted with a halogen atom, and A is an alkylene group having 2 to 6 carbon atoms. , X represents a CO group or a bond, R1 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and R2 represents a hydrogen atom and R3 represents a hydrogen atom or a hydroxy group. , or R2 and R3 may be combined to form a bond, and R4 represents hydrogen or a halogen atom] or a pharmaceutically acceptable acid addition salt thereof. It is.

Preferred piperidine derivatives of the invention are Ar1 and A
r2 individually represents a 2-chenyl, 2-pyridinyl, phenyl or 4-fluorophenyl group, R4 represents a hydrogen atom, and the other symbols are derivatives according to the above definitions.

Preferably, K is hydrogen and R3 is a hydroxy group.
, derivatives in which Ar2 represents a 4-fluorophenyl group or a 2-pyridinyl group are also preferred.

According to the invention, these piperidine derivatives have the formula (II
): [Symbols in the formula have the same meanings as above] A compound represented by the formula (■): ■ In the formula C, Y is a halogen atom or an unstable group, and other various symbols are as defined above. ] in a protic or aprotic solvent at 25-120°C.
If desired, the resulting compound of the formula fIl can be converted into an acid addition salt by a method described above.

When Y is an unstable group, it is preferably tosyl or mesyl. Preferred protic solvents are alcohols and preferred aprotic solvents include methyl isobutyl ketone.

Among the compounds represented by formula (II), U.S. Pat.
04.222 and Duncan et al., Journal e of Medical Chemistry +
(J, Med, Chem,) 13, l51970
Some are listed in.

Compound (II) in which Ar or Ar2 represents a pyridinyl or phenyl group is a compound represented by formula (■): [wherein R is a protecting group such as acetyl or benzyl], which is a compound represented by formula (V): ArLi1 or Ar2Mg .

Compound (III) is described in Vernin et al., Journal of Heterocyclic Chemistry (J, Het. Chem, ), 18.85 (
1981).

Compounds of formula (Il) in which R2=R3=H can also be obtained by hydrogenolyzing a compound of formula (I) in which R2=H and R3-0R, or by hydrogenolyzing a compound of formula (I) in which R2=H and R3-0R, or by combining R and R3 to form a bond. It can be obtained by hydrogenating a compound of formula (I).

Compounds of formula (I) in which X is co and ≮==t-iSA is -(c H2) 2- can be prepared by preparing a compound of formula (■): in a solvent such as toluene or methyl isobutyl ketone. It can be produced by reacting with the compound (■).

Compounds of formula (■) are described in the literature.

The following examples illustrate the invention.

The structure of the compound was confirmed by elemental analysis, IR and NMR spectra.

Example 1 1-(2-(:4-(hydroxydiphenylmethyl)-1-piperidinyl]ethyl]-1,3-dihydro-2(2H)-benzimidacylon methyl isobutyl ketone alpha in 7Swzl, Alpha diphenyl-4-piperidine methanol 2
．． 7 g (0.01 mol), 1-(1-bromo-2-ethyl)-2-benzimidacylone 2.4 g (0.01 mol), sodium carbonate (N a 2 COa ) 1.2
The mixture of IJium crystals (f and iodide) is heated at reflux temperature for 18 hours.

The mixture is cooled and then evaporated to dryness.

The evaporation residue is taken up in a mixture of water and chloroform and the organic phase is dried and then forced through and evaporated. Compound (I) is thus obtained, which is recrystallized from UM of ethyl acetate/isopropyl ether (85/15). M,P,=
193-196°C.

Example 2 1-[2-(4-(diphenylmethylene)-
1-piperidinyl]ethyl) -1,3-dihydro-2
(2H)-Benzimidasilone methylin butyl ketone, 4-(diphenylmethylene)piperidine 1.010.
004 mol), 1-(i-bromo-2-ethyl)-2-
Benzimidasilone 0.96g (0,004mol), N
a 2 GO30,53i (10.008 mol) and a small amount of crystals of .NaI are heated at reflux temperature for 9 hours.

The solvent was evaporated and the residue was taken up in water and methylene chloride;
The reaction mixture is then separated by gravity and the organic phase is dried and evaporated. The obtained yellow solid was subjected to silica gel column chromatography [eluent: a′l2Ce]
2/MC0H (97/3)]. After evaporation, the solid is collected and recrystallized from ethyl acetate: M, P, = 202-203.
℃.

Example 111 Example 3 1-(2-(4-diphenylmethyl--
1-(2=(4-diphenylmethylene-1-
piperidinyl]ethyl)-1.

A solution of 4 g of 3-dihydro-2(2H)-benzimidacylone is hydrogenated using a Parr apparatus at ambient temperature, 50 psi hydrogen pressure, and the presence of 5% palladium on carbon. After hydrogen absorption is completed, the catalyst is removed and the r-liquid is evaporated. Recrystallize the obtained product from ethyl acetate? M. P, = 195-196°C.

Example 4 1-(2-(4-[:bis(4-fluorophenyl)methyl)-1-piperidinyl]ethyl]-
1.3-dihydro-2(2H)-benzimidacylon methyl isobutyl ketone, 1-(1-bromo-2
-ethyl)-1.3-dihydro-2(2H)-benzimidacylone 1.6 g (0.(106 mol)
, bis(4-fluorophenyl)-4-methylpiperidine 1,9 fl (0.0066 mol), NazCO
30.8 g (0.11075 mol) and a small amount of Na
The crystals of I are heated at reflux temperature for about 6 hours. The solvent is evaporated off, the residue is taken up in a mixture of ester and water, the reaction mixture is phase separated and the ether phase is filtered and evaporated. The oil obtained is crystallized from isopropyl ether.

Seize the pure white product and dry: M, P, = 1
04-106℃.

Example s 1-[:3-(:4-(:bis(4-fluorophenyl)hydroxymethyl]piperidinyl]propyl)-1,3-dihydro-2(2H)-benzimidacylone 4-[bis( 2.1 g (0,007 mol) of 4-fluorophenyl)hydroxymethylcopiperidine, 1-(1-
Bromo-3-propyl)-1,3-dihydro-2(2H
)-Benzimidacilone 1.8 g (0,007 mo/l/
), Na2Go30.851 (0,008 mol) and a small amount of NaI crystals were dissolved in methyl isobutyl ketone60
Pour into a bowl and heat at reflux temperature for 5 hours. The solvent is evaporated, the residue is taken up in a mixture of water and CHz Cl 2 and the organic phase is dried and evaporated. The resulting solid residue was subjected to silica gel column chromatography [CH2Ce2/
MeO■ ((97/3.9 ff4, then 94/6
)]. The purified product fractions are evaporated, the evaporation residue is taken up in ether, the white product is collected and crystallized from 90 ml of ethyl acetate: M, P, = 1
41-143℃.

Example 6 1-(z-(4-[(z-pyridinyl)(phenyl)hydroxymethyl]piperidinyl]ethyl]
-1,3-dihydro-2(2H)-benzimidacylone 1.1. 4-(:(2-pyridinyl)(phenyl)hydroxymethylcopiperidine 1.1.1.4-[(2-pyridinyl)(phenyl)hydroxymethylco-1-benzylpiperidinetetrahydrofuran (THF) 2- in 10ral A solution of 2.1 g/(2,210 mol) of bromopyridine, -
n -BuLi cooled to 65°C 15.6. cl(2
, 510-2 mol) and THF 20 g? dropwise into the solution. The mixture was stirred at -65°C for 174 hours, then
Tl-lF20trtl while maintaining the temperature at -65°C
5.6 g of 1-benzyl-4-benzoylpiperidine in
(2i10-2 mol) is added dropwise. Take this mixture into a mixture of water and ether. The ether phase was washed with water and dried,
Filter and evaporate. Silica Alk 0 Futography [
Eluent: CH2 (J2/MeOH (9515)) and collect the product crystallized from petroleum ether:
M, P, = 142-143°C.

1.1.2. 4-((2-pyridinyl)(phenyl)
A solution of 5.4 g (1,510 mol) of the derivative obtained above in 50 x l of methanol containing 1 x t of hydroquine methylcopiperidine acetic acid was prepared in a Parr apparatus at 40°C in the presence of palladium on carbon.
Hydrogenate at Mpa. After the absorption has ended, the catalyst is removed and the mixture is then evaporated to dryness.

Take the residue in a small amount of water and hydroxylate it) Make alkaline with IJium, extract with ether, dry and filter.
Evaporate.

The product crystallized from isopropyl ether is ground: M, P, = 125-128°C.

1.2. 1-[2-[4-[(2-pyridinyl)(phenyl)hydroxymethyl]-1-piperidinyl]ethyl:]-]1,3-dihydro 2(2t-t) -benzimidacylone 4- (< 2-pyridinyl)(phenyl)hydroxymethylcopiperidine 2.59 (l O-2 mol),
1-(1-bromo-2-ethyl)-1,3-dihydro-2(2H)-benzimidacylone 2,5 ff (1
0-2 mol), Na 2 GO31,29, Na I
Nocrystal 1 [-j and methyl isobutyl ketone 75m?
' into a round bottom flask.

The mixture is kept at reflux for 4 hours and then evaporated to dryness; the residue is taken up in a mixture of water and methylene chloride and the organic phase is dried, filtered and evaporated. The product obtained is triturated in ether and then recrystallized from methyl ethyl ketone: M, P, -206-207°C.

Example 7 3-[2-[:4-[diphenylhydroxymethyl]-1-piperidinyl]ethyl]-2,4(LH
, 3H)-Quinazolinedione Add 1 drop of 7.5N hydrochloric acid and add 4-(diphenylhydroxymethyl)piperidine in 50 liters of toluene. f (0,00748 mol) and 2,3-dihydro(2,5-b)-(5H)oxazolo-5-quinolino 71.4 mol (0,00748-E-l) of l Put it in a flask. This mixture is heated at 100-120°C for 28 hours.

The generated precipitate is collected, washed with a small amount of toluene, and dried. This compound is recrystallized from methanol: M, P
, =206-208°C.

Example F3 1-(3-(4-(diphenylhydroxymethyl)-1-piperidinyl]propyl]-2,4-(
IH,3H) quinazolinedione 4-(diphenylhydroxymethyl)piperidine 2.79 (0,01 mol) and 1-(3-chloropropyl)-2,4-(lH,3
1.2 g (0,005 mol) of H)-quinazolinedione are placed in 7 stnl of ethanol and heated at reflux temperature for 7 hours.

The precipitate formed is filtered, taken up in a mixture of water and CHCl3, made alkaline with sodium hydroxide, stirred for half an hour and filtered. Recrystallize this compound from pyridine:
M, P, = 248-250°C.

The compounds prepared according to the method of the Examples are shown in the table below.

The piperidine derivatives of the present invention were subjected to various pharmacological tests to demonstrate their antagonist activity against histamine and serotonin.

1. In vitro activity: The isolated guinea pig ileum test was performed using the Magnus method (7-
f ・I:/)-7 Armakoda Ia (Arch,
Inc., pHa'rmacodyn, ), 113.15
7), using three-color male guinea pigs (weight 3ooy) after fasting for 18 hours.

The ileum fragment was excised and placed in a Tyrode's tube at 39°C, passed through a stream of carbon dioxide gas (95% 02.5% CO2), and connected to an isotonic sensor with a maximum tension adjusted to 2.5 g. The temperature was set at 39°C. Ugo Basijemicrod
ynamomecer).

Induce contractions with various convulsant-inducing agents and determine the concentration that induces a supramaximal response (histamine: 1 to 8.10"
-817me). The piperidine derivative of the present invention is mixed with distilled water or 0.00% water. Dissolved in IN methanesulfonic acid solution and brought into contact with the ileum 1 minute before introduction of the proconvulsant. The A Cso values (concentrations that reduce histamine-induced contractions by 50%) of certain piperidine derivatives of the invention range from 10-7 to 10-8 molar.

2. In vivo activity: inflammation induced by histamine or serotonin; histamine (200μg) and serotonin (lμg)
The edema induced by planar 7 injections in the hind paws of rats was treated with mercury Ugo 1 hour after injection.
Measure with a Ba5ile plethysmometer.

A piperidine derivative of the invention suspended in a 1% Tween solution in distilled water was administered orally (0
, 5 go/100F).

A D 4 U value (R for reducing edema volume by 40%)
).

When the inflammatory agent is histamine, the A D and io of the piperidine derivative of the present invention are in the range of 1 to 511 Ig/kg.

When the inflammatory agent is serotonin, some of the piperidine derivatives of the present invention have an A D40 of 0.2 to lIIg/
There are some that are in the range of ky.

Therefore, the piperidine derivatives of the present invention can be used for respiratory allergies such as rhinitis and hay fever, skin allergies such as dermatitis and urticaria, eye allergies, Quinke's disease (Quinke's disease), etc.
diseaae) and as an anti-allergic and anti-pruritic agent for the treatment of various allergic symptoms.

Piperidine derivatives of the invention having more specific activity as serotonin antagonists can be used to suppress certain undesirable effects of this mediator in the peripheral or central system. These are especially used in the treatment of migraines.

Therefore, the present invention encompasses all pharmaceutical compositions containing at least one of the piperidine derivatives of the present invention as an active ingredient, together with a pharmaceutically acceptable carrier.

The route of administration may be oral or parenteral.

The daily dosage may range from 5 to 200q.

Claims (1)

[Claims] 1. Formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, Ar^1 and Ar^2 may be individually substituted with a halogen atom. represents a phenyl group, thienyl group or pyridinyl group, A represents an alkylene group having 2 to 6 carbon atoms, X represents a CO group or a bond, R^1
represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and R^2 and R^3 represent a hydrogen atom and R^2 represents a hydrogen atom.
3 represents a hydrogen atom or a hydroxy group, or R^
2 and R^3 may combine to form a bond, and R^4
represents hydrogen or a halogen atom] A piperidine derivative or a pharmaceutically acceptable acid addition salt thereof. 2. A method for producing a piperidine derivative according to item 1, in which a compound represented by formula (II): ▲There are mathematical formulas, chemical formulas, tables, etc. , tables, etc. ▼React the compound represented by (III) in a protic or aprotic solvent at 25 to 120°C, and if desired, react the compound represented by formula (I) obtained by a method known per se. [wherein Y is a halogen atom or an unstable group, and various other symbols follow the definitions in item 1]. 3. The piperidine derivative described in item 1 is used as an active ingredient,
A pharmaceutical composition comprising a pharmaceutically acceptable excipient.