CA2018942A1 - Piperidine derivative, method for preparation thereof, and a pharmaceutical composition comprising the same - Google Patents
Piperidine derivative, method for preparation thereof, and a pharmaceutical composition comprising the sameInfo
- Publication number
- CA2018942A1 CA2018942A1 CA002018942A CA2018942A CA2018942A1 CA 2018942 A1 CA2018942 A1 CA 2018942A1 CA 002018942 A CA002018942 A CA 002018942A CA 2018942 A CA2018942 A CA 2018942A CA 2018942 A1 CA2018942 A1 CA 2018942A1
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- Prior art keywords
- lower alkyl
- alkyl group
- ylidene
- group
- formula
- Prior art date
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
ABSTRACT:
A piperidine derivative represented by the following general formula (I):
(I) wherein R represents a hydrogen atom or a lower alkyl group; X
represents -CH=CH-, -CH2CH2-, or -CH2O-; Y represents an alkylene group having 1 to 5 carbon atoms which may be optionally substituted with a lower alkyl group, or Y represents an -A-O-B- group wherein A
and B are the same or different and each independently represents an alkylene group having 1 to 3 carbon atoms which may be optionally substituted with a lower alkyl group is disclosed. Also disclosed are a pharmacologically acceptable salt of a compound of formula (I), a method for preparation of a compound of formula (I), an antihistaminic and antiallergic agent comprising a compound of formula (I), a pharmaceutical composition comprising a compound of formula (I), and a method for the treatment of an allergic disease by administering a compound of formula (I).
A piperidine derivative represented by the following general formula (I):
(I) wherein R represents a hydrogen atom or a lower alkyl group; X
represents -CH=CH-, -CH2CH2-, or -CH2O-; Y represents an alkylene group having 1 to 5 carbon atoms which may be optionally substituted with a lower alkyl group, or Y represents an -A-O-B- group wherein A
and B are the same or different and each independently represents an alkylene group having 1 to 3 carbon atoms which may be optionally substituted with a lower alkyl group is disclosed. Also disclosed are a pharmacologically acceptable salt of a compound of formula (I), a method for preparation of a compound of formula (I), an antihistaminic and antiallergic agent comprising a compound of formula (I), a pharmaceutical composition comprising a compound of formula (I), and a method for the treatment of an allergic disease by administering a compound of formula (I).
Description
~0~8~3~2 SPECIFICATION
TITLE OF THE INVENTION
PIPERIDINE DERIVATIVE, METHOD FOR PREPARATION THEREOF, AND A
PHARMACEUTICAL COMPOSITION COMPRISING THE SAME
BACKGROUND OF THE INVENTION
Field of the Invention The present invention relates to novel piperidine derivatives and pharmacologically acceptable salts thereof which have an antihistaminic and.antialler~ic activity and are useful for the treatment of, for example, bronchial asthma, allergic rhinitis, dermatosis, and urticaria, and to the method for preparation thereof.
The present invention also relates to a pharmaceutical composition comprising the effective amount of the same.
' Description of the Prior Art Among the piperidlne compounds having a tricyclic rin~
substituent, for example, dibenzocycloheptene ring or a dibenæoxepine ring, in the 4 position of the piperldine ring, such compound as cyproheptadine (The Merck Index, 11th edition, 2779: 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-l-methylpiperidine) represented by the following formula:
TITLE OF THE INVENTION
PIPERIDINE DERIVATIVE, METHOD FOR PREPARATION THEREOF, AND A
PHARMACEUTICAL COMPOSITION COMPRISING THE SAME
BACKGROUND OF THE INVENTION
Field of the Invention The present invention relates to novel piperidine derivatives and pharmacologically acceptable salts thereof which have an antihistaminic and.antialler~ic activity and are useful for the treatment of, for example, bronchial asthma, allergic rhinitis, dermatosis, and urticaria, and to the method for preparation thereof.
The present invention also relates to a pharmaceutical composition comprising the effective amount of the same.
' Description of the Prior Art Among the piperidlne compounds having a tricyclic rin~
substituent, for example, dibenzocycloheptene ring or a dibenæoxepine ring, in the 4 position of the piperldine ring, such compound as cyproheptadine (The Merck Index, 11th edition, 2779: 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-l-methylpiperidine) represented by the following formula:
2- ~CK.
20~39~;2 has been developed as an antihistaminic agent and is widely used clinically for the treatment of such ailments as allergic rhinitis and dermatosis.
However, this class of compounds those havin~ a carboxyl or a lower alkoxycarbonyl group in the substituent at the l-position of the piperidine ring have never been known to date.
A large number of antihistaminic agents have been developed so far and are used for the treatment of, for example, allergic dermatosis or rhinitis. However, adverse reactions of a central inhibltory action caused by the administration of the known antihistaminic agents such as sleepiness or sedation are found to be a great problem with these known agents. In addi~ion, an anti-cholinergic action which is considered to be one of the possible reasons for hydrodips1a or mydriasis i5 another undesired adverse reaction of the antihistaminic agents. Various kinds of research have been conducted to solve the above problems, however, presently avallable antihistaminic agents are insu~icient from a clinical point o~ view.
SUMMARY OF THE INVENTION
An object o~ ~he present invention is to provide novel compounds having an excellent antihistaminic activity as well as excellent antiallergic activity.
~5 Another object of the present invention is to provide novel compounds which extensively eliminate undesired adverse reactions such ;
.
~o~
as a central inhibitory action when administered ~or the treatrnent Or such ailments as bronchial asthma, allergic rhinitis, dermatosis and urticaria.
A further object of the present invention is to provide a method for preparation of the above novel compounds. Yet another object is to provide a pharmaceuti~al composition comprising the novel compounds which is useful for the treatment o~ such ailments as bronchial asthma, allergic rhinitis, dermatosis and urticaria.
The inventors of the present invention have conducted various studies to achieve the foregoing objects and found that the objects can be effectively attained by providing novel piperidine derivatives of the present invention. These derivatives have potent antihistaminic and antiallergic activity and induce few adverse reactions such as central inhibition.
In accordance with the above objects, the present invention provides a piperidine derivative represented by the following general formula (I): ~
COOR
~ (I) wherein R represen~s a hydrogen atom or a lower alkyl group; X
represents ~CH=CH-, -CH2CH2~, or ~CH20-; Y represents an alkylene group having 1 to 5 carbon atoms which may be optionally substituted with a lower alkyl group, or Y represents an -A-0-B- group wherein A
and B are the same or di~erent and each independently represents an .
~)18~
alkylene group having l to 3 carbon a~orns which may be optionally substituted with a lower alkyl group, and pharmacologically acceptable salts of the above compounds.
In accordance with another embodiment of the present invention, the present invention provides a process for preparing a piperidine derivative represented by the general formula (I). The process comprises the steps of reacting a piperidine derivative represented by the following general formula (II):
~3 ~ /~
X ~ NH
~ \ -wherein X is the same as that defined above, with a compound represented by Z-Y-COOR (IIIa) or CH2=CHCOOR (IIIb) wherein R and Y are the same as those deflned above, and Z represents a halogen atom, in a solvent or without a solvent, and in the presence or absence of a base as a acid scaveneer, followed by the step of hydrolysis in a solvent using an acid or a base, if necessary.
In accordance with yet another embodiment, the present invention provides an antihistamlnic and antiallergic agent comprising an effective amount of a piperidine derivative represented ~: by general formula (I).
:~ In accordance with a further embodiment, the present invention provides a pharmaceutical composition for treatment of an allergic disease comprising an effective amount of a compounA represented by general formula (I).
, .
.
.
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The invention also provides a mekhod of treating an allergic disease comprising the step of administering to a mammal an ef~ective amount of a piperidine derivative represented by general formula (I), a pharmacologically acceptable sal~ of the above compound, an antihistaminic and antiallergic agent comprising the same, or a pharmaceutical composi~ion comprising the same.
Further objects, features and advantages of the present invention will become apparent from the Description of the Preferred Embodiments which follows, when read in light of the attached Examples.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention provides ,a piperidine derivative represented by the following general formula (I):
~
X _~CN -Y--C O OR
wherein R represents a hydrogen atom or a lower alkyl group; X
represents -CH=CH-, -CH2CH2-~, or -CH2O-; Y represents an alkylene group having 1 to 5 carbon atoms which may be optionally substituked with a lower alkyl group, or Y represents an -A-O-B- group wherein A
and B are the same or different and each independently represents an alkylene group havine 1 to 3 carbon atoms which may be optionally substituted with a lower alkyl group. The present invention also provides pharmacologically acceptable salts of ~he above compounds.
20~ 4LZ
In addition, the present invention provides a process for preparing the compounds of the general formula (I), and a pharmaceutical composition comprising an effective amount of the same together with a pharmaceutically acceptable carrier or coating.
In the above general formula (I), the lower alkyl group represented by R or the lower alkyl group which may be a substituent of the alkylene group represented by Y, A, or B may be, ~or example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl group.
Preferred examples of the present invention include:
4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidineacetic acid;
4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinepropionic acid;
4-(5H-dibenzo~a,d]cyclohepten-5-ylidene)-1-piperidinebutyric acid;
4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinevaleric acid;
4-(5H dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinecaproic acid;
2-[4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidino]ethoxyacetic acid;
4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidine-acetic acid;
4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidine-propionic acid;
4-(10,11-dihydro-5H-dlbenzo[a,d]cyclohepten-5-ylidene)-1-piperidine-butyric acid;
4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidine-valeric acid;
4-(10,11-dihydro-5H-dibenzo[a,d3cyclohepten-5-ylidene)-1-piperidine-- . .
, 34;~
caproic acid;
2-[4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidino]ethoxyacetic acid;
4-(dibenz[b,e]oxepin-11(6H)-ylidene)-1-piperidineacetic acid;
4-(dibenz[b,e]oxepin-11(6H)-ylidene)-1-piperidinepropionic acid;
4-(dibenz[b,e]oxepin-11(6H)-ylidene)-1-piperidinebutyric acid;
4-(dibenz~b,e]oxepin-11(6H)-ylidene)-1-piperidinevaleric acid;
4-(dibenzo[b,e]oxepin-11(6H)-ylidene)-1-piperidinecaproic acid;
2-[4-(dibenz[b,e]oxepin-11(6H)-ylidene)piperidino]ethoxyacetic acid;
ethyl 4-(5H-dibenzo[~,d]cyclohepten-5-ylidene)-1-piperidine-propionate;
methyl 2-[4-(5~-dibenzo[a,d]cyclohepten-5-ylidene)piperidino]ethoxy-acetate;
ethyl 4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidené)-1-piperidinepropionate;
ethyl 4-(dibenz~b,e~oxepin-11(6H)-ylidene)-1-piperidineacetate;
and methyl 2-[ll~(dlbenz[b,e]oxepin-11(6H)-ylldene)plperidino]ethoxy-acetate.
The compounds of the present invention represented by the above general formula (I) may be converted to pharmacologically acceptable salts, if deslred, and may then be reconverted to produce the free compound from the obtained salts.
The pharmacologlcally acceptable salts of the compounds of the present invention represented by the ~eneral formula (I) may be acid additlon salts or alkali addition salts. Examples of the acid 8~Z
addition salts include mineral acids .such as for example hydrochloride, hydrobromide, sulfate, nitrate, and phosphate, and organic acid salt such as for example acetate, maleate, fumarate, malate, citrate, oxalate, lactate, and tartarate. Examples of the alkali addition salts include metal salts such as for example sodium, potassium, and calcium salt, and or~anic alkali salts such as for example ammonium salts, methylamine, ethylamine, dimethylamine, triethylamine, ethanolamine, piperidine, and piperazine salts.
The compound of the present invention represented by the above general formula (I) may have one or more asymmetric carbon atoms in the molecule, and consequently, optically active isomers and diastereoisomers may exist. These isomers as well as the racemate and the mixture of the diastereoisomers are incorporated within the scope of the present invention.
The novel piperidine derivatives of the present invention represented by the above general formula (I) can be prepared by reacking a piperidine derivative represented by the followin~ general ~ormula (II):
~NH ( II) ~ .
wherein X is the same as that defined above, with a compound represented by Z-Y-COOR tIIIa) or CH2-CHCOOR (IIIb) wherein R and Y are the same as those defined above, and Z represents a halogen atom, in a solvent or without a solvent, and in the presence . ., .
~ . . ..................... ' , . . -or absence of a base as a acid scavenger, follo~l~d by the st~p oP
hydrolysis in a solvent using an acid or a base, if necessary.
Any inert solvent may be used in the alkylation process of the present invention. Examples of the inert solvent include benzene, toluene, tetrahydrofuran, dioxane, acetone, acetonitrile, methanol, ethanol, isopropanol, n-butanol, dime~hyl sulfoxide, and N,N-dimethylformamide.
Examples of the base used in the process of the present invention include potassium carbonate, sodium carbonate, pyridine, and triethylamine. The reaction may be carried out at from 0 to 200 ~C-For the hydrolysis process, an acid such as ~or examplehydrochloric acid or sulfuric acid, or a base such as for example sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, or sodium bicarbonate may be used. A solvent used in the hydrolysis may be, for example, water, methanol, ethanol, acetone, or tetrahydrofuran, and the hydrolysis may be carried out at from 0 to In addition, khe compounds represented by th~ above generalf'ormula (II), used as startin~ materials for the above process, are known compounds disclosed in Journal of Medicinal Chemistry, 8, 829 (1965) and the Japanese Unexamined Patent Publication No. 18478/1975, which can be readily prepared by the following process:
2s X~l\\l-CH, ~ X~{~N_co or ) ~ .
, .
. ' ~ , ' ' ' ~ , , Z0~ 4Z
wherein, X represents the same as that defined above, Zl represents a halogen atom, and R' represents a lower alkyl ~roup.
The novel piperidine compound of the present invention represented by the above general formula (I) and the pharmacologically acceptable salt thereof has an excellent antihistaminic and antia1lergic activity, and thus is quite useful for the treatment o~ an allergic disease, such as, for example, bronchial asthma, allergic rhinitis, dermatosis, and urticaria.
10-~ The piperidine compounds of the present invention and their pharmacologically acceptable;salts may be administered orally or parenterally to a patient as a pharmaceutical composition which comprises an effective amount of said compound or said salt together . .
with a pharmaceutically acceptable carrier or coating.
The pharm~aceutica1 composition suitable ~or oral administration may be, for example, tablet, capsule, powder, subtilized granule, granule, solution, or syrup. The pharmaceutical composition suitable for parenteral administration may be injection, suppository, inhalant, eye drop, nasal drop, ointment, or cataplasm.
The pharmaceutica1ly acceptable carrier or coating used for the preparation o~ the pharmaceutical composition may be excipient, disintegrant or agent for accelerating disintegration, binder, lubricant, coating agent, pigment, diluent, base, solubilizing agent, solubilizer, isotonicity, pH adjusting agent, stabilizer, propellant, ~; 25 and adhesive.
:
~or the preparation of the pharmaceutical composition suitable ::
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. ~ ~ - , ; ~, ,, , .:.: . :
, 20~8S~
for oral administration, dermal administration, or mucosal application, the coatin~ or carrier may comprise the following: an excipient such as for example glucose, lactose, D-mannitol, starch, or crystalline cellulose; a disinte~rant or an agent for accelerating disintegration such as for example carboxymethylcellulose, s~arch, or calcium carboxymethylcellulose; a binder such as for example hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, or gelatin; a lubricant such as for example magnesium steara~e or talc; a coating agent such as for example hydroxypropylmethylcellulose, sucrose, polyethylene glycol, or titanium oxide; a base such as for example petrolatum, liquid paraffin, polyethyleneglycol, gelatin, kaolin, glycerin, purified water, or hard fat; a propellant such as for example fron, diethylether, or compressed gas; an adhesive such as for example sodium polyacrylate, polyvinylalcohol, methylcellulose, polyisobutylene, or polybutene; or a base sheet such as for example cloth or plastic sheet. The pharmaceutical composi~ion suitable ror injection may comprise the following: a solubilizinK agent or a solubilizer, e.g., distilled water for injection, saline, or propylene ~ glycol which is useful for an aqueous composition or a composition for preparing aqueous solution before use, an isotonicity agent such as for example glucose, sodium chloride, D-mannitol, or glycerin; and a pH adjusting aKent such as for example an inorganic or organic acid or an inorganic or organic base.
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The dose of the pharmaceutical composition Or the present invention for an adult patient may generally be from about 1 to 300 mg per day for oral administration, which may be increased or decreased depending on the conditions of the patient to be treated.
The present invention will be further illustrated by the following Examples and Reference Examples. The Examples are given by way of illustration only and are not to be construed as limiting.
EXAMPLE~
The following example shows the excellent effectiveness of the compounds of the present invention. The results of 48 hr homologous passive cutaneous anaphlaxis (PCA) in rats with the monitoring of antiallergic activity; and the results of potentiation of hexobarbital-induced anesthesia in mice with the monitoring of central nervous depressive activity are summarized in Table 1. The reference compound used was cyproheptadine hydrochloride.
1. 48 hr homologous passive cutaneou~ anaphylaxts (PCA) in rat,s _ _ _ _ a) Preparation of DNP-As and rat anti-DNP-As serum Ascaris extract coupled with a 2,4-dinitrophenyl group (DNP-As) was prepared by the method of Koda et al. (Folia pharmacol. japon., 78t 319-334,1981); and anti-DNP-As containing IgE antibody serum was prepared by the method of Tada and Okumura (J. Immunol., 106, 1019-1025, 1971). The PCA titer of the antiserum was estimated to be 1:128 ~.
by 48 hr PCA in rats.
. . .
,, " ~ ' ' ~ ' ' z b) ll8 hr homologous passive cutaneous anaphylaxis (PCA) in rats Male Wistar rats weighing 160 to 200 g were sensitized passively by intradermal injection, in the back, of 0.05 ml of anti-DNP-As serum diluted 21-fold with saline. After 48 hr, the animals (18-20 hr fasted) were given i.v. 0.5 ml of 1% Evans blue solution containin~ 1 mg of UNP-As. After an additional 30 min, the anlmals were killed by stunning and the skins were removed. The intensity of the response was evaluated by assaying the amount of dye leaked according to the method of Katayama et al. (Microbiol. Immunol., 22, 89-101,1978). The percent inhibition of PCA was calculated using the following ~ormula Amount of dye leaked Amount o~ dye leaked Percent with control with test compound lS inhibition = - X 100 Amount of dye leaked with control Test compounds were given orally in a dose Or 1 mg/kg 1 hr prior to challenge with antigen. As a control, 5 ml/kg of vehicle (0.
5 % CMC) alone were given in a similar manner.
The results are shown in Table 1.
2. Potentiation of hexobarbital-induced anesthesia in mice The loss of riBhting reflex induced by hexobarbital was used as an index Or anesthesia. Groups of eight male ddY mice (20-24 hr z~
fasted) weighing l9 to 27 g were treated orally with the test compounds (30 mg/kg) or vehicle. Thirty min. later, 80 mg/kg of hexobarbital sodium were injected i.p. to the animals and the duration of loss of righting reflex was observed. The percent increase of sleeping time was calculated using the following ~ormula:
Sleeping time with _ Sleeping time with Percent ~est compound control increase = x 100 Sleeping time with control The results are listed in Table l.
l5Table 1 .
the percent inhibition the percent incre~se Q~
Test compound o~ PCA in rats hexobarbital~induced (%, l m~/kg, p.o.) anesthesia in mice (~, 30 mg/kg, p.o.) -Example l 71 106 Example 21 91 29 Example 22 81 37 25Example 23 81 51 Example 24 87 75 Example 25 78 80 Example 26 59 22 Example 28 89 83 Example 29 94 45 Example 30 91 53 Example 31 59 36 Example 32 77 15 Example 33 91 3g Example 34 69 31 Example 35 85 76 Example 36 54 34 Example 37 85 49 Example 38 83 41 Example 39 78 80 Reference compound 47 203 _ _ .
The present compounds exhibited more a potent of antiallerKic activlty and less potent of cent,ral nervous depressive activity than the reference compound.
.
Reference l Ethyl 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-l-piperidinecarboxylate A mixture of 33.0 g of 4-(5H-dibenzo[a,d]cyclohepten-5-~.
9~
ylidene)-1-methylpiperidine, 74.9 g of ethyl chlorocarbona~e and 170 ml of toluene was refluxed for 3.5 hrs. After cooling, the reaction mixture was washed with hydrochloric acid and water, and then dried and concentrated. The residue was solidified by treatment with n-hexane to give 37.4 g of pale yellow crystals, which were recrystallized from ethanol to give slightly yellow needles, rnp 123-12~C -Analysis for C23H23N02:
Calculated C, 79.97; H, 6.71; N, 4.05.
Found C, 80.24; H, 6.73; N, 3.95.
The compounds of Reference 2 to 3 were prepared in the same manner as described in Reference 1. .
Reference 2 Ethyl 4-(10,1l-dihydro-5H-dibenzo~a,d}cyclohepten-5-ylidene)-1-piperidine-carboxylate Yellow liquid.
Mass spectrum m/z: 347 (M + ).
IR spectrum v (liq) cm -': 1700 (C00).
NMR spectrum ~ (CDCl3) ppm: 1.25(3H,t,J=7Hz),2.36(4H,t,J=6Hz), 2.60-3.96 (8H,m),4.14(2H,q,J=7Hz),6.97-7.31(8H,m).
.
z~
Re~erence 3 Ethyl 4-(dibenz[b?e]oxepin~11(6H)-ylidene)-1-piperidinecarboxylate Pale yellowish brown liquid.
Mass spectrum m/z: 349 (M ~
IR spectrum ~ (liq) cm -': 1700 (C00).
NMR spectrum ~ (CDCl3) ppm: 1.25(3H,t,J=7Hz),2.20-4.03(8H,m), 4.14(2H,q,J=7Hz),4.77(1H,d,J=12Hz),5.69(1H,d,J=12Hz),6.70-7.50(8H,m).
Reference 4 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine A mixture of 65.6 g of ethyl 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinecarboxylate, 32.0 g o~ potassium hydroxide and 250 ml o~ n-butanol was refluxed for 2hrs and concentrated. Water was added to the residue and extracted with toluene. The toluene layer was washed with water, dried and concentrated to ~ive 53.2 ~ of pale yellow solid, which was recrystallized ~rom methanol to give 47.9 g of colorless needles, mp 145-147 C-Analysis for C20 HlgN
Calculated C, 87.87; H, 7.01; N, 5.12.
Found C, 87.81; H, 7.00; N, 5.07.
;Z0~L8~
The compounds of Reference 5 to 6 were prepared in the same manner as described in Reference 4.
Reference 5 4-(~0,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine hydrochloride Colorless plates, mp ~ 300c (MeOH).
Analysis for C2DH21N HCl:
Calculated C, 77.03; H, 7.11; N, 4.49. -Found C, 77.00; H, 7.12; N, 4.47.
- ..
Reference 6 4-(Dibenz[b,eJoxepin-11t6H)-ylidene)piperidine hydrochlorlde Colorless prisms, mp > 300~C (E~O~).
Analysis Por C, D H1 9 NO HCl:
Calculated C, 72.72; H, 6.42; N, 4.46.
Found C, 72.72; H, 6.51; N, 4.27 Example 1 Ethyl 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)~1-piperidinepropionate hydrochloride Z~l~L8~2 A mixture of 3.01 B of 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene~piperidine, 2.20 g of ethyl 3-bromopropionate, 1.52 e of potassium carbonate and 20 ml of N,N-dimethylformamide was stirred at 80C for 4 hrs. After cooling, water was added to the reaction mixture and then extracted with ether. The extract was washed with water, dried and concentrated to give 4.40 g of brown liquid, which was converted to the hydrochloride in the usual manner to give 4.20 g of colorless crystals. The crude hydrochloride was recrystallized from a mixture of acetone and ether to give colorless needles, mp 151-152 C-Analysis for C2sH27N02 HCl ~ H20:
Calculated C, 70.16; H, 7.07; N, 3.27.
Found C7 70.26; H, 6.99; N, 3.01.
Example 2 Methyl 2-[ll-(5tl-dibenzo~a,d~cyclohepten-5-ylidene)piperidino~ethoxy-____ _._ acetate fumarate A mixture of 3.01 g of 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine, 2.90 g of methyl 2-chloroethoxyacetate, 2.43 g of potassium carbonate and 20 ml of N,N-dimethylformamide was stirred at 80 C for 22 hrs. After cooling, water was added to the reaction mixture and then extracted with ether. The e~her layer was extracted .
.
, with aq. hydrochloric acid. The aqueous layer was made alkaline with potassium carbonate and extracted with ether. The ether layer was washed with water, dried and concentrated to give 3.16 g of yellowish brown liquid, which was converted to the fumarate in the usual manner and then recrystallized from ethanol to give pale yellow needles, mp Analysis for C2 5 H 2 7 N03 C4H404:Calculated C, 68.90; H, 6.18; N, 2.77.
Found C, 68.76; H, 6.22; N, 2.68.
Example 3 Ethyl 4-(10,11-dihydro-5H-dibenzo[a,d~cyclohepten-5-ylidene)-1-piperidinebutyrate hydrochloride A mixturè of 3.00 g of 4-tlO,ll-dihYdro~5H-dib enzo~a,d]cyclohepten-5-ylidene)piperidine, 2.3ll 8 of ethyl ll-bromobutyra~e, 1.51 g of` potassium carbonate and 1~ ml of N,N-dimethylformamide was stirred at 70c for 3 hrs. After coolin~,water was added to the reaction mixture and then extracted with ether.
The ether layer was washed with water, dried and concentrated ~o give pale brown solid, which was converted to the hydrochloride in the usual manner to give 3.88 g of colorless solid. The crude hydrochloride was recrystallized from a mixture of acetone and ether to give colorless crystals, mp 182-184C-, .
ZQ~
Analysis for C26H3,N02 o HCl:Calculated C, 73.31; H, 7.57; N, 3.29.
Found C, 73.27; H, 7.70; N, 3.33.
Example 4 Ethyl 4-(dibenz[b,e]oxepin-11(6H)-ylidene)-1-piperidinepropionate -, .
A mixture of 3.61 g of 4-(dibenz[b9e]0xepin-11(6H)-ylidene)-piperidine, 2.60 g of ethyl 3-bromopropionate, 1.80 g of potassium carbonate and 25 ml of N,N-dimethylformamide was stirred at 80 C for 2 hrs. After cooling, water was added to the reaction mixture and extracted with ether. The ether layer was washed with water and e~tracted with hydrochloric acid. The aqueous layer was made alkaline with potassium carbonate and extracted with ether. The ether layer was washed with water, dried and concentrated to give L,.20 g of yellowish brown liqui~, which was puri~ied by column chromatography on silica gel (eluent: chloroform) to give 3.90 g o~
pale yellow liquid.
Mass spectrum m/z: 377 (M + ).
IR spectrum ~ (liq) cm -': 1734 (C00).
NMR spectrum ~ (CDCl3) ppm: 1.25(3H,t,J=7Hz),1.92-2.94(12H,m), 4.13(2H,q,J=7Hz),4.76(1H,d,J=12Hz),5.72(1H,d,J=12Hz),6.66-7.48(8H,m).
2 l , ~ .' -, .~n~ z Example 5 Ethyl 4-(dibenz[b,e]oxepin-11(6H)-ylidene)-1-piperidinevalerate hydrochloride A mixture of 3.61 g of 4-(dibenz[b,e]oxepin-11(6H)-ylidene)-piperidine, 3.00 g of ethyl 5-bromovalerate, 1.~0 g of potassium carbonate and 25 ml of:N,N-dimethylformamide was stirred at 80 C for 2 hrs. After cooling, water was added to the reaction mixture and extracted with ether. The ether layer was washed with water, dried and concentrated to give 5.40~g of brown liquid, which was converted to the hydrochloride in the usual manner to give 4.76 g o~ colorless crystals. The crude hydrochloride was recrystallized from ethanol to give colorless needles, mp 228-230 C-Analysis ~or C26H3,N03 HCl: .
Calculated C, 70.65; H, 7.30; N, 3.17.
Found . C, 70.76; H, 7.05; N, 3.22.
The c~mpounds of Example 6 to l9 were prepared in the same manner as described in Example 1 to 5.
Example 6 .
Ethyl 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-l-piperidineacetate 4~
Pale bro~1n liquid.
Mass spectrum m/z: 359 (M ' ).
IR spectrum ~ (liq) cm -l: 1746 (COO).
NMR spectrum ~ ~CDCl3) ppm: 1.24(3H,t7J=7Hz),1.98-2.92(8H,m), 3.17(2H,s),4.16(2H,q,J=7Hz),6.91(2H,s),7.08-7.46(8H,m).
Example 7 Ethyl 4-(5H-dibenzo~a,d]cyclohepten-5-ylidene)- ~ -methyl-1-piperidineacetate hydrochloride .. _ _ . . . _ . ....
Pale bro~n pillars, mp 190-191G (EtOH-Et20).
Analysis for C2sH27NO2- HCl:
Calculated C, 73.25; H, 6.88; N, 3.42.
Found C, 73.10; H, 6.81; N, 3.31.
Example 8 Ethyl ll~(5H-dibenzo~a~d]cyclohept~n-5-ylidene)-l-piperidinebutyrate _. _ Yellowish hrown liquid.
Mass spectrum m/z: 387 (M + ).
IR spectrum ~ (liq) cm ~': 1734 (cooj.
NMR spectrum ~ (CDCl3) ppm: 1.23(3H,t,J=7Hz),1.56-2.80(14H7m), 4.10(2H,q,J=7Hz),6.90(2H,s),7.10-7.45(8H,m).
. ~ .
. . :, ,,:
, ~8~
Example 9 _ Ethyl 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)~1-piperidinevalerate hydrochloride Pale yellow prisms, mp 185.5-186.5C (EtOH-Et20).
Analysis for C2,H31NO2- HCl:
Calculated C, 74.04; H, 7.36; N, 3.20.
Found C, 74.04; H, 7.22; N, 3.14.
Example 10 Methyl 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinecaproate _ hydrochloride ; Colorless pillars, mp 200-201 C (EtOH).
Analysis for Cz7H31NOz- HC1:
Calculated C, 711.04; H, 7.36; N, 3.20.
Found C, 73.~2; H, 'l.ll2; N, 3.10.
Example 11 Ethyl 4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piPeridineacetate hydrochloride Colorless crystals, mp 173-175C (MezCO).
2 ~
2~9~Z
Analysis for C24H27NOz- HCl:
Calculated C, 72. 44; H, 7.09; N, 3.52.
Found C, 72.23; H, 7.17; N, 3.45.
Example 12 Ethyl 4-(10,11-dihydro-5H-dibenzo~a,d~cyclohepten-5-ylidene)-1-_ piperidinepropionate hydrochloride Colorless needles, mp 198-202 C (EtOH-Et20).
Analysis for C2sH2~NO2- HCl l/4 H20:
Calculated C, 72.10; H, 7.38; N, 3.36.
Found C, 72.04; H, 7.25; N, 3.33.
Example 13 Ethyl 4~(10,11-dih ~ ]cyclohepken 5-ylidene)~
piperidinevalerate hydrochloride Colorless crystals, mp 183.5-185C (Me2CO-Et20).
Analysis for C27H33NO2~ HCl: ~
Calculated C, 73.70; H, 7.79; N, 3.18.
Found C, 73.40; H, 7.75; N, 3.22.
.
~ , , . ., j . ., ~ .
- ., ~, Example 14 Methyl 2-[4-(10,11-dihydro-5H-dibenzo[a,d]cyclohep_en-5-ylidene)-piperidino]ethoxyacetate Yellow liquid.
Mass spectrum m/z: 391 (M t ).
IR spectrum ~ (liq) cm -': 1758 (COO).
NMR spectrum ~ (CDCl3) ppm: 2.04-3.54(12H,m),2.63(2H,t,J=5.5Hz), 3.68(2H,t,J=5.5Hz),3.73(3H,s),4.12(2H,s),6.98-7.22~8H,m).
Example 15 . .
Ethyl 4-(dibenz[b,e]oxepin-11(6H)-ylidene)-1-piperidineaceta~e hydrochloride Colorless needles, mp 153-154 C (EtOH-Et20).
Analysis for C23HzsNO3- HCl 1/2 HzO:
Calculated C, 67.56; H, 6.66; N, 3.43.
Found C, 67.61; H, 6.119; N, 3 115.
Example 16 Ethyl 4-(dibenz[b,e}oxepin-11(6Hj-ylidene)-1-piperidinebutyrate hydrochloride 39~;~
Colorless needles, mp 242-2llll C (EtOH).
Analysis for C 2 5 H29NO3- HCl:
Calculated C, 70.16; H, 7.07; N, 3.27.
Found C, 70 08; H, 7.04; N, 3.16.
Example 17 Methyl 2-[4-(dibenz[b,e]oxepin-11(6H)-ylidene)piperidino]ethoxyacetate Pale yellow liquid.
Mass spectrum m/z: 3g3 (M + ).
IR spectrum ~ (liq) cm ~': 1756 (COO).
NMR spectrum ~ (CDCl3) ppm: 2.00-3.00(10H,m),3.68(2H,t,J=5.5Hz~, 3.73~3H,s),4.11(2H,s),4.76(1H,djJ-12Hz),5.72(1H,d,J=12Hz)96.64-7~46(8H, m)-Example 18 Methyl 4-(10,11-dihydro-5H-dibenzo[a,d~cyclohepten-5-ylidene)-1-piperidinecaproate hydrochloride Colorless needles, mp 188-190 C (Me2CO). ?
Analysis for C27H33NO2^ HCl:
Calculated C, 73.70; H, 7.79; N, 3.18.
Found C, 73.47; H, 7.74; N, 3.14.
~ ~.
4;2 Example 19 Methyl_4-(dibenz[b,e]oxepin-11(6H)-ylidene)-1-piperidinecaproate hydrochloride .
Colorless needles, mp 214-217 C (Me2C0).
Analysis for C2ôH31N03- HCl:
Calculated C, 70.65; H, 7.30; N, 3.17.
Found C, 70.61; H, 7.41, N, 3.31.
Example 20 Ethyl 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinepropionate A mixture of 4.00 g of 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine, 2.1 ml of ethyl acrylate and 20 ml of ethanol was refluxed for 1 hr and concentrated to give 5.35 g of colorless liquid The liquid was puri~ied by column chromatography on silica eel (eluen~: chloroform) to give 5.30 e of colorless solid, ~hich was recrystallized from n-hexane to give colorless crystals, mp 66-67 C-Analysis for C25H27N02:
Calculated C, 80.40; H, 7.29; N, 3.75.
Found C, 80.35; H, 7.39; N, 3.77.
Example 21 4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinepropionic acid _. .
A mixture of 5.30 ~ of ethyl 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-l-piperidinepropionate hydrochloride, 19.3 ml of 2N sodium hydroxide aqueous solution and 30ml of methanol was refluxed for 1 hr and concentrated. Water was added to the residue, washed with ethyl acetate and adjusted to pH 4 to 5 with 10% hydrochloric acid. The precipitate was collected by filtration to give 4.47 g of pale yellow crystals, which were recrystallized from a mixture of water and N,N-dimethylformamide to give 4.23 g of pale yellow needles, mp 201-203 C.
Analysis ~or C2 3 H23N02- 2H20:
Calculated C, 72.42; H, 7.13; N, 3.67.
Found C, 72.23; H, 6.94; N, 3.67.
Example 22 2-~4-(5H-Dibenzo~a,d]cyclohepten-5~ylidene)piperidino~ethoxyacetic acid hydrochlor~de A mixture of 2.56 g of methyl 2-[4-~5H-dibenzo-[a,d]cyclohepten-5-ylidene)piperidino]ethoxyacetate, 6.6 ml of 2N
sodium hydroxide aqueous solution and 25 ml of methanol was refluxed for 1 hr and concentrated. Water was added to the residue, adjusted to pH 2 with 10 % hydrochloric acid and extracted with chloroform.
, , ., , ' ~ ' .' '.' 201~3~4;ë:
The chloroform layer was washed with water, dried and concentrated to give yellowish brown liquid, which was solidified with a mixture of chloroform and ether to give 2.70 g of pale yellow amorphous solid, mp s Analysis for C24H25N03 HCl H20.
Calculated C, 67005; H, 6.56; N, 3.26.
Found C, 66.99; H, 6.37; N, 3.04.
Example 23 4-(10,11-Dihydro-5H-dibenzo~a,d]cyclohepten-5-ylidene)-1-piperidine-butyric acid hydrochloride A mixture of 3.31 g of ethyl 4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinebutyrate hydrochloride, 11.7 ml of 2N sodium hydroxide aqueous solution and 35 ml of methanol was refluxed for 1 hr and concentrated. Water was added to the resldu~, adjusted to pH 1 with lO % hydrochloric acid. The precipitate was collected by filtlation to give 2.97 g of brown solid, which was recrystallized from a mixture of ethanol and ether to give 2.48 6 of colorless needles~ mp 211.5-214.5 C-Analysis for C24H27N02 HCl :
Calculated C, 72.44; H1 7.09; N, 3.52.
Found C, 72.26; H, 7.04; N, 3.50.
Z4~
Example 24 4-(Dibenz[b,e]oxepin-11(6H)-ylidene)-1-piperidinepropionic acid A mixture of 3.70 g of ethyl 4-(dibenz[b,e]oxepin-11(6H)-ylidene)-1-piperidinepropionate, 9.9 ml of 2N sodium hydroxide aqueous solution and 40ml of methanol was refluxed for 30 min and concentrated. Water was added to the residue, adjusted to pH 3 with 10% hydrochloric acid. The precipitate was collected by filtration and washed with water and ether to give 3.30 g of pale yellow crystals, which were recrystallized from a mixture of water and N,N-dimethyl~ormamide to give 2.75 g of pale yellow crystals, mp 142-143 C .
: 15 Anàlysis for C22H23N03- 2HzO:
Calculated C, 68.55; H, 7.06; N, 3.63.
Found C, 68.8~; H, 6.97; N, 3.62.
Example 25 4 (Dibenz~b,e]oxepin-11(6H)-ylidene)-l-piperidinevaleric acid hydrochloride :: :
A mixture of 4.20 g Or ethyl 4-(dibenz[b,e]oxep1n-11(6H~-ylidene)-l-piperidinevalerate hydrochloride, 14.5 ml of 2N sodium .
- 3 1 - ; ~
- .,. ' ' ' ! ' . ' ' ' ''' ' , ',.'', ' . ' ' ~ ' ~
hydroxide aqueous solution and 40 ml o~ rnethanol wa~ re~luxed for 1 hr and concentrated. Water was added to the residue, adjusted to pH
2 with 10% hydrochloric acid. The precipitate was collected by filtration and washed with water and ether to give 3.92 g of colorless crystals, which were recrystallized from water to give 3 08 g o~
colorless prisms, mp 304-306C(dec.).
Analysis ~or C24H27NO3- HCl:
Calculated C, 69.64; H, 6.82; N, 3.38.
Found C, 69.86; H, 6~62; N, 3.53.
The compounds of Example 26 to 39 were prepared in the same manner as described in Example 21 to 25.:
Example 26 ., 4-(5H-Dibenzo~a,d]cyclohepten-5-ylidene)-1-piperidineacetic acid -hydrochloride Pale brown needles, mp 162-165 C (EtOH-Et20).
Analysis ~or C22H2,NO2 HCl 1/2H20:
Calculated C, 70.11; H 3 6.15; N, 3.72.
Found C, 70.29; H, 6.23; N, 3.51.
Example 27 , .
4;~:
11-(5H-Dibenzo~a~d]cyclohept,en-5~ylidene)- a -m0thyl-l-piperidineacetic acid Pale brown pillars, mp 184-186C (MeOH-Et20).
Analysis for C23H23NO2- H20:
Calculated C, 76.01; H, 6.93; N, 3.85.
Found C, 76.11; H, 7.03; N, 3.87.
Example 28 .,.
4-(5H-Dibenzo[a,d]cyclohepten-S~ylidene)-l~piperidinebutyric acid hydrochloride Pale yellpw prisms, mp 237-239C (H20).
lS Analysis for C24H2sNO2- HCl ~1/2 H20:
Calculated C, 71.19; H, 6.72; N,~3.46.
Found C, 71.46; H, 6.82; N, 3.37.
Example 29 4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinevaleric acid hydrochloride;
Pale brown needles, mp 229-230C (EtOH~Et20).
Analysis for C~sH27N02 HCl: ;
Calculated C, 73.25; H, 6.88; N, 3.42.
.
~- 3 3 -,. ., ,,~ . . .
. . .
- : , ~n~4z Found C, 73.25; H, 6.84; N, 3.30.
Example 30 4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinecaproic acid hydrochloride Pale brown prisms, mp 213-21ll C (EtOH-Et20).
Analysis for C25H29NO2 HCl:
Calculated C, 73.66; H, 7.13; N, 3.30.
Found C, 73.37; H, 7.25; N, 3.26.
Example 31 4-(10,11-Dihydro-5H-dibenzo~a,d]cyclohepten-5-ylidene)-1-piperidineacetic acid hydrocKloride Colorless crys~als, mp 237.5-239C(dec.) (EtOH-Et20~.
Analysis ~or Cz2H23NO2~ HCl:
Calculated C, 71~ll4; H, 6.5LI; N, 3.79.
Found C, 71.17; H, 6.81; N, 3 80.
Example 32 4-(10,11-Dihydro-SH-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidine-propionic acid ;Z~18~
Colorless needles, mp 189-l91 C (DMF-H20).
Analysis for C23H2sN02-5/2 H20:
Calculated C, 70.38; H, 7.70; N, 3.57.
Found C, 70.70; H, 7.40; N, 3.63.
Example 33 4-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidine-valeric acid hydrochloride Colorless needles, mp 204-206 C (H20).
Analysis for C25H29N02- HCl l/4 H20:
Calculated C, 72.10; H, 7.38; N, 3.36.
lS Found C, 72.20; H, 7.19; N, 3.33.
. .
Example 34 2-~4--(10,11-Dihydro-5H-dibenzo~a,d]cyclohepten-5-ylidene)piperidino~-ethoxyacetic acid Colorless needles, mp 167.5-169 C (H20).
~;; Mass spectrum m/z:~ 377 (M t ).
IR spectrum ~ (KBr) cm -': 1590 (C00 - ) NMR spectrum ~ (DMS0-d6) ppm: 2.24-3.04(12H,m),3.14-3.56(2H.m), 3.65(2H,t,J=5.5Hz)~3.89(2H,s),6.96-7.28(8H9m).
-"
2~
Example 35 -4-(Dibenz[b,e]oxepin-11(6H)-ylidene)-l-piperidinebutyric acid -hydrochloride Colorless needles, mp 244-245 C (HzO).
Analysis for C23H25N03~ HCl:
Calculated C, 69.08; H, 6.55; N, 3.50.
Found C, 69.09; H, 6.50; N, 3.42.
Example 36 . .
2-[4-(Dibenz[b,e]oxepin-11(6H)-ylidene)piperidino~ethoxyacetic acid _ hydrochloride -Pale yellow crystals, mp 223~224C (MeOH~Me2C0).
Analysis for Cz 3 Hz 5 NOI, HCl:
Calculated C, 66.42; H, 6.30; N, 3.37.
Found C, 66.25; H, 6.30; N, 3.41.
Example 37 :
4-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidine-caproic acid hydrochloride .
.
, ~ z Colorless needles, mp 215-219 C ( EtOH).
Analysis for C26H31NOz- HCl:
Calculated C, 73.31; H, 7.57; N, 3.29.
Found C, 73.32; H, 7.70; N, 3.38.
Example 38 4-(Dibenz[b,e]oxepin-11(6H)-ylidene)-1-piperidineacetic acid Colorless crystals, mp 132-135C (H20).
Analysis for C2lH2~NO3-2H20:
Calculated C, 67.91; H, 6.78; N, 3.77.
Found C, 67.76; H, 6.58; N, 3.68.
. . . , ' .
Example 39 , 4-(Dibenz~b,e]oxepin-11(6H)-ylidene)-l-piperidinecaproic acid hydrochloride Colorless crystals, mp 228-231C (E~Oi-l-Et20).
Analysis for C2sH29NO3- HCl:
Calculated C, 70.16; H, 7.07; N, 3.27.
Found C, 70.12; H, 7.15; N, 3.26.
Example 40 , ;
zo~
4-(5H-DibenzoEa,d]cyclohepten-5-ylidene)-1-piperidinepropionic acid _ A mixture of 146 g of 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-piperidine, 73.0 g of ethyl acrylate and 500 ml of methanol was refluxed for 1 hr and then 675 ml of 2N sodium hydroxide aqueous solution was added to the reaction mixture. The reaction mixture was refluxed for 1 hr and concentrated. Water was added to the residue and adjusted to pH 4 with hydrochloric acid. The precipitate was collected by filtration to give 200 g of colorless crystals, which were recrystallized from a mixture of water and N,N-dimethylformamide to give 198 g of colorless crystals. This compound was identified by comparing its mp, IR spectrum and NMR spectrum with those of the compound of Example 21.
Example 4?
Tablets of a pharmaceutical preparation according ko the present invention are prepared in the usual manner using the following constituent~:
Compound of the present invention 10 mg Lactose q.s.
Corn starch 34 mg Magnesium stearate 2 mB
Hydroxypropylmethylcellulose 8 mg Polyethyleneglycol 6000 0.5 mg - 3 8 ~
2~
Titanium oxide 0.5 mg 120 mB
Example 42 Capsules of a pharmaceutical preparation according to the present invention are prepared in the usual manner using the following constituents:
Compound of the present lnvention 10 mg Lactose ~ ~ q.s.
Calcium carboxymethylcellulose 15 mg Hydroxypropylcellulose 2 mg Magnesium stearate 2 mg 100 m~
Example Ll3 Powders of a pharmaceutical preparation according to the present invention are prepared in the usual manner using the ~: following constituents:
Compound of the present invention 20 mg Lactose q.s.
zn~
D-Mannitol 500 mg Hydroxypropylcellulose 5 mg Talc 2 mg .
lOOO mg Example 44 Injections of a pharmaceutical preparation according to the present invention are prepared in the usual manner using the following constituents:
Compound of the present invention l mg Glucose 50 mg Hydrochloric acid q~s.
Distilled water for~in~ectionq.s.
2 ml Example 45 Suppositories of a pharmaceutical preparation according to the present invention are prepared in the usual manner using the following constituents:
Compound o~ the present invention 5 m~
:
, 94~ ~
Hard fat 1295 mg 1300 mg Example 46 Plasters of a pharmaceutical preparation according to the present invention are prepared in the usual manner using the following constituents:
1~
Compound of the present invention 10 mg Gelatin llO0 mg Polyvinylalcohol 250 mg Methylcellulose 100 mg Glycerin 1500 mg ;~ Kaolin .850 mg Sodlum polyacrylate 50 mg Polybutene 150 mg Purified water 990 mg - -5000 mg :.
,. . . ~ ~ - , .
,. ~ ` ' . ' - - . - . :
.
20~39~;2 has been developed as an antihistaminic agent and is widely used clinically for the treatment of such ailments as allergic rhinitis and dermatosis.
However, this class of compounds those havin~ a carboxyl or a lower alkoxycarbonyl group in the substituent at the l-position of the piperidine ring have never been known to date.
A large number of antihistaminic agents have been developed so far and are used for the treatment of, for example, allergic dermatosis or rhinitis. However, adverse reactions of a central inhibltory action caused by the administration of the known antihistaminic agents such as sleepiness or sedation are found to be a great problem with these known agents. In addi~ion, an anti-cholinergic action which is considered to be one of the possible reasons for hydrodips1a or mydriasis i5 another undesired adverse reaction of the antihistaminic agents. Various kinds of research have been conducted to solve the above problems, however, presently avallable antihistaminic agents are insu~icient from a clinical point o~ view.
SUMMARY OF THE INVENTION
An object o~ ~he present invention is to provide novel compounds having an excellent antihistaminic activity as well as excellent antiallergic activity.
~5 Another object of the present invention is to provide novel compounds which extensively eliminate undesired adverse reactions such ;
.
~o~
as a central inhibitory action when administered ~or the treatrnent Or such ailments as bronchial asthma, allergic rhinitis, dermatosis and urticaria.
A further object of the present invention is to provide a method for preparation of the above novel compounds. Yet another object is to provide a pharmaceuti~al composition comprising the novel compounds which is useful for the treatment o~ such ailments as bronchial asthma, allergic rhinitis, dermatosis and urticaria.
The inventors of the present invention have conducted various studies to achieve the foregoing objects and found that the objects can be effectively attained by providing novel piperidine derivatives of the present invention. These derivatives have potent antihistaminic and antiallergic activity and induce few adverse reactions such as central inhibition.
In accordance with the above objects, the present invention provides a piperidine derivative represented by the following general formula (I): ~
COOR
~ (I) wherein R represen~s a hydrogen atom or a lower alkyl group; X
represents ~CH=CH-, -CH2CH2~, or ~CH20-; Y represents an alkylene group having 1 to 5 carbon atoms which may be optionally substituted with a lower alkyl group, or Y represents an -A-0-B- group wherein A
and B are the same or di~erent and each independently represents an .
~)18~
alkylene group having l to 3 carbon a~orns which may be optionally substituted with a lower alkyl group, and pharmacologically acceptable salts of the above compounds.
In accordance with another embodiment of the present invention, the present invention provides a process for preparing a piperidine derivative represented by the general formula (I). The process comprises the steps of reacting a piperidine derivative represented by the following general formula (II):
~3 ~ /~
X ~ NH
~ \ -wherein X is the same as that defined above, with a compound represented by Z-Y-COOR (IIIa) or CH2=CHCOOR (IIIb) wherein R and Y are the same as those deflned above, and Z represents a halogen atom, in a solvent or without a solvent, and in the presence or absence of a base as a acid scaveneer, followed by the step of hydrolysis in a solvent using an acid or a base, if necessary.
In accordance with yet another embodiment, the present invention provides an antihistamlnic and antiallergic agent comprising an effective amount of a piperidine derivative represented ~: by general formula (I).
:~ In accordance with a further embodiment, the present invention provides a pharmaceutical composition for treatment of an allergic disease comprising an effective amount of a compounA represented by general formula (I).
, .
.
.
. ~ ` . ., ,,, ; :.
~()3L~94~
The invention also provides a mekhod of treating an allergic disease comprising the step of administering to a mammal an ef~ective amount of a piperidine derivative represented by general formula (I), a pharmacologically acceptable sal~ of the above compound, an antihistaminic and antiallergic agent comprising the same, or a pharmaceutical composi~ion comprising the same.
Further objects, features and advantages of the present invention will become apparent from the Description of the Preferred Embodiments which follows, when read in light of the attached Examples.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention provides ,a piperidine derivative represented by the following general formula (I):
~
X _~CN -Y--C O OR
wherein R represents a hydrogen atom or a lower alkyl group; X
represents -CH=CH-, -CH2CH2-~, or -CH2O-; Y represents an alkylene group having 1 to 5 carbon atoms which may be optionally substituked with a lower alkyl group, or Y represents an -A-O-B- group wherein A
and B are the same or different and each independently represents an alkylene group havine 1 to 3 carbon atoms which may be optionally substituted with a lower alkyl group. The present invention also provides pharmacologically acceptable salts of ~he above compounds.
20~ 4LZ
In addition, the present invention provides a process for preparing the compounds of the general formula (I), and a pharmaceutical composition comprising an effective amount of the same together with a pharmaceutically acceptable carrier or coating.
In the above general formula (I), the lower alkyl group represented by R or the lower alkyl group which may be a substituent of the alkylene group represented by Y, A, or B may be, ~or example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl group.
Preferred examples of the present invention include:
4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidineacetic acid;
4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinepropionic acid;
4-(5H-dibenzo~a,d]cyclohepten-5-ylidene)-1-piperidinebutyric acid;
4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinevaleric acid;
4-(5H dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinecaproic acid;
2-[4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidino]ethoxyacetic acid;
4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidine-acetic acid;
4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidine-propionic acid;
4-(10,11-dihydro-5H-dlbenzo[a,d]cyclohepten-5-ylidene)-1-piperidine-butyric acid;
4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidine-valeric acid;
4-(10,11-dihydro-5H-dibenzo[a,d3cyclohepten-5-ylidene)-1-piperidine-- . .
, 34;~
caproic acid;
2-[4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidino]ethoxyacetic acid;
4-(dibenz[b,e]oxepin-11(6H)-ylidene)-1-piperidineacetic acid;
4-(dibenz[b,e]oxepin-11(6H)-ylidene)-1-piperidinepropionic acid;
4-(dibenz[b,e]oxepin-11(6H)-ylidene)-1-piperidinebutyric acid;
4-(dibenz~b,e]oxepin-11(6H)-ylidene)-1-piperidinevaleric acid;
4-(dibenzo[b,e]oxepin-11(6H)-ylidene)-1-piperidinecaproic acid;
2-[4-(dibenz[b,e]oxepin-11(6H)-ylidene)piperidino]ethoxyacetic acid;
ethyl 4-(5H-dibenzo[~,d]cyclohepten-5-ylidene)-1-piperidine-propionate;
methyl 2-[4-(5~-dibenzo[a,d]cyclohepten-5-ylidene)piperidino]ethoxy-acetate;
ethyl 4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidené)-1-piperidinepropionate;
ethyl 4-(dibenz~b,e~oxepin-11(6H)-ylidene)-1-piperidineacetate;
and methyl 2-[ll~(dlbenz[b,e]oxepin-11(6H)-ylldene)plperidino]ethoxy-acetate.
The compounds of the present invention represented by the above general formula (I) may be converted to pharmacologically acceptable salts, if deslred, and may then be reconverted to produce the free compound from the obtained salts.
The pharmacologlcally acceptable salts of the compounds of the present invention represented by the ~eneral formula (I) may be acid additlon salts or alkali addition salts. Examples of the acid 8~Z
addition salts include mineral acids .such as for example hydrochloride, hydrobromide, sulfate, nitrate, and phosphate, and organic acid salt such as for example acetate, maleate, fumarate, malate, citrate, oxalate, lactate, and tartarate. Examples of the alkali addition salts include metal salts such as for example sodium, potassium, and calcium salt, and or~anic alkali salts such as for example ammonium salts, methylamine, ethylamine, dimethylamine, triethylamine, ethanolamine, piperidine, and piperazine salts.
The compound of the present invention represented by the above general formula (I) may have one or more asymmetric carbon atoms in the molecule, and consequently, optically active isomers and diastereoisomers may exist. These isomers as well as the racemate and the mixture of the diastereoisomers are incorporated within the scope of the present invention.
The novel piperidine derivatives of the present invention represented by the above general formula (I) can be prepared by reacking a piperidine derivative represented by the followin~ general ~ormula (II):
~NH ( II) ~ .
wherein X is the same as that defined above, with a compound represented by Z-Y-COOR tIIIa) or CH2-CHCOOR (IIIb) wherein R and Y are the same as those defined above, and Z represents a halogen atom, in a solvent or without a solvent, and in the presence . ., .
~ . . ..................... ' , . . -or absence of a base as a acid scavenger, follo~l~d by the st~p oP
hydrolysis in a solvent using an acid or a base, if necessary.
Any inert solvent may be used in the alkylation process of the present invention. Examples of the inert solvent include benzene, toluene, tetrahydrofuran, dioxane, acetone, acetonitrile, methanol, ethanol, isopropanol, n-butanol, dime~hyl sulfoxide, and N,N-dimethylformamide.
Examples of the base used in the process of the present invention include potassium carbonate, sodium carbonate, pyridine, and triethylamine. The reaction may be carried out at from 0 to 200 ~C-For the hydrolysis process, an acid such as ~or examplehydrochloric acid or sulfuric acid, or a base such as for example sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, or sodium bicarbonate may be used. A solvent used in the hydrolysis may be, for example, water, methanol, ethanol, acetone, or tetrahydrofuran, and the hydrolysis may be carried out at from 0 to In addition, khe compounds represented by th~ above generalf'ormula (II), used as startin~ materials for the above process, are known compounds disclosed in Journal of Medicinal Chemistry, 8, 829 (1965) and the Japanese Unexamined Patent Publication No. 18478/1975, which can be readily prepared by the following process:
2s X~l\\l-CH, ~ X~{~N_co or ) ~ .
, .
. ' ~ , ' ' ' ~ , , Z0~ 4Z
wherein, X represents the same as that defined above, Zl represents a halogen atom, and R' represents a lower alkyl ~roup.
The novel piperidine compound of the present invention represented by the above general formula (I) and the pharmacologically acceptable salt thereof has an excellent antihistaminic and antia1lergic activity, and thus is quite useful for the treatment o~ an allergic disease, such as, for example, bronchial asthma, allergic rhinitis, dermatosis, and urticaria.
10-~ The piperidine compounds of the present invention and their pharmacologically acceptable;salts may be administered orally or parenterally to a patient as a pharmaceutical composition which comprises an effective amount of said compound or said salt together . .
with a pharmaceutically acceptable carrier or coating.
The pharm~aceutica1 composition suitable ~or oral administration may be, for example, tablet, capsule, powder, subtilized granule, granule, solution, or syrup. The pharmaceutical composition suitable for parenteral administration may be injection, suppository, inhalant, eye drop, nasal drop, ointment, or cataplasm.
The pharmaceutica1ly acceptable carrier or coating used for the preparation o~ the pharmaceutical composition may be excipient, disintegrant or agent for accelerating disintegration, binder, lubricant, coating agent, pigment, diluent, base, solubilizing agent, solubilizer, isotonicity, pH adjusting agent, stabilizer, propellant, ~; 25 and adhesive.
:
~or the preparation of the pharmaceutical composition suitable ::
: ~ , :: :
" . , - , ~; , :. ~ - .
. ~ ~ - , ; ~, ,, , .:.: . :
, 20~8S~
for oral administration, dermal administration, or mucosal application, the coatin~ or carrier may comprise the following: an excipient such as for example glucose, lactose, D-mannitol, starch, or crystalline cellulose; a disinte~rant or an agent for accelerating disintegration such as for example carboxymethylcellulose, s~arch, or calcium carboxymethylcellulose; a binder such as for example hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, or gelatin; a lubricant such as for example magnesium steara~e or talc; a coating agent such as for example hydroxypropylmethylcellulose, sucrose, polyethylene glycol, or titanium oxide; a base such as for example petrolatum, liquid paraffin, polyethyleneglycol, gelatin, kaolin, glycerin, purified water, or hard fat; a propellant such as for example fron, diethylether, or compressed gas; an adhesive such as for example sodium polyacrylate, polyvinylalcohol, methylcellulose, polyisobutylene, or polybutene; or a base sheet such as for example cloth or plastic sheet. The pharmaceutical composi~ion suitable ror injection may comprise the following: a solubilizinK agent or a solubilizer, e.g., distilled water for injection, saline, or propylene ~ glycol which is useful for an aqueous composition or a composition for preparing aqueous solution before use, an isotonicity agent such as for example glucose, sodium chloride, D-mannitol, or glycerin; and a pH adjusting aKent such as for example an inorganic or organic acid or an inorganic or organic base.
. .
z~
The dose of the pharmaceutical composition Or the present invention for an adult patient may generally be from about 1 to 300 mg per day for oral administration, which may be increased or decreased depending on the conditions of the patient to be treated.
The present invention will be further illustrated by the following Examples and Reference Examples. The Examples are given by way of illustration only and are not to be construed as limiting.
EXAMPLE~
The following example shows the excellent effectiveness of the compounds of the present invention. The results of 48 hr homologous passive cutaneous anaphlaxis (PCA) in rats with the monitoring of antiallergic activity; and the results of potentiation of hexobarbital-induced anesthesia in mice with the monitoring of central nervous depressive activity are summarized in Table 1. The reference compound used was cyproheptadine hydrochloride.
1. 48 hr homologous passive cutaneou~ anaphylaxts (PCA) in rat,s _ _ _ _ a) Preparation of DNP-As and rat anti-DNP-As serum Ascaris extract coupled with a 2,4-dinitrophenyl group (DNP-As) was prepared by the method of Koda et al. (Folia pharmacol. japon., 78t 319-334,1981); and anti-DNP-As containing IgE antibody serum was prepared by the method of Tada and Okumura (J. Immunol., 106, 1019-1025, 1971). The PCA titer of the antiserum was estimated to be 1:128 ~.
by 48 hr PCA in rats.
. . .
,, " ~ ' ' ~ ' ' z b) ll8 hr homologous passive cutaneous anaphylaxis (PCA) in rats Male Wistar rats weighing 160 to 200 g were sensitized passively by intradermal injection, in the back, of 0.05 ml of anti-DNP-As serum diluted 21-fold with saline. After 48 hr, the animals (18-20 hr fasted) were given i.v. 0.5 ml of 1% Evans blue solution containin~ 1 mg of UNP-As. After an additional 30 min, the anlmals were killed by stunning and the skins were removed. The intensity of the response was evaluated by assaying the amount of dye leaked according to the method of Katayama et al. (Microbiol. Immunol., 22, 89-101,1978). The percent inhibition of PCA was calculated using the following ~ormula Amount of dye leaked Amount o~ dye leaked Percent with control with test compound lS inhibition = - X 100 Amount of dye leaked with control Test compounds were given orally in a dose Or 1 mg/kg 1 hr prior to challenge with antigen. As a control, 5 ml/kg of vehicle (0.
5 % CMC) alone were given in a similar manner.
The results are shown in Table 1.
2. Potentiation of hexobarbital-induced anesthesia in mice The loss of riBhting reflex induced by hexobarbital was used as an index Or anesthesia. Groups of eight male ddY mice (20-24 hr z~
fasted) weighing l9 to 27 g were treated orally with the test compounds (30 mg/kg) or vehicle. Thirty min. later, 80 mg/kg of hexobarbital sodium were injected i.p. to the animals and the duration of loss of righting reflex was observed. The percent increase of sleeping time was calculated using the following ~ormula:
Sleeping time with _ Sleeping time with Percent ~est compound control increase = x 100 Sleeping time with control The results are listed in Table l.
l5Table 1 .
the percent inhibition the percent incre~se Q~
Test compound o~ PCA in rats hexobarbital~induced (%, l m~/kg, p.o.) anesthesia in mice (~, 30 mg/kg, p.o.) -Example l 71 106 Example 21 91 29 Example 22 81 37 25Example 23 81 51 Example 24 87 75 Example 25 78 80 Example 26 59 22 Example 28 89 83 Example 29 94 45 Example 30 91 53 Example 31 59 36 Example 32 77 15 Example 33 91 3g Example 34 69 31 Example 35 85 76 Example 36 54 34 Example 37 85 49 Example 38 83 41 Example 39 78 80 Reference compound 47 203 _ _ .
The present compounds exhibited more a potent of antiallerKic activlty and less potent of cent,ral nervous depressive activity than the reference compound.
.
Reference l Ethyl 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-l-piperidinecarboxylate A mixture of 33.0 g of 4-(5H-dibenzo[a,d]cyclohepten-5-~.
9~
ylidene)-1-methylpiperidine, 74.9 g of ethyl chlorocarbona~e and 170 ml of toluene was refluxed for 3.5 hrs. After cooling, the reaction mixture was washed with hydrochloric acid and water, and then dried and concentrated. The residue was solidified by treatment with n-hexane to give 37.4 g of pale yellow crystals, which were recrystallized from ethanol to give slightly yellow needles, rnp 123-12~C -Analysis for C23H23N02:
Calculated C, 79.97; H, 6.71; N, 4.05.
Found C, 80.24; H, 6.73; N, 3.95.
The compounds of Reference 2 to 3 were prepared in the same manner as described in Reference 1. .
Reference 2 Ethyl 4-(10,1l-dihydro-5H-dibenzo~a,d}cyclohepten-5-ylidene)-1-piperidine-carboxylate Yellow liquid.
Mass spectrum m/z: 347 (M + ).
IR spectrum v (liq) cm -': 1700 (C00).
NMR spectrum ~ (CDCl3) ppm: 1.25(3H,t,J=7Hz),2.36(4H,t,J=6Hz), 2.60-3.96 (8H,m),4.14(2H,q,J=7Hz),6.97-7.31(8H,m).
.
z~
Re~erence 3 Ethyl 4-(dibenz[b?e]oxepin~11(6H)-ylidene)-1-piperidinecarboxylate Pale yellowish brown liquid.
Mass spectrum m/z: 349 (M ~
IR spectrum ~ (liq) cm -': 1700 (C00).
NMR spectrum ~ (CDCl3) ppm: 1.25(3H,t,J=7Hz),2.20-4.03(8H,m), 4.14(2H,q,J=7Hz),4.77(1H,d,J=12Hz),5.69(1H,d,J=12Hz),6.70-7.50(8H,m).
Reference 4 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine A mixture of 65.6 g of ethyl 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinecarboxylate, 32.0 g o~ potassium hydroxide and 250 ml o~ n-butanol was refluxed for 2hrs and concentrated. Water was added to the residue and extracted with toluene. The toluene layer was washed with water, dried and concentrated to ~ive 53.2 ~ of pale yellow solid, which was recrystallized ~rom methanol to give 47.9 g of colorless needles, mp 145-147 C-Analysis for C20 HlgN
Calculated C, 87.87; H, 7.01; N, 5.12.
Found C, 87.81; H, 7.00; N, 5.07.
;Z0~L8~
The compounds of Reference 5 to 6 were prepared in the same manner as described in Reference 4.
Reference 5 4-(~0,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine hydrochloride Colorless plates, mp ~ 300c (MeOH).
Analysis for C2DH21N HCl:
Calculated C, 77.03; H, 7.11; N, 4.49. -Found C, 77.00; H, 7.12; N, 4.47.
- ..
Reference 6 4-(Dibenz[b,eJoxepin-11t6H)-ylidene)piperidine hydrochlorlde Colorless prisms, mp > 300~C (E~O~).
Analysis Por C, D H1 9 NO HCl:
Calculated C, 72.72; H, 6.42; N, 4.46.
Found C, 72.72; H, 6.51; N, 4.27 Example 1 Ethyl 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)~1-piperidinepropionate hydrochloride Z~l~L8~2 A mixture of 3.01 B of 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene~piperidine, 2.20 g of ethyl 3-bromopropionate, 1.52 e of potassium carbonate and 20 ml of N,N-dimethylformamide was stirred at 80C for 4 hrs. After cooling, water was added to the reaction mixture and then extracted with ether. The extract was washed with water, dried and concentrated to give 4.40 g of brown liquid, which was converted to the hydrochloride in the usual manner to give 4.20 g of colorless crystals. The crude hydrochloride was recrystallized from a mixture of acetone and ether to give colorless needles, mp 151-152 C-Analysis for C2sH27N02 HCl ~ H20:
Calculated C, 70.16; H, 7.07; N, 3.27.
Found C7 70.26; H, 6.99; N, 3.01.
Example 2 Methyl 2-[ll-(5tl-dibenzo~a,d~cyclohepten-5-ylidene)piperidino~ethoxy-____ _._ acetate fumarate A mixture of 3.01 g of 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine, 2.90 g of methyl 2-chloroethoxyacetate, 2.43 g of potassium carbonate and 20 ml of N,N-dimethylformamide was stirred at 80 C for 22 hrs. After cooling, water was added to the reaction mixture and then extracted with ether. The e~her layer was extracted .
.
, with aq. hydrochloric acid. The aqueous layer was made alkaline with potassium carbonate and extracted with ether. The ether layer was washed with water, dried and concentrated to give 3.16 g of yellowish brown liquid, which was converted to the fumarate in the usual manner and then recrystallized from ethanol to give pale yellow needles, mp Analysis for C2 5 H 2 7 N03 C4H404:Calculated C, 68.90; H, 6.18; N, 2.77.
Found C, 68.76; H, 6.22; N, 2.68.
Example 3 Ethyl 4-(10,11-dihydro-5H-dibenzo[a,d~cyclohepten-5-ylidene)-1-piperidinebutyrate hydrochloride A mixturè of 3.00 g of 4-tlO,ll-dihYdro~5H-dib enzo~a,d]cyclohepten-5-ylidene)piperidine, 2.3ll 8 of ethyl ll-bromobutyra~e, 1.51 g of` potassium carbonate and 1~ ml of N,N-dimethylformamide was stirred at 70c for 3 hrs. After coolin~,water was added to the reaction mixture and then extracted with ether.
The ether layer was washed with water, dried and concentrated ~o give pale brown solid, which was converted to the hydrochloride in the usual manner to give 3.88 g of colorless solid. The crude hydrochloride was recrystallized from a mixture of acetone and ether to give colorless crystals, mp 182-184C-, .
ZQ~
Analysis for C26H3,N02 o HCl:Calculated C, 73.31; H, 7.57; N, 3.29.
Found C, 73.27; H, 7.70; N, 3.33.
Example 4 Ethyl 4-(dibenz[b,e]oxepin-11(6H)-ylidene)-1-piperidinepropionate -, .
A mixture of 3.61 g of 4-(dibenz[b9e]0xepin-11(6H)-ylidene)-piperidine, 2.60 g of ethyl 3-bromopropionate, 1.80 g of potassium carbonate and 25 ml of N,N-dimethylformamide was stirred at 80 C for 2 hrs. After cooling, water was added to the reaction mixture and extracted with ether. The ether layer was washed with water and e~tracted with hydrochloric acid. The aqueous layer was made alkaline with potassium carbonate and extracted with ether. The ether layer was washed with water, dried and concentrated to give L,.20 g of yellowish brown liqui~, which was puri~ied by column chromatography on silica gel (eluent: chloroform) to give 3.90 g o~
pale yellow liquid.
Mass spectrum m/z: 377 (M + ).
IR spectrum ~ (liq) cm -': 1734 (C00).
NMR spectrum ~ (CDCl3) ppm: 1.25(3H,t,J=7Hz),1.92-2.94(12H,m), 4.13(2H,q,J=7Hz),4.76(1H,d,J=12Hz),5.72(1H,d,J=12Hz),6.66-7.48(8H,m).
2 l , ~ .' -, .~n~ z Example 5 Ethyl 4-(dibenz[b,e]oxepin-11(6H)-ylidene)-1-piperidinevalerate hydrochloride A mixture of 3.61 g of 4-(dibenz[b,e]oxepin-11(6H)-ylidene)-piperidine, 3.00 g of ethyl 5-bromovalerate, 1.~0 g of potassium carbonate and 25 ml of:N,N-dimethylformamide was stirred at 80 C for 2 hrs. After cooling, water was added to the reaction mixture and extracted with ether. The ether layer was washed with water, dried and concentrated to give 5.40~g of brown liquid, which was converted to the hydrochloride in the usual manner to give 4.76 g o~ colorless crystals. The crude hydrochloride was recrystallized from ethanol to give colorless needles, mp 228-230 C-Analysis ~or C26H3,N03 HCl: .
Calculated C, 70.65; H, 7.30; N, 3.17.
Found . C, 70.76; H, 7.05; N, 3.22.
The c~mpounds of Example 6 to l9 were prepared in the same manner as described in Example 1 to 5.
Example 6 .
Ethyl 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-l-piperidineacetate 4~
Pale bro~1n liquid.
Mass spectrum m/z: 359 (M ' ).
IR spectrum ~ (liq) cm -l: 1746 (COO).
NMR spectrum ~ ~CDCl3) ppm: 1.24(3H,t7J=7Hz),1.98-2.92(8H,m), 3.17(2H,s),4.16(2H,q,J=7Hz),6.91(2H,s),7.08-7.46(8H,m).
Example 7 Ethyl 4-(5H-dibenzo~a,d]cyclohepten-5-ylidene)- ~ -methyl-1-piperidineacetate hydrochloride .. _ _ . . . _ . ....
Pale bro~n pillars, mp 190-191G (EtOH-Et20).
Analysis for C2sH27NO2- HCl:
Calculated C, 73.25; H, 6.88; N, 3.42.
Found C, 73.10; H, 6.81; N, 3.31.
Example 8 Ethyl ll~(5H-dibenzo~a~d]cyclohept~n-5-ylidene)-l-piperidinebutyrate _. _ Yellowish hrown liquid.
Mass spectrum m/z: 387 (M + ).
IR spectrum ~ (liq) cm ~': 1734 (cooj.
NMR spectrum ~ (CDCl3) ppm: 1.23(3H,t,J=7Hz),1.56-2.80(14H7m), 4.10(2H,q,J=7Hz),6.90(2H,s),7.10-7.45(8H,m).
. ~ .
. . :, ,,:
, ~8~
Example 9 _ Ethyl 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)~1-piperidinevalerate hydrochloride Pale yellow prisms, mp 185.5-186.5C (EtOH-Et20).
Analysis for C2,H31NO2- HCl:
Calculated C, 74.04; H, 7.36; N, 3.20.
Found C, 74.04; H, 7.22; N, 3.14.
Example 10 Methyl 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinecaproate _ hydrochloride ; Colorless pillars, mp 200-201 C (EtOH).
Analysis for Cz7H31NOz- HC1:
Calculated C, 711.04; H, 7.36; N, 3.20.
Found C, 73.~2; H, 'l.ll2; N, 3.10.
Example 11 Ethyl 4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piPeridineacetate hydrochloride Colorless crystals, mp 173-175C (MezCO).
2 ~
2~9~Z
Analysis for C24H27NOz- HCl:
Calculated C, 72. 44; H, 7.09; N, 3.52.
Found C, 72.23; H, 7.17; N, 3.45.
Example 12 Ethyl 4-(10,11-dihydro-5H-dibenzo~a,d~cyclohepten-5-ylidene)-1-_ piperidinepropionate hydrochloride Colorless needles, mp 198-202 C (EtOH-Et20).
Analysis for C2sH2~NO2- HCl l/4 H20:
Calculated C, 72.10; H, 7.38; N, 3.36.
Found C, 72.04; H, 7.25; N, 3.33.
Example 13 Ethyl 4~(10,11-dih ~ ]cyclohepken 5-ylidene)~
piperidinevalerate hydrochloride Colorless crystals, mp 183.5-185C (Me2CO-Et20).
Analysis for C27H33NO2~ HCl: ~
Calculated C, 73.70; H, 7.79; N, 3.18.
Found C, 73.40; H, 7.75; N, 3.22.
.
~ , , . ., j . ., ~ .
- ., ~, Example 14 Methyl 2-[4-(10,11-dihydro-5H-dibenzo[a,d]cyclohep_en-5-ylidene)-piperidino]ethoxyacetate Yellow liquid.
Mass spectrum m/z: 391 (M t ).
IR spectrum ~ (liq) cm -': 1758 (COO).
NMR spectrum ~ (CDCl3) ppm: 2.04-3.54(12H,m),2.63(2H,t,J=5.5Hz), 3.68(2H,t,J=5.5Hz),3.73(3H,s),4.12(2H,s),6.98-7.22~8H,m).
Example 15 . .
Ethyl 4-(dibenz[b,e]oxepin-11(6H)-ylidene)-1-piperidineaceta~e hydrochloride Colorless needles, mp 153-154 C (EtOH-Et20).
Analysis for C23HzsNO3- HCl 1/2 HzO:
Calculated C, 67.56; H, 6.66; N, 3.43.
Found C, 67.61; H, 6.119; N, 3 115.
Example 16 Ethyl 4-(dibenz[b,e}oxepin-11(6Hj-ylidene)-1-piperidinebutyrate hydrochloride 39~;~
Colorless needles, mp 242-2llll C (EtOH).
Analysis for C 2 5 H29NO3- HCl:
Calculated C, 70.16; H, 7.07; N, 3.27.
Found C, 70 08; H, 7.04; N, 3.16.
Example 17 Methyl 2-[4-(dibenz[b,e]oxepin-11(6H)-ylidene)piperidino]ethoxyacetate Pale yellow liquid.
Mass spectrum m/z: 3g3 (M + ).
IR spectrum ~ (liq) cm ~': 1756 (COO).
NMR spectrum ~ (CDCl3) ppm: 2.00-3.00(10H,m),3.68(2H,t,J=5.5Hz~, 3.73~3H,s),4.11(2H,s),4.76(1H,djJ-12Hz),5.72(1H,d,J=12Hz)96.64-7~46(8H, m)-Example 18 Methyl 4-(10,11-dihydro-5H-dibenzo[a,d~cyclohepten-5-ylidene)-1-piperidinecaproate hydrochloride Colorless needles, mp 188-190 C (Me2CO). ?
Analysis for C27H33NO2^ HCl:
Calculated C, 73.70; H, 7.79; N, 3.18.
Found C, 73.47; H, 7.74; N, 3.14.
~ ~.
4;2 Example 19 Methyl_4-(dibenz[b,e]oxepin-11(6H)-ylidene)-1-piperidinecaproate hydrochloride .
Colorless needles, mp 214-217 C (Me2C0).
Analysis for C2ôH31N03- HCl:
Calculated C, 70.65; H, 7.30; N, 3.17.
Found C, 70.61; H, 7.41, N, 3.31.
Example 20 Ethyl 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinepropionate A mixture of 4.00 g of 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine, 2.1 ml of ethyl acrylate and 20 ml of ethanol was refluxed for 1 hr and concentrated to give 5.35 g of colorless liquid The liquid was puri~ied by column chromatography on silica eel (eluen~: chloroform) to give 5.30 e of colorless solid, ~hich was recrystallized from n-hexane to give colorless crystals, mp 66-67 C-Analysis for C25H27N02:
Calculated C, 80.40; H, 7.29; N, 3.75.
Found C, 80.35; H, 7.39; N, 3.77.
Example 21 4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinepropionic acid _. .
A mixture of 5.30 ~ of ethyl 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-l-piperidinepropionate hydrochloride, 19.3 ml of 2N sodium hydroxide aqueous solution and 30ml of methanol was refluxed for 1 hr and concentrated. Water was added to the residue, washed with ethyl acetate and adjusted to pH 4 to 5 with 10% hydrochloric acid. The precipitate was collected by filtration to give 4.47 g of pale yellow crystals, which were recrystallized from a mixture of water and N,N-dimethylformamide to give 4.23 g of pale yellow needles, mp 201-203 C.
Analysis ~or C2 3 H23N02- 2H20:
Calculated C, 72.42; H, 7.13; N, 3.67.
Found C, 72.23; H, 6.94; N, 3.67.
Example 22 2-~4-(5H-Dibenzo~a,d]cyclohepten-5~ylidene)piperidino~ethoxyacetic acid hydrochlor~de A mixture of 2.56 g of methyl 2-[4-~5H-dibenzo-[a,d]cyclohepten-5-ylidene)piperidino]ethoxyacetate, 6.6 ml of 2N
sodium hydroxide aqueous solution and 25 ml of methanol was refluxed for 1 hr and concentrated. Water was added to the residue, adjusted to pH 2 with 10 % hydrochloric acid and extracted with chloroform.
, , ., , ' ~ ' .' '.' 201~3~4;ë:
The chloroform layer was washed with water, dried and concentrated to give yellowish brown liquid, which was solidified with a mixture of chloroform and ether to give 2.70 g of pale yellow amorphous solid, mp s Analysis for C24H25N03 HCl H20.
Calculated C, 67005; H, 6.56; N, 3.26.
Found C, 66.99; H, 6.37; N, 3.04.
Example 23 4-(10,11-Dihydro-5H-dibenzo~a,d]cyclohepten-5-ylidene)-1-piperidine-butyric acid hydrochloride A mixture of 3.31 g of ethyl 4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinebutyrate hydrochloride, 11.7 ml of 2N sodium hydroxide aqueous solution and 35 ml of methanol was refluxed for 1 hr and concentrated. Water was added to the resldu~, adjusted to pH 1 with lO % hydrochloric acid. The precipitate was collected by filtlation to give 2.97 g of brown solid, which was recrystallized from a mixture of ethanol and ether to give 2.48 6 of colorless needles~ mp 211.5-214.5 C-Analysis for C24H27N02 HCl :
Calculated C, 72.44; H1 7.09; N, 3.52.
Found C, 72.26; H, 7.04; N, 3.50.
Z4~
Example 24 4-(Dibenz[b,e]oxepin-11(6H)-ylidene)-1-piperidinepropionic acid A mixture of 3.70 g of ethyl 4-(dibenz[b,e]oxepin-11(6H)-ylidene)-1-piperidinepropionate, 9.9 ml of 2N sodium hydroxide aqueous solution and 40ml of methanol was refluxed for 30 min and concentrated. Water was added to the residue, adjusted to pH 3 with 10% hydrochloric acid. The precipitate was collected by filtration and washed with water and ether to give 3.30 g of pale yellow crystals, which were recrystallized from a mixture of water and N,N-dimethyl~ormamide to give 2.75 g of pale yellow crystals, mp 142-143 C .
: 15 Anàlysis for C22H23N03- 2HzO:
Calculated C, 68.55; H, 7.06; N, 3.63.
Found C, 68.8~; H, 6.97; N, 3.62.
Example 25 4 (Dibenz~b,e]oxepin-11(6H)-ylidene)-l-piperidinevaleric acid hydrochloride :: :
A mixture of 4.20 g Or ethyl 4-(dibenz[b,e]oxep1n-11(6H~-ylidene)-l-piperidinevalerate hydrochloride, 14.5 ml of 2N sodium .
- 3 1 - ; ~
- .,. ' ' ' ! ' . ' ' ' ''' ' , ',.'', ' . ' ' ~ ' ~
hydroxide aqueous solution and 40 ml o~ rnethanol wa~ re~luxed for 1 hr and concentrated. Water was added to the residue, adjusted to pH
2 with 10% hydrochloric acid. The precipitate was collected by filtration and washed with water and ether to give 3.92 g of colorless crystals, which were recrystallized from water to give 3 08 g o~
colorless prisms, mp 304-306C(dec.).
Analysis ~or C24H27NO3- HCl:
Calculated C, 69.64; H, 6.82; N, 3.38.
Found C, 69.86; H, 6~62; N, 3.53.
The compounds of Example 26 to 39 were prepared in the same manner as described in Example 21 to 25.:
Example 26 ., 4-(5H-Dibenzo~a,d]cyclohepten-5-ylidene)-1-piperidineacetic acid -hydrochloride Pale brown needles, mp 162-165 C (EtOH-Et20).
Analysis ~or C22H2,NO2 HCl 1/2H20:
Calculated C, 70.11; H 3 6.15; N, 3.72.
Found C, 70.29; H, 6.23; N, 3.51.
Example 27 , .
4;~:
11-(5H-Dibenzo~a~d]cyclohept,en-5~ylidene)- a -m0thyl-l-piperidineacetic acid Pale brown pillars, mp 184-186C (MeOH-Et20).
Analysis for C23H23NO2- H20:
Calculated C, 76.01; H, 6.93; N, 3.85.
Found C, 76.11; H, 7.03; N, 3.87.
Example 28 .,.
4-(5H-Dibenzo[a,d]cyclohepten-S~ylidene)-l~piperidinebutyric acid hydrochloride Pale yellpw prisms, mp 237-239C (H20).
lS Analysis for C24H2sNO2- HCl ~1/2 H20:
Calculated C, 71.19; H, 6.72; N,~3.46.
Found C, 71.46; H, 6.82; N, 3.37.
Example 29 4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinevaleric acid hydrochloride;
Pale brown needles, mp 229-230C (EtOH~Et20).
Analysis for C~sH27N02 HCl: ;
Calculated C, 73.25; H, 6.88; N, 3.42.
.
~- 3 3 -,. ., ,,~ . . .
. . .
- : , ~n~4z Found C, 73.25; H, 6.84; N, 3.30.
Example 30 4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinecaproic acid hydrochloride Pale brown prisms, mp 213-21ll C (EtOH-Et20).
Analysis for C25H29NO2 HCl:
Calculated C, 73.66; H, 7.13; N, 3.30.
Found C, 73.37; H, 7.25; N, 3.26.
Example 31 4-(10,11-Dihydro-5H-dibenzo~a,d]cyclohepten-5-ylidene)-1-piperidineacetic acid hydrocKloride Colorless crys~als, mp 237.5-239C(dec.) (EtOH-Et20~.
Analysis ~or Cz2H23NO2~ HCl:
Calculated C, 71~ll4; H, 6.5LI; N, 3.79.
Found C, 71.17; H, 6.81; N, 3 80.
Example 32 4-(10,11-Dihydro-SH-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidine-propionic acid ;Z~18~
Colorless needles, mp 189-l91 C (DMF-H20).
Analysis for C23H2sN02-5/2 H20:
Calculated C, 70.38; H, 7.70; N, 3.57.
Found C, 70.70; H, 7.40; N, 3.63.
Example 33 4-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidine-valeric acid hydrochloride Colorless needles, mp 204-206 C (H20).
Analysis for C25H29N02- HCl l/4 H20:
Calculated C, 72.10; H, 7.38; N, 3.36.
lS Found C, 72.20; H, 7.19; N, 3.33.
. .
Example 34 2-~4--(10,11-Dihydro-5H-dibenzo~a,d]cyclohepten-5-ylidene)piperidino~-ethoxyacetic acid Colorless needles, mp 167.5-169 C (H20).
~;; Mass spectrum m/z:~ 377 (M t ).
IR spectrum ~ (KBr) cm -': 1590 (C00 - ) NMR spectrum ~ (DMS0-d6) ppm: 2.24-3.04(12H,m),3.14-3.56(2H.m), 3.65(2H,t,J=5.5Hz)~3.89(2H,s),6.96-7.28(8H9m).
-"
2~
Example 35 -4-(Dibenz[b,e]oxepin-11(6H)-ylidene)-l-piperidinebutyric acid -hydrochloride Colorless needles, mp 244-245 C (HzO).
Analysis for C23H25N03~ HCl:
Calculated C, 69.08; H, 6.55; N, 3.50.
Found C, 69.09; H, 6.50; N, 3.42.
Example 36 . .
2-[4-(Dibenz[b,e]oxepin-11(6H)-ylidene)piperidino~ethoxyacetic acid _ hydrochloride -Pale yellow crystals, mp 223~224C (MeOH~Me2C0).
Analysis for Cz 3 Hz 5 NOI, HCl:
Calculated C, 66.42; H, 6.30; N, 3.37.
Found C, 66.25; H, 6.30; N, 3.41.
Example 37 :
4-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidine-caproic acid hydrochloride .
.
, ~ z Colorless needles, mp 215-219 C ( EtOH).
Analysis for C26H31NOz- HCl:
Calculated C, 73.31; H, 7.57; N, 3.29.
Found C, 73.32; H, 7.70; N, 3.38.
Example 38 4-(Dibenz[b,e]oxepin-11(6H)-ylidene)-1-piperidineacetic acid Colorless crystals, mp 132-135C (H20).
Analysis for C2lH2~NO3-2H20:
Calculated C, 67.91; H, 6.78; N, 3.77.
Found C, 67.76; H, 6.58; N, 3.68.
. . . , ' .
Example 39 , 4-(Dibenz~b,e]oxepin-11(6H)-ylidene)-l-piperidinecaproic acid hydrochloride Colorless crystals, mp 228-231C (E~Oi-l-Et20).
Analysis for C2sH29NO3- HCl:
Calculated C, 70.16; H, 7.07; N, 3.27.
Found C, 70.12; H, 7.15; N, 3.26.
Example 40 , ;
zo~
4-(5H-DibenzoEa,d]cyclohepten-5-ylidene)-1-piperidinepropionic acid _ A mixture of 146 g of 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-piperidine, 73.0 g of ethyl acrylate and 500 ml of methanol was refluxed for 1 hr and then 675 ml of 2N sodium hydroxide aqueous solution was added to the reaction mixture. The reaction mixture was refluxed for 1 hr and concentrated. Water was added to the residue and adjusted to pH 4 with hydrochloric acid. The precipitate was collected by filtration to give 200 g of colorless crystals, which were recrystallized from a mixture of water and N,N-dimethylformamide to give 198 g of colorless crystals. This compound was identified by comparing its mp, IR spectrum and NMR spectrum with those of the compound of Example 21.
Example 4?
Tablets of a pharmaceutical preparation according ko the present invention are prepared in the usual manner using the following constituent~:
Compound of the present invention 10 mg Lactose q.s.
Corn starch 34 mg Magnesium stearate 2 mB
Hydroxypropylmethylcellulose 8 mg Polyethyleneglycol 6000 0.5 mg - 3 8 ~
2~
Titanium oxide 0.5 mg 120 mB
Example 42 Capsules of a pharmaceutical preparation according to the present invention are prepared in the usual manner using the following constituents:
Compound of the present lnvention 10 mg Lactose ~ ~ q.s.
Calcium carboxymethylcellulose 15 mg Hydroxypropylcellulose 2 mg Magnesium stearate 2 mg 100 m~
Example Ll3 Powders of a pharmaceutical preparation according to the present invention are prepared in the usual manner using the ~: following constituents:
Compound of the present invention 20 mg Lactose q.s.
zn~
D-Mannitol 500 mg Hydroxypropylcellulose 5 mg Talc 2 mg .
lOOO mg Example 44 Injections of a pharmaceutical preparation according to the present invention are prepared in the usual manner using the following constituents:
Compound of the present invention l mg Glucose 50 mg Hydrochloric acid q~s.
Distilled water for~in~ectionq.s.
2 ml Example 45 Suppositories of a pharmaceutical preparation according to the present invention are prepared in the usual manner using the following constituents:
Compound o~ the present invention 5 m~
:
, 94~ ~
Hard fat 1295 mg 1300 mg Example 46 Plasters of a pharmaceutical preparation according to the present invention are prepared in the usual manner using the following constituents:
1~
Compound of the present invention 10 mg Gelatin llO0 mg Polyvinylalcohol 250 mg Methylcellulose 100 mg Glycerin 1500 mg ;~ Kaolin .850 mg Sodlum polyacrylate 50 mg Polybutene 150 mg Purified water 990 mg - -5000 mg :.
,. . . ~ ~ - , .
,. ~ ` ' . ' - - . - . :
.
Claims (15)
1. A piperidine derivative represented by the following general formula (I):
(I) wherein R represents a hydrogen atom or a lower alkyl group; X
represents -CH=CH-, -CH2CH2-, or -CH20-; Y represents an alkylene group having 1 to 5 carbon atoms which may be optionally substituted with a lower alkyl group, or Y represents an -A-0-B- group wherein A
and B are the same or different and each independently represents an alkylene group having 1 to 3 carbon atoms which may be optionally substituted with a lower alkyl group; and pharmacologically acceptable salts of the compounds of formula (I).
(I) wherein R represents a hydrogen atom or a lower alkyl group; X
represents -CH=CH-, -CH2CH2-, or -CH20-; Y represents an alkylene group having 1 to 5 carbon atoms which may be optionally substituted with a lower alkyl group, or Y represents an -A-0-B- group wherein A
and B are the same or different and each independently represents an alkylene group having 1 to 3 carbon atoms which may be optionally substituted with a lower alkyl group; and pharmacologically acceptable salts of the compounds of formula (I).
2. 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidine propionic acid and pharmacologically acceptable salts thereof.
3. 2-[4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidino]ethoxy-acetic acid and pharmacologically acceptable salts thereof.
4. 4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5 ylidene)-1-piperidinepropionic acid and pharmacologically acceptable salts thereof.
5. 4-(dibenz[b,e]oxepin-11(6H)-ylidene)-1-piperidineacetic acid and pharmacologically acceptable salts thereof.
6. 2-[4-(dibenz[b,e]oxepin-11(6H)-ylidene)piperidino]ethoxy-acetic acid and pharmacologically acceptable salts thereof.
7. A process for preparing a piperidine derivative represented by the following general formula (I):
(I) wherein R represents a hydrogen atom or a lower alkyl group; X
represents -CH=CH-, -CH2CH2-, or -CH20-; Y represents an alkylene group having 1 to 5 carbon atoms which may be optionally substituted with a lower alkyl group, or Y represents an -A-0-B- group wherein A
and B are the same or different and each independently represents an alkylene group having 1 to 3 carbon atoms which may be optionally substituted with a lower alkyl group; and pharmacologically acceptable salts of the compounds of formula (I); wherein said process comprises the steps of reacting a piperidine derivative represented by the following general formula (II):
(II) wherein X is the same as that defined above, with a compound represented by Z-Y-COOR (IIIa) or CH2=CHCOOR (IIIb) wherein R and Y are the same as those defined above, and Z represents a halogen atom, followed by the step of hydrolysis in a solvent using an acid or a base, if necessary.
(I) wherein R represents a hydrogen atom or a lower alkyl group; X
represents -CH=CH-, -CH2CH2-, or -CH20-; Y represents an alkylene group having 1 to 5 carbon atoms which may be optionally substituted with a lower alkyl group, or Y represents an -A-0-B- group wherein A
and B are the same or different and each independently represents an alkylene group having 1 to 3 carbon atoms which may be optionally substituted with a lower alkyl group; and pharmacologically acceptable salts of the compounds of formula (I); wherein said process comprises the steps of reacting a piperidine derivative represented by the following general formula (II):
(II) wherein X is the same as that defined above, with a compound represented by Z-Y-COOR (IIIa) or CH2=CHCOOR (IIIb) wherein R and Y are the same as those defined above, and Z represents a halogen atom, followed by the step of hydrolysis in a solvent using an acid or a base, if necessary.
8. A process according to claim 7, wherein said step of reacting is carried out in the presence of a solvent.
9. A process according to claim 7, wherein said step of reacting is carried out in the absence of a solvent.
10. A process according to claim 7, wherein said step of reacting is carried out in the presence of a base as a dehydrohalogenating agent.
11. A process according to claim 7, wherein said step or reacting is carried out in the absence of a base as a dehydrohalogenating agent.
12. An antihistaminic and antiallergic agent comprising an effective amount of a piperidine derivative represented by the following general formula (I):
(I) wherein R represents a hydrogen atom or a lower alkyl group; X
represents -CH=CH-, -CH2CH2-, or -CH20-; Y represents an alkylene group having 1 to 5 carbon atoms which may be optionally substituted with a lower alkyl group, or Y represents an -A-0-B- group wherein A
and B are the same or different and each independently represents an alkylene group having 1 to 3 carbon atoms which may be optionally substituted with a lower alkyl group; and pharmacologically acceptable salts of the compounds of formula (I).
(I) wherein R represents a hydrogen atom or a lower alkyl group; X
represents -CH=CH-, -CH2CH2-, or -CH20-; Y represents an alkylene group having 1 to 5 carbon atoms which may be optionally substituted with a lower alkyl group, or Y represents an -A-0-B- group wherein A
and B are the same or different and each independently represents an alkylene group having 1 to 3 carbon atoms which may be optionally substituted with a lower alkyl group; and pharmacologically acceptable salts of the compounds of formula (I).
13. A pharmaceutical composition for the treatment of an allergic disease comprising an effective amount of a piperidine derivative represented by the following general formulla (I):
(I) wherein R represents a hydrogen atom or a lower alkyl group; X
represents -CH=CH-, -CH2CH2-, or -CH2O-; Y represents an alkylene group having 1 to 5 carbon atoms which may be optionally substituted with a lower alkyl group, or Y represents an -A-0-B- group wherein A
and B are the same or different and each independently represents an alkylene group having 1 to 3 carbon atoms which may be optionally substituted with a lower alkyl group; and pharmacologically acceptable salts of the compounds of formula (I).
(I) wherein R represents a hydrogen atom or a lower alkyl group; X
represents -CH=CH-, -CH2CH2-, or -CH2O-; Y represents an alkylene group having 1 to 5 carbon atoms which may be optionally substituted with a lower alkyl group, or Y represents an -A-0-B- group wherein A
and B are the same or different and each independently represents an alkylene group having 1 to 3 carbon atoms which may be optionally substituted with a lower alkyl group; and pharmacologically acceptable salts of the compounds of formula (I).
14. A method for the treatment of an allergic disease comprising the step of administering to a mammal an effective amount of a substance selected from the group consisting essentially of (a) a piperidine derivative represented by the following general formula (I):
(I) wherein R represents a hydrogen atom or a lower alkyl group; X
represents -CH=CH- -CH2CH2- or -CH2O-; Y represents an alkylene group having 1 to 5 carbon atoms which may be optionally substituted with a lower alkyl group, or Y represents an -A-O-B- group wherein A
and B are the same or different and each independently represents an alkylene group having 1 to 3 carbon atoms which may be optionally substituted with a lower alkyl group; (b) a pharmacologically acceptable salt of the compound of formula (I); (c) an antihistaminic and antiallergic agent comprising the compounds of formula (I); or (d) a pharmaceutical composition comprising the compounds of formula (I).
(I) wherein R represents a hydrogen atom or a lower alkyl group; X
represents -CH=CH- -CH2CH2- or -CH2O-; Y represents an alkylene group having 1 to 5 carbon atoms which may be optionally substituted with a lower alkyl group, or Y represents an -A-O-B- group wherein A
and B are the same or different and each independently represents an alkylene group having 1 to 3 carbon atoms which may be optionally substituted with a lower alkyl group; (b) a pharmacologically acceptable salt of the compound of formula (I); (c) an antihistaminic and antiallergic agent comprising the compounds of formula (I); or (d) a pharmaceutical composition comprising the compounds of formula (I).
15. A method according to a claim 14 wherein said step of administration is performed on a human being.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP171,090 | 1989-07-04 | ||
| JP17109089 | 1989-07-04 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2018942A1 true CA2018942A1 (en) | 1991-01-04 |
Family
ID=15916808
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002018942A Abandoned CA2018942A1 (en) | 1989-07-04 | 1990-06-13 | Piperidine derivative, method for preparation thereof, and a pharmaceutical composition comprising the same |
Country Status (5)
| Country | Link |
|---|---|
| JP (1) | JPH03128354A (en) |
| KR (1) | KR910002796A (en) |
| CA (1) | CA2018942A1 (en) |
| PT (1) | PT94599A (en) |
| ZA (1) | ZA904665B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2914324B2 (en) * | 1995-10-23 | 1999-06-28 | 味の素株式会社 | Crystal of piperidine derivative, intermediate for producing the same, and production method |
-
1990
- 1990-04-09 JP JP2092194A patent/JPH03128354A/en active Pending
- 1990-06-13 CA CA002018942A patent/CA2018942A1/en not_active Abandoned
- 1990-06-15 ZA ZA904665A patent/ZA904665B/en unknown
- 1990-07-04 PT PT94599A patent/PT94599A/en not_active Application Discontinuation
- 1990-07-04 KR KR1019900010077A patent/KR910002796A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| KR910002796A (en) | 1991-02-26 |
| ZA904665B (en) | 1991-04-24 |
| PT94599A (en) | 1991-03-20 |
| JPH03128354A (en) | 1991-05-31 |
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