US20020147195A1 - Piperidine derivatives and anti-platelet agents containing the same - Google Patents

Piperidine derivatives and anti-platelet agents containing the same Download PDF

Info

Publication number
US20020147195A1
US20020147195A1 US10/101,980 US10198002A US2002147195A1 US 20020147195 A1 US20020147195 A1 US 20020147195A1 US 10198002 A US10198002 A US 10198002A US 2002147195 A1 US2002147195 A1 US 2002147195A1
Authority
US
United States
Prior art keywords
ylidene
dibenzo
cyclohepten
piperidinyl
ethyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US10/101,980
Inventor
Shingo Makino
Harumi Arisaka
Hiroshi Yamamoto
Masataka Shoji
Ryota Yoshimoto
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ajinomoto Co Inc
Original Assignee
Ajinomoto Co Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ajinomoto Co Inc filed Critical Ajinomoto Co Inc
Priority to US10/101,980 priority Critical patent/US20020147195A1/en
Publication of US20020147195A1 publication Critical patent/US20020147195A1/en
Priority to US10/658,322 priority patent/US20040063701A1/en
Abandoned legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the present invention relates to a novel serotonin antagonist and an anti-platelet agent, more particularly, a serotonin antagonist and an anti-platelet agent which potently and specifically inhibit the serotonin 2 receptor with low adverse side effect.
  • thrombus greatly participates in ischemic disorders such as cardiac infarction and cerebral infarction and, in particular, the platelet plays an important role in the formation of the arterial thrombus.
  • Known anti-platelet agents include arachidonic acid metabolism-inhibiting agents, platelet cyclic nucleoside-related agents, thromboxane receptor antagonists. Aspirin and ticlopidine have also been clinically used. However, the effect of these agents is not sufficient and thus development of more effective agents has been in demand.
  • serotonin which is stored in a granules of the platelet, is released by activation of the platelet caused by various stimulations, and the released serotonin increases the calcium ion level in the cell via the serotonin 2 (5HT 2 ) receptor on the platelet membrane, resulting in aggregation of the platelet.
  • the 5HT 2 receptor existing in the vascular smooth muscle participates in the blood vessel contraction. Accordingly, the 5HT 2 receptor antagonist is expected to have vasoconstriction inhibiting activity in addition to the platelet aggregation inhibiting activity and, therefore, may also have potent anti-thrombus function.
  • one object of this invention is to provide a novel serotonin antagonist and an anti-platelet agent which potently and specifically inhibit the serotonin 2 receptor with low adverse side effect.
  • the present invention relates to a serotonin antagonist or an anti-platelet agent which comprises as an active ingredient a piperidine derivative represented by the following general formula (I):
  • a 1 represents an unsubstituted or substituted pyridyl, piperidyl, piperidino, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino or piperazinyl group, a substituted alkyl group having from 1 to 8 carbon atoms, a substituted cycloalkyl group having from 4 to 8 carbon atoms, or an unsubstituted or substituted alkoxyl group having 1 to 8 carbon atoms,
  • X 1 represents a hydrogen atom or a halogen atom selected from the group consisting of bromine, chlorine, flourine and iodine,
  • Y 1 represents one of the following organic groups:
  • n is an integer of from 0 to 4.
  • Z 1 represents one of the following organic groups:
  • Preferred substituents for A 1 in the above general formula (I) include:
  • R 1 is a hydrogen atom, an alkyl or alkoxyl group having from 1 to 6 carbon atoms, an amino group which may be substituted by an alkyl group having from 1 to 6 carbon atoms, or an acylaminoalkyl group having from 1 to 6 carbon atoms
  • R 2 and R 3 which may be the same or different, each represents a hydrogen atom, an alkyl, acyl or alkoxycarbonyl group having from 1 to 6 carbon atoms, or an aminocarbonyl group which may be substituted by an alkyl group having from 1 to 6 carbon atoms.
  • Illustrative examples of such preferred substituents of A 1 include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-formylglycyl, N-acetylglycyl, N-formyl- ⁇ -alanyl, N-acetyl-N-alanyl, N-methyl-N-formyl, N-methyl-N-acetyl, N-methyl-N-propionyl, N-ethyl-N-formyl and N-ethyl-N-acetyl.
  • Preferred examples of Y 1 in the general formula (I) include a group —CONH—.
  • Preferred examples of Z 1 include —CH ⁇ CH—.
  • a 2 represents an unsubstituted or substituted piperidyl, piperidino, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino or piperazinyl group, a substituted alkyl group having from 1 to 8 carbon atoms, a substituted cycloalkyl group having from 4 to 8 carbon atoms, or an unsubstituted or substituted alkoxyl group having 1 to 8 carbon atoms.
  • a 2 has a substituent
  • the substituent is one of the following groups.
  • R 4 represents an alkyl or alkoxyl group having from 1 to 6 carbon atoms, an amino group which may be substituted by an alkyl group, or an acylaminoalkyl group, and
  • R 5 and R 6 which may be the same or different, each represents a hydrogen atom, an alkyl, acyl or alkoxycarbonyl group having from 1 to 6 carbon atoms, or an aminocarbonyl group which may be substituted by an alkyl group, and
  • X 2 , Y 2 , and Z 2 respectively, have the same meanings as X 1 , Y 1 , and Z 1 .
  • Preferred substituents for A 2 include acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-formylglycyl, N-acetylglycyl, N-formyl- ⁇ -alanyl, N-acetyl- ⁇ -alanyl, N-methyl-N-formyl, N-methyl-N-acetyl, N-methyl-N-propionyl, N-ethyl-N-formyl, N-ethyl-N-acetyl, and the like.
  • Y 2 is a group —CONH—.
  • Z 2 is a group —CH ⁇ CH—.
  • the piperidine derivative represented by the above general formula (I) may be prepared by the conventional method, for example, by the method described in an unexamined published Japanese patent application 3-47168, incorporated herein by reference.
  • 1-formyl-N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl))ethylisonipecotamide (compound (6)) included in the general formula (I) can be easily obtained by subjecting the compound 4, which is obtained by removing a t-butoxycarbonyl group from the compound 3 using 4 M hydrochloric acid/dioxane, etc., and 1-formylisonipecotic-acid (compound (5)) to the condensation reaction using a condensation agent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, as shown in the Reaction Scheme II.
  • a condensation agent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
  • reaction product obtained by these production methods is isolated and purified as a free compound or a salt thereof. Isolation and purification may be carried out by extraction, concentration, evaporation, crystallization, and various types of chromatography.
  • Examples of the salt of the piperidine derivative include acid addition salts with inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid and with organic acids such as formic acid, acetic acid, lactic acid, salicylic acid, mandelic acid, citric acid, oxalic acid, maleic acid, fumaric acid, tartaric acid, tannic acid, malic acid, p-toluenesulfonic acid, methanesulfonic acid, and benzenesulfonic acid.
  • inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid
  • organic acids such as formic acid, acetic acid, lactic acid, salicylic acid, mandelic acid, citric acid, oxalic acid, maleic acid, fumaric acid, tartaric acid, tannic acid, malic acid, p-toluenesul
  • the piperidine derivative represented by the general formula (I) exhibits a serotonin antagonizing activity and is useful as an agent for the treatment of ischemic disorders, thrombosis, obstruction, mental diseases (depression, anxiety), diabetic complication, arteriosclerosis, hypertension, arrhythmia, migraine, microcirculation failure, and the like.
  • the piperidine derivative represented by the general formula (I) is useful as an agent for the treatment of various ischemic disorders, thrombosis, obstruction, angiitis, diabetic complication, arteriosclerosis, nephropathy, and ulcer, pain, rhigosis, etc. due to chronic arterial obstruction, and also can be used as a treating agent for improving various ischemia accompanying circulation failure, for preventing restenosis after surgical treatment of ischemic heart diseases, and for improving blood circulation.
  • the administration route may be either oral or parenteral.
  • the clinical dose may differ depending on the age, body weight, and condition of the patient and on the administration method, but the dose per an adult per day is generally from 0.01 mg to 500 preferably from 0.1 mg to 50 mg in the case of oral administration and 1 ⁇ g to 100 mg preferably from 0.01 mg to 10 mg in the case of parenteral administration.
  • dosage form usual dosage forms such as tablets, powders, sugar-coated preparations, capsules and solutions may be employed and such dosage forms can be prepared by the conventional method making use of usual pharmaceutical adjuvants.
  • reaction mixture was washed with 30 ml of 1N hydrochloric acid, 30 ml of a 1N aqueous sodium hydroxide solution, and 30 ml of a saturated aqueous sodium chloride solution, dried over magnesium sulfate powder, and purified by silica gel chromatography to obtain the titled compound.
  • the binding affinity to the serotonin 2 receptor was evaluated using a bovine cerebral cortex membrane sample.
  • a bovine membrane sample adjusted to 50 mg (wet weight) membrane/ml were added 200 ⁇ l of 3 nM [ 3 H]-ketanserin and 200 ⁇ l of a test compound solution prepared by dissolving a test compound in 1.7% ethanol, followed by mixing.
  • the mixture was incubated at 25° C. for 30 minutes and filtered-with a glass filter.
  • the radioactivity trapped on the filter was measured with a liquid scintillation counter.
  • the non-specific binding was defined by 10 ⁇ 6 M LY53857.
  • Ki indicates the dissociation constant and [L] indicates the concentration of [ 3 H]-ketanserin.
  • the anti-platelet effect due to the serotonin antagonistic activity was measured in vitro using the platelet of SD rats (body weight: about 300 to 400 g, male).
  • Platelet rich plasma (PRP) and platelet poor plasma (PPP) were prepared from blood with 0.38% sodium citrate which was obtained from aorta abdominalis of a rat under diethyl ether anesthesia.
  • the platelet concentration of PRP was adjusted to 5 ⁇ 10 8 platelets/ml by adding PPP. Then, the test compound dissolved in 0.4% aqueous ethanol was added, and the mixture was incubated at 37° C. for 3 minutes.
  • the platelet aggregation induced by addition of 0.5 ⁇ M or 0.8 ⁇ M adenosine diphosphate (ADP)+serotonin was measured as an increase in optical transmittance of PRP.
  • concentration of the test compound which inhibits 50% of the increase in platelet aggregation which is obtained with serotonin without a test compound was measured, and its negative logarithm (pIC 50 ) was calculated.
  • pIC 50 negative logarithm
  • the anti-platelet effect due to the serotonin antagonistic activity was measured in vivo using SD rats (body weight: about 210 to 330 g, male).
  • the test compound was dissolved or suspended in arabic gum and orally administered to the rat in a dose shown in Table 3.
  • the rat was anesthetized with diethyl ether and platelet rich plasma (PRP) and platelet poor plasma (PPP) were prepared from blood with 0.38% sodium citrate which was obtained from aorta abdominalis of the rat.
  • PRP platelet rich plasma
  • PPP platelet poor plasma
  • the platelet concentration of PRP was adjusted to 5 ⁇ 10 8 platelets/ml by adding PPP. Then, the PRP was incubated at 37° C.
  • the serotonin antagonistic activity in the central nerve system was evaluated by measuring the inhibiting effect on head twitch of mouse induced by 5-hydroxytryptophan (5HTP)
  • a test compound in an amount of 1, 3, 10, or 30 mg was respectively dissolved in 100 ml of water and, 90 minutes before 5HTP administration, the solution (10 ml/kg body weight) was orally administered to a ICR mouse (body wight: 27 to 32 g, male) fasted from the previous day.
  • 5% arabic gum was used as a control.
  • Carbidopa (6 mg/kg) was subcutaneously administered and, after 15 minutes, 5HTP (180 mg/kg) was intraperitoneally administered.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Urology & Nephrology (AREA)
  • Dermatology (AREA)
  • Vascular Medicine (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Obesity (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

The present invention relates to a novel serotonin antagonist and an anti-platelet agent, more particularly, a serotonin antagonist and an anti-platelet agent which potently and specifically inhibit the serotonin 2 receptor with low adverse side effect.

Description

    BACKGROUND OF THE INVENTION
  • 1. Field of the Invention [0001]
  • The present invention relates to a novel serotonin antagonist and an anti-platelet agent, more particularly, a serotonin antagonist and an anti-platelet agent which potently and specifically inhibit the serotonin 2 receptor with low adverse side effect. [0002]
  • 2. Discussion of the Background [0003]
  • It is believed that the thrombus greatly participates in ischemic disorders such as cardiac infarction and cerebral infarction and, in particular, the platelet plays an important role in the formation of the arterial thrombus. Known anti-platelet agents include arachidonic acid metabolism-inhibiting agents, platelet cyclic nucleoside-related agents, thromboxane receptor antagonists. Aspirin and ticlopidine have also been clinically used. However, the effect of these agents is not sufficient and thus development of more effective agents has been in demand. [0004]
  • It is known that serotonin (5HT), which is stored in a granules of the platelet, is released by activation of the platelet caused by various stimulations, and the released serotonin increases the calcium ion level in the cell via the serotonin 2 (5HT[0005] 2) receptor on the platelet membrane, resulting in aggregation of the platelet. It is believed that the 5HT2 receptor existing in the vascular smooth muscle participates in the blood vessel contraction. Accordingly, the 5HT2 receptor antagonist is expected to have vasoconstriction inhibiting activity in addition to the platelet aggregation inhibiting activity and, therefore, may also have potent anti-thrombus function.
    • SUMMARY OF THE INVENTION
  • Accordingly, one object of this invention is to provide a novel serotonin antagonist and an anti-platelet agent which potently and specifically inhibit the serotonin 2 receptor with low adverse side effect. [0006]
  • This and objects which will become apparent hereinafter have been achieved with the following novel serotonin agents. [0007]
    • DESCRIPTION OF THE PREFERRED EMBODIMENTS
  • The present invention relates to a serotonin antagonist or an anti-platelet agent which comprises as an active ingredient a piperidine derivative represented by the following general formula (I): [0008]
    Figure US20020147195A1-20021010-C00001
  • wherein [0009]
  • A[0010] 1 represents an unsubstituted or substituted pyridyl, piperidyl, piperidino, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino or piperazinyl group, a substituted alkyl group having from 1 to 8 carbon atoms, a substituted cycloalkyl group having from 4 to 8 carbon atoms, or an unsubstituted or substituted alkoxyl group having 1 to 8 carbon atoms,
  • X[0011] 1 represents a hydrogen atom or a halogen atom selected from the group consisting of bromine, chlorine, flourine and iodine,
  • Y[0012] 1 represents one of the following organic groups:
  • —CONH—, —NHCO—, —CONHCH[0013] 2—, —(CH2)n— or —COO—,
  • wherein n is an integer of from 0 to 4, and [0014]
  • Z[0015] 1 represents one of the following organic groups:
  • —CH═CH—, —S—CH[0016] 2—, —S— or —CH2—CH2—,
  • or a salt thereof. [0017]
  • Preferred substituents for A[0018] 1 in the above general formula (I) include:
  • R[0019] 1—CO— and
    Figure US20020147195A1-20021010-C00002
  • wherein [0020]
  • R[0021] 1 is a hydrogen atom, an alkyl or alkoxyl group having from 1 to 6 carbon atoms, an amino group which may be substituted by an alkyl group having from 1 to 6 carbon atoms, or an acylaminoalkyl group having from 1 to 6 carbon atoms, and R2 and R3, which may be the same or different, each represents a hydrogen atom, an alkyl, acyl or alkoxycarbonyl group having from 1 to 6 carbon atoms, or an aminocarbonyl group which may be substituted by an alkyl group having from 1 to 6 carbon atoms.
  • Illustrative examples of such preferred substituents of A[0022] 1 include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-formylglycyl, N-acetylglycyl, N-formyl-β-alanyl, N-acetyl-N-alanyl, N-methyl-N-formyl, N-methyl-N-acetyl, N-methyl-N-propionyl, N-ethyl-N-formyl and N-ethyl-N-acetyl.
  • Preferred examples of Y[0023] 1 in the general formula (I) include a group —CONH—.
  • Preferred examples of Z[0024] 1 include —CH═CH—.
  • Among the compounds represented by the general formula (I), the compounds represented by the following general formula (II) are novel compounds. [0025]
    Figure US20020147195A1-20021010-C00003
  • wherein [0026]
  • A[0027] 2 represents an unsubstituted or substituted piperidyl, piperidino, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino or piperazinyl group, a substituted alkyl group having from 1 to 8 carbon atoms, a substituted cycloalkyl group having from 4 to 8 carbon atoms, or an unsubstituted or substituted alkoxyl group having 1 to 8 carbon atoms.
  • When A[0028] 2 has a substituent, the substituent is one of the following groups.
  • R[0029] 4—CO— and
    Figure US20020147195A1-20021010-C00004
  • wherein [0030]
  • R[0031] 4 represents an alkyl or alkoxyl group having from 1 to 6 carbon atoms, an amino group which may be substituted by an alkyl group, or an acylaminoalkyl group, and
  • R[0032] 5 and R6, which may be the same or different, each represents a hydrogen atom, an alkyl, acyl or alkoxycarbonyl group having from 1 to 6 carbon atoms, or an aminocarbonyl group which may be substituted by an alkyl group, and
  • X[0033] 2, Y2, and Z2, respectively, have the same meanings as X1, Y1, and Z1.
  • Preferred substituents for A[0034] 2 include acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-formylglycyl, N-acetylglycyl, N-formyl-β-alanyl, N-acetyl-β-alanyl, N-methyl-N-formyl, N-methyl-N-acetyl, N-methyl-N-propionyl, N-ethyl-N-formyl, N-ethyl-N-acetyl, and the like.
  • Preferably, Y[0035] 2 is a group —CONH—.
  • Preferably, Z[0036] 2 is a group —CH═CH—.
  • The piperidine derivative represented by the above general formula (I) may be prepared by the conventional method, for example, by the method described in an unexamined published Japanese patent application 3-47168, incorporated herein by reference. [0037]
  • For example, 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene-1-(2-t-butoxycarbonylamino)ethyl)piperidine (compound (3)) included in the general formula (I) can be easily obtained by subjecting N-t-butoxycarbonyl-2-bromoethylamine (compound (1)) and 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine (compound (2)) to the condensation reaction in the presence of a base such as triethylamine, as shown in the Reaction Scheme I. [0038]
    Figure US20020147195A1-20021010-C00005
  • Similarly, 1-formyl-N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl))ethylisonipecotamide (compound (6)) included in the general formula (I) can be easily obtained by subjecting the compound 4, which is obtained by removing a t-butoxycarbonyl group from the compound 3 using 4 M hydrochloric acid/dioxane, etc., and 1-formylisonipecotic-acid (compound (5)) to the condensation reaction using a condensation agent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, as shown in the Reaction Scheme II. [0039]
    Figure US20020147195A1-20021010-C00006
  • The reaction product obtained by these production methods is isolated and purified as a free compound or a salt thereof. Isolation and purification may be carried out by extraction, concentration, evaporation, crystallization, and various types of chromatography. [0040]
  • Examples of the salt of the piperidine derivative include acid addition salts with inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid and with organic acids such as formic acid, acetic acid, lactic acid, salicylic acid, mandelic acid, citric acid, oxalic acid, maleic acid, fumaric acid, tartaric acid, tannic acid, malic acid, p-toluenesulfonic acid, methanesulfonic acid, and benzenesulfonic acid. [0041]
  • The piperidine derivative represented by the general formula (I) exhibits a serotonin antagonizing activity and is useful as an agent for the treatment of ischemic disorders, thrombosis, obstruction, mental diseases (depression, anxiety), diabetic complication, arteriosclerosis, hypertension, arrhythmia, migraine, microcirculation failure, and the like. In particular, as an anti-platelet agent, the piperidine derivative represented by the general formula (I) is useful as an agent for the treatment of various ischemic disorders, thrombosis, obstruction, angiitis, diabetic complication, arteriosclerosis, nephropathy, and ulcer, pain, rhigosis, etc. due to chronic arterial obstruction, and also can be used as a treating agent for improving various ischemia accompanying circulation failure, for preventing restenosis after surgical treatment of ischemic heart diseases, and for improving blood circulation. [0042]
  • When the piperidine derivative of the general formula (I) is used as a serotonin antagonist or an anti-platelet agent, the administration route may be either oral or parenteral. Though the clinical dose may differ depending on the age, body weight, and condition of the patient and on the administration method, but the dose per an adult per day is generally from 0.01 mg to 500 preferably from 0.1 mg to 50 mg in the case of oral administration and 1 μg to 100 mg preferably from 0.01 mg to 10 mg in the case of parenteral administration. [0043]
  • As the dosage form, usual dosage forms such as tablets, powders, sugar-coated preparations, capsules and solutions may be employed and such dosage forms can be prepared by the conventional method making use of usual pharmaceutical adjuvants. [0044]
  • This application is based on Japanese Patent Application No. 081499/1944, the text of which is incorporated herein by reference.[0045]
    • EXAMPLES
  • Having generally described this invention, a further understanding can be obtained by reference to certain specific examples which are provided herein for purposes of illustration only and are not intended to be limiting unless otherwise specified. [0046]
    • Preparation Procedure A Synthesis of 1-methoxycarbonyl-N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)) ethylisonipecotamide hydrochloride
  • Step 1 [0047]
    • Synthesis of 2-t-Butoxycarbonylaminoethylbromide
  • 2-Aminoethylbromide hydrobromide (35.77 g, 174.6 mmol) and di-t-butyl dicarbonate (22.80 g, 104.5 mmol) were added to a mixed solvent of 300 ml of diethyl ether and 300 ml of water. Then, sodium hydrogencarbonate (44.00 g, 523.7 mmol) was gradually added and the mixture was stirred at room temperature overnight. The diethyl ether layer was washed with 80 ml of 1N hydrochloric acid and then with 80 ml of a saturated aqueous sodium chloride solution, and dried over magnesium sulfate powder. The solvent was evaporated to obtain the titled compound. Amount obtained: 21.57 g (96.25 mmol); Yield: 92% [0048]
  • Step 2 [0049]
    • Synthesis of 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-(2-t-butoxycarbonylamino)ethyl)piperidine
  • 2-t-Butoxycarbonylaminoethylbromide (4.5 g, 20.1 mmol), 4(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine (2.7 g, 10.0 mmol), and triethylamine (4.2 ml, 30 mmol) were added to acetonitrile (300 ml), and the mixture was stirred on an oil bath at 50° C. for 16 hours. The temperature was lowered to room temperature, the solvent was evaporated, and the residue was dissolved in 300 ml of ethyl acetate. After removing insoluble matters by filtration, the filtrate was washed with 100 ml of 1N hydrochloric acid, 100 ml of a 1N aqueous sodium hydroxide solution, and 100 ml of a saturated sodium chloride aqueous solution, and dried over magnesium sulfate powder. The solvent was evaporated and the residue was purified by silica gel column chromatography to obtain the titled compound. Amount obtained: 3.6 g (8.6 mmol); Yield: 86% [0050]
  • Step 3 [0051]
    • Synthesis of 1-(2-aminoethyl)-4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine dihydrochloride
  • 4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-(2-t-butoxycarbonylamino)ethyl)piperidine (8.47 g, 20.4 mmol) was dissolved in 100 ml of dichloromethane, and 100 ml of a 4N hydrochloric acid-dioxane solution was added thereto, followed by stirring at room temperature for 1 hour. The solvent was evaporated to obtain the titled compound (8.56 g). [0052]
  • Step 4 [0053]
    • Synthesis of 1-t-butoxycarbonyl-N-(2-(4-(5H-dibenzo[a, d]cyclohepten-5-ylidene)-1-piperidinyl))ethylisonipecotamide
  • 1-(2-Aminoethyl)-4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine dihydrochloride (2.3 g, 6.0 mmol), 1-t-butoxycarbonylisonipecotic acid (1.6 g, 7.2 mmol), triethylamine (3.0 ml, 21.6 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.4 g, 7.2 mmol) were mixed, and the mixture was stirred at room temperature overnight. After evaporating the solvent, the residue was dissolved in 100 ml of dichloromethane, washed with 100 ml of 1N hydrochloric acid, 100 ml of a 1N aqueous sodium hydroxide solution, and 50 ml of a saturated aqueous sodium chloride solution. The solvent was evaporated and the residue was purified by silica gel chromatography to obtain the titled compound. Amount obtained: 2.0 g (3.8 mmol); Yield: 63% [0054]
  • Step 5 [0055]
    • Synthesis of N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)1-piperidinyl))ethylisonipecotamide dihydrochloride
  • 10 ml of 4N hydrochloric acid-dioxane solution was added to 1-t-butoxycarbonyl-N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl))ethylisonipecotamide (0.10 g, 0.185 mmol), and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated to obtain the titled compound. Amount obtained: 0.093 g (0.186 mmol); Yield: 100% [0056]
  • Step 6 [0057]
    • Synthesis of 1-methoxycarbonyl-N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene-1-piperidinyl))ethylisonipecotamide hydrochloride
  • N-(2-(4-(5H-Dibenzo[a,dlcyclohepten-5-ylidene)-1-piperidinyl))ethylisonipecotamide dihydrochloride (0.59 g, 1.18 mmol) and triethylamine (0.8 ml, 5.70 mmol) were dissolved in 50 ml of dichloromethane, and methyl chloroformate (0.1 ml, 1.40 mmol) was added. The mixture was stirred for 1 hour and 100 ml of dichloromethane was added. The mixture was washed with 70 ml of water, 70 ml of a 1N aqueous sodium hydroxide solution, and 70 ml of a saturated aqueous sodium chloride solution, and purified by silica gel chromatography. The product obtained was converted into the hydrochloride form to give the titled compound. Amount obtained: 0.39 g (0.75 mmol); Yield: 63% [0058]
  • The compounds shown in Table 1 were produced by the similar manner as described in Preparation procedure A. [0059]
    Figure US20020147195A1-20021010-C00007
    A Y X Z pKi pIC50
    1
    Figure US20020147195A1-20021010-C00008
         		—CONH— H —CH═CH— 8.2 7.5
    2
    Figure US20020147195A1-20021010-C00009
         		8.6 7.3
    3
    Figure US20020147195A1-20021010-C00010
         		8.4 7.2
    4
    Figure US20020147195A1-20021010-C00011
         		8.5 7.2
    5
    Figure US20020147195A1-20021010-C00012
         		8.0 6.5
    6
    Figure US20020147195A1-20021010-C00013
         		— 6.9
    7
    Figure US20020147195A1-20021010-C00014
         		8.5 6.7
    8
    Figure US20020147195A1-20021010-C00015
         		7.9 6.6
    9
    Figure US20020147195A1-20021010-C00016
         		7.8 7.1
    10
    Figure US20020147195A1-20021010-C00017
         		8.8 —
    11
    Figure US20020147195A1-20021010-C00018
         		8.8 7.0
    12
    Figure US20020147195A1-20021010-C00019
         		8.6 6.6
    13
    Figure US20020147195A1-20021010-C00020
         		9.3 —
    14
    Figure US20020147195A1-20021010-C00021
         		—CONH— H —CH═CH— — —
    15
    Figure US20020147195A1-20021010-C00022
         		— —
    16 CH3CH2O— — 7.6
    17 (CH3)3CO— — 7.0
    18
    Figure US20020147195A1-20021010-C00023
         		8.9 7.3
    19
    Figure US20020147195A1-20021010-C00024
         		8.3 6.4
    20
    Figure US20020147195A1-20021010-C00025
         		8.0 6.3
    21
    Figure US20020147195A1-20021010-C00026
         		7.8 6.5
    22
    Figure US20020147195A1-20021010-C00027
         		8.2 5.8
    23 H2N(CH2)3— — 7.6
    24 HCONH(CH2)3— 9.8 7.2
    25 CH3CONH(CH2)3— 9.2 6.6
    26 (CH3)3COCONH(CH2)3— — 7.2
    27 (CH3)2NCONH(CH2)3— —CONH— H —CH═CH— 9.2 6.9
    28 CH3NH(CH2)3— — 6.6
    29 (CH3)3COCON(CH2)3—CH3 — 7.1
    30
    Figure US20020147195A1-20021010-C00028
         		—CONHCH2— 8.3 6.4
    31 (CH3)3CO— 8.8 —
    32 H2N— —CH2— — —
    33
    Figure US20020147195A1-20021010-C00029
         		—COO— 8.3 7.4
    34 H2N— — —CH2—CH2— — —
    35 (CH3)3CO— —CONH— 8.3 —
    36
    Figure US20020147195A1-20021010-C00030
         		8.9 5.8
    37 H2N— — —S— 8.4 5.0
    38 (CH3)3CO— —CONH— 9.1 7.3
    39
    Figure US20020147195A1-20021010-C00031
         		9.2 7.1
    40
    Figure US20020147195A1-20021010-C00032
         		F —S—CH2— 7.1 5.6
    • Preparation Procedure B Synthesis of 1-(4-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)butyl)morpholine
  • Step 1 [0060]
    • Synthesis of 1-(4-oxo-4-morpholinobutyryl)-4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine
  • In 50 ml of dichloromethane, 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine (0.27 g, 1.0 mmol), succinic anhydride (0.12 g, 1.2 mmol), and triethylamine (0.17 ml, 1.2 mmol) were stirred at room temperature overnight. Morpholine (0.14 ml, 1.6 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.27 g, 1.4 mmol) were added and the mixture was further stirred at room temperature for 8 hours. The reaction mixture was washed with 30 ml of 1N hydrochloric acid, 30 ml of a 1N aqueous sodium hydroxide solution, and 30 ml of a saturated aqueous sodium chloride solution, dried over magnesium sulfate powder, and purified by silica gel chromatography to obtain the titled compound. Amount obtained: 0.44 g (1.0 mol); Yield: 100% [0061]
  • Step 2 [0062]
    • Synthesis of 1-(4-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)1-piperidinyl)butyl)morpholine dihydrochloride
  • In tetrahydrofuran (60 ml), 1-(4-oxo-4-morpholinobutyryl)-4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine (0.44 g, of 1.00 mmol) was reacted with lithium aluminum hydride (0.38 g, 10.0 mol) at 0° C., and further treated in accordance with the conventional method to obtain the titled compound. Amount obtained: 0.32 g (0.66 mmol); Yield: 66% [0063]
  • The compounds shown in Table 2 were produced by the similar manner as described in Preparation procedure B. [0064]
    Figure US20020147195A1-20021010-C00033
    A Y X Z pKi pIC50
    41
    Figure US20020147195A1-20021010-C00034
         		—(CH2)2— H —CH═CH— 8.2 6.9
    42
    Figure US20020147195A1-20021010-C00035
         		8.7 6.6
    43
    Figure US20020147195A1-20021010-C00036
         		—(CH2)3— 7.3 —
    44
    Figure US20020147195A1-20021010-C00037
         		—(CH2)2— —CH2—CH2— 7.9 —
    45
    Figure US20020147195A1-20021010-C00038
         		—S— 8.1 —
    • Test Example 1
  • The binding affinity to the serotonin 2 receptor was evaluated using a bovine cerebral cortex membrane sample. To 200 μl of a bovine membrane sample adjusted to 50 mg (wet weight) membrane/ml were added 200 μl of 3 nM [[0065] 3H]-ketanserin and 200 μl of a test compound solution prepared by dissolving a test compound in 1.7% ethanol, followed by mixing. The mixture was incubated at 25° C. for 30 minutes and filtered-with a glass filter. The radioactivity trapped on the filter was measured with a liquid scintillation counter. The non-specific binding was defined by 10−6 M LY53857. The concentration of the test compound which inhibits 50% of the specific binding of [3H]-ketanserin (i.e., IC50 value) was obtained, and the Ki value was calculated in accordance with the following equation. The results are shown as the negative logarithm of the Ki value (i.e., pKi value). K i = IC 50 1 + [ L ] K d
    Figure US20020147195A1-20021010-M00001
  • In the equation, Ki indicates the dissociation constant and [L] indicates the concentration of [[0066] 3H]-ketanserin.
  • From the results in Tables 1 and 2, it is apparent that the piperidine derivative of the present invention exhibits strong binding affinity to the serotonin 2 receptor. [0067]
    • Test Example 2
  • The anti-platelet effect due to the serotonin antagonistic activity was measured in vitro using the platelet of SD rats (body weight: about 300 to 400 g, male). Platelet rich plasma (PRP) and platelet poor plasma (PPP) were prepared from blood with 0.38% sodium citrate which was obtained from aorta abdominalis of a rat under diethyl ether anesthesia. The platelet concentration of PRP was adjusted to 5×10[0068] 8 platelets/ml by adding PPP. Then, the test compound dissolved in 0.4% aqueous ethanol was added, and the mixture was incubated at 37° C. for 3 minutes. The platelet aggregation induced by addition of 0.5 μM or 0.8 μM adenosine diphosphate (ADP)+serotonin was measured as an increase in optical transmittance of PRP. The concentration of the test compound which inhibits 50% of the increase in platelet aggregation which is obtained with serotonin without a test compound was measured, and its negative logarithm (pIC50) was calculated. The results are shown in the Table 1 and 2. From these results, it is apparent that the piperidine compound of the present invention potently inhibits the platelet aggregation by serotonin.
    • Test Example 3
  • The anti-platelet effect due to the serotonin antagonistic activity was measured in vivo using SD rats (body weight: about 210 to 330 g, male). The test compound was dissolved or suspended in arabic gum and orally administered to the rat in a dose shown in Table 3. Two hours after the administration of the test compound, the rat was anesthetized with diethyl ether and platelet rich plasma (PRP) and platelet poor plasma (PPP) were prepared from blood with 0.38% sodium citrate which was obtained from aorta abdominalis of the rat. The platelet concentration of PRP was adjusted to 5×10[0069] 8 platelets/ml by adding PPP. Then, the PRP was incubated at 37° C. for 3 minutes, and platelet aggregation induced by addition of 0.7 μM adenosine diphosphate (ADP)+serotonin was measured as an increase in optical transmittance of PRP. The aggregation occurred by addition of ADP alone and the maximum aggregation ratio by the simultaneous addition of ADP and serotonin were measured with respect to each group, and increase in aggregation caused by serotonin was calculated. The increase in aggregation caused by serotonin in the arabic gum administered group was taken as 100%, and the effect of the test compound was judged using as an index the increase in aggregation caused by the serotonin in the test compound-administered group (n=3). The results are shown in the Table 3.
    Amount of Increase in aggregation
    administration by serotonin
    Test Compound (mg/kg) (%)
    arabic gum — 100
    compound of No. 3 0.1 75.7
    0.3 57.3
    1 24.3
    3 27
    10 −2.7
    compound of No. 9 0.3 57.3
    compound of No. 17 0.3 50.7
    compound of No. 18 0.3 94.9
    compound of No. 38 0.3 82.4
    compound of No. 39 0.3 54.5
    compound of No. 41 0.3 91.5
  • From the results in the Table 3, it is apparent that the piperidine compound of the present invention potently inhibits the platelet aggregation by serotonin even in the case of oral administration. [0070]
    • Test Example 4
  • The serotonin antagonistic activity in the central nerve system was evaluated by measuring the inhibiting effect on head twitch of mouse induced by 5-hydroxytryptophan (5HTP) A test compound in an amount of 1, 3, 10, or 30 mg was respectively dissolved in 100 ml of water and, 90 minutes before 5HTP administration, the solution (10 ml/kg body weight) was orally administered to a ICR mouse (body wight: 27 to 32 g, male) fasted from the previous day. As a control, 5% arabic gum was used. Carbidopa (6 mg/kg) was subcutaneously administered and, after 15 minutes, 5HTP (180 mg/kg) was intraperitoneally administered. From the 15 minutes after 5HTP administration, the number of head twitches occurred within 2 minutes were counted. The concentration of the test compound which inhibits 50% of the number of head twitches in the 5% arabic gum administered group was obtained. The results are shown in the Table 4. [0071]
    TABLE 4
    Test compound ID50 (mg/kg)
    compound of No. 3 0.39
    cycloheptadine 0.12
  • From the results in the Table 4, it is apparent that the piperidine compound of the present invention has low effect on the central nerve system and is a highly safe compound. [0072]
  • Having now fully described the invention, it will be apparent to one of ordinary skill in the art that many changes and modifications can be made thereto without departing from the spirit or scope of the invention as set forth herein. [0073]

Claims (13)

What is claimed as new and is desired to be secured by Letters Patent of the United States is:
1. A method of treating or preventing a disease caused by seretonin comprising administering effective amount of a piperidine derivative of general formula (I) or pharmaceutically acceptable salt thereof:
Figure US20020147195A1-20021010-C00039
wherein A1 represents an unsubstituted or substituted pyridyl, piperidyl, piperidino, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino or piperazinyl group, a substituted alkyl group having from 1 to 8 carbon atoms, a substituted cycloalkyl group having from 4 to 8 carbon atoms, or an unsubstituted or substituted alkoxyl group having 1 to 8 carbon atoms,
X1 is a hydrogen atom or a halogen atom,
Y1 is —CONH—, —NHCO—, —CONHCH2—, —(CH2) n or —COO—,
wherein n is an integer of from 0 to 4, and
Z1 is —CH═CH—, —S—CH2—, —S— or —CH2—CH2—.
2. The composition of claim 1, wherein A1 has a substituent and said substituent is
R1—CO— or
Figure US20020147195A1-20021010-C00040
wherein R1 is a hydrogen atom, an alkyl or alkoxyl group having from 1 to 6 carbon atoms, an amino group which may be substituted by an alkyl group having from 1 to 6 carbon atoms, or an acylaminoalkyl group having from 1 to 6 carbon atoms, and
R2 and R3, which may be the same or different, each represents a hydrogen atom, an alkyl, acyl or alkoxycarbonyl group having from 1 to 6 carbon atoms, or an aminocarbonyl group which may be substituted by an alkyl group having from 1 to 6 carbon atoms.
3. The method of claim 1, wherein said substituent on A1 is formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-formylglycyl, N-acetylglycyl, N-formyl-β-alanyl, N-acetyl-β-alanyl, N-methyl-N-formyl, N-methyl-N-acetyl, N-methyl-N-propionyl, N-ethyl-N-formyl or N-ethyl-N-acetyl.
4. The method of claim 1, wherein Y1 is a —CONH—.
5. The method of claim 1, wherein Z1 is a —CH═CH—.
6. The method of claim 1, wherein the piperidine derivative is 1-formyl-N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1piperidinyl))ethylisonipecotamide.
7. A method of treating or preventing platelet aggregation comprising administering an effective amount of a piperidine derivative of the formula (I) or a salt thereof or an active ingredient of a pharmaceutical composition:
Figure US20020147195A1-20021010-C00041
wherein A1 represents an unsubstituted or substituted pyridyl, piperidyl, piperidino, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino or piperazinyl group, a substituted alkyl group having from 1 to 8 carbon atoms, a substituted cycloalkyl group having from 4 to 8 carbon atoms, or an unsubstituted or substituted alkoxyl group having 1 to 8 carbon atoms,
X1 is a hydrogen atom or a halogen atom,
Y1 is —CONH—, —NHCO—, —CONHCH2—, —(CH2) or —COO—,
wherein n is an integer of from 0 to 4, and
Z1 is —CH═CH—, —S—CH2—, —S— or —CH2—CH2—.
8. The method of claim 7, wherein the piperidine derivative is 1-formyl-N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1piperidinyl))ethylisonipecotamide.
9. A piperidine derivative represented by the general formula (II) or a salt thereof:
Figure US20020147195A1-20021010-C00042
wherein A2 represents an unsubstituted or substituted piperidino, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino or piperazinyl group, a substituted alkyl group having from 1 to 8 carbon atoms, a substituted cycloalkyl group having from 4 to 8 carbon atoms, or an unsubstituted or substituted alkoxyl group having 1 to 8 carbon atoms,
wherein suitable substituents include:
R4—CO— or
Figure US20020147195A1-20021010-C00043
wherein R4 represents an alkyl or alkoxyl group having from 1 to 6 carbon atoms, an amino group which may be substituted by an alkyl group having from 1 to 6 carbon atoms, or an acylaminoalkyl group having from 1 to 6 carbon atoms.
R1 and R6, which may be the same or different, each represents a hydrogen atom, an alkyl, acyl or alkoxycarbonyl group having from 1 to 6 carbon atoms, or an aminocarbonyl group which may be substituted by an alkyl group having from 1 to 6 carbon atoms, and
X2 is a hydrogen atom or a halogen atom,
Y2 is —CONH—, —NHCO—, —CONHCH2—, —(CH2)n— or —COO—,
wherein n is an integer of from 0 to 4, and
Z2 is —CH═CH—, —S—CH2—, —S— or —CH2—CH2—.
10. The piperidine derivative of claim 9, wherein A2 is substituted with a substituent selected from the group consisting of acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-formylglycyl, N-acetylglycyl, N-formyl-β-alanyl, N-acetyl-β-alanyl, N-methyl-N-formyl, N-methyl-N-acetyl, N-methyl-N-propionyl, N-ethyl-N-formyl, and N-ethyl-N-acetyl.
11. The piperidine derivative of claim 9, wherein Y2 is a group —CONH—.
12. The piperidine derivative of claim 9, wherein Z2 is a group —CH═CH—.
13. A compound selected from the group consisting of 1-methoxycarbonyl-N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)1-piperidinyl))ethylisonipecotamide,
N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl))ethylisonipecotamide,
1-acetyl-N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl))ethylisonipecotamide,
1-t-butoxycarbonyl-N-(2-(4-(5H-dibenzo[[a,d]cyclohepten-5-ylidene)-1piperidinyl))ethylisonipecotamide,
1-carbamoyl-N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl))ethylisonipecotamide,
1-(N,N-dimethylcarbamoyl)-N-(2(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1piperidinyl))ethylisonipecotamide,
1-(N-acetylglycyl)-N-(2-(4(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1piperidinyl))ethylisonipecotamide,
N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidinyl)) ethylpipecolamide,
N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)) ethyl-(N-acetyl)pipecolamide,
1-formyl-4-((2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl))ethylcarbamoyl)piperazine,
N-(2-1(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)) ethyl-4-aminocyclohexanecarboxamide,
N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)) ethyl-4-acetylaminocyclohexanecarboxamide,
N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)) ethyl-4-(1-t-butoxycarbonylamino)cyclohexanecarboxamide,
4-5H-dibenzo[a,d]cyclohepten-5-ylidene))1-2-ethoxycarbonylamino)ethyl)piperidine,
4-(5H-dibenzo[a,d]cyclohepten-5-ylidene-1-(2-t-butoxycarbonylamino)ethyl)piperidine,
N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl))ethyl-1-(1-amino)cyclohexanecarboxamide,
N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)) ethyl-1-(1-acetylamino)cyclohexanecarboxamide,
N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl))ethyl-1-(1-t-butoxycarbonylamino) cyclohexanecarboxamide,
N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl))ethyl-1-(formylamino)cyclohexanecarboxamide,
N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl))ethyl-1-(1-N,N-dimethylcarbamoylamino) cyclohexanecarboxamide,
N-(2-(4-(5Hdibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl))ethyl-4-aminobutyramide,
N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-piperidinyl)) ethyl-4-formylaminobutyramide,
N-(2-(4-(5H-dibenzo[a,d] cyclohepten-5-ylidene)-1-piperidinyl))ethyl-4-acetylaminobutyramide,
N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl))ethyl-4-t-butoxycarbonylaminobutyramide,
N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl))ethyl-4-(N,N-dimethylcarbamoylamino) butyramide,
N-(2(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl))ethyl-4-(N-methylamino)butyramide,
N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl))ethyl-4-(N-methyl-t-butoxycarbonylamino) butyramide,
1-formyl-N-(3-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl))propylisonipecotamide,
4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1(3-t-butoxycarbonyl aminopropyl)piperidine,
1-(3-aminopropyl)-4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine,
1-formyl-isonipecotic acid 2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)) ethyl ester,
1-(2-aminoethyl)-4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine,
4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-(2-t-butoxycarbonylamino)ethyl)piperidine,
1-formyl-N-(2-(4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl))ethylisonipecotamide,
1-(2-aminoethyl)-4-(9-thioxanthinidene)piperidine,
4-(9-thioxanthinidene)-1-((2-t-butoxycarbonylamino)ethyl) piperidine,
1-formyl-N-(2-(4-(9-thioxanthinidene)piperidinyl)) ethylisonipecotamide,
1-formyl-N-(2(4-(11-H-dibenzo[b,e]thiepin-2-fluoro-11-ylidene)-1-piperidinyl))ethylisonipecotamide,
1-(4-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)butyl)morpholine,
1-(4-(4-(5H-dibenzo[a,d]cyclohepten-5ylidene)-1-piperidinyl)butyl)thiomorpholine,
1-(4-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)pentyl)morpholine,
1-(4-(4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)butyl)piperidine and
1-(4-(4-(9-thioxanthilidene)piperidinyl)butyl)morpholine.
US10/101,980 1994-04-20 2002-03-21 Piperidine derivatives and anti-platelet agents containing the same Abandoned US20020147195A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US10/101,980 US20020147195A1 (en) 1994-04-20 2002-03-21 Piperidine derivatives and anti-platelet agents containing the same
US10/658,322 US20040063701A1 (en) 1994-04-20 2003-09-10 Piperidine derivatives and anti-platelet agents containing the same

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
JP081499/1994 1994-04-20
JP8149994 1994-04-20
US42564595A 1995-04-20 1995-04-20
US08/917,180 US5932593A (en) 1994-04-20 1997-08-25 Piperidine derivatives and anti-platelet agents containing the same
US09/245,846 US20020019533A1 (en) 1994-04-20 1999-02-08 Piperidine derivatives and anti-platelet agents containing the same
US10/101,980 US20020147195A1 (en) 1994-04-20 2002-03-21 Piperidine derivatives and anti-platelet agents containing the same

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US09/245,846 Division US20020019533A1 (en) 1994-04-20 1999-02-08 Piperidine derivatives and anti-platelet agents containing the same

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US10/658,322 Continuation US20040063701A1 (en) 1994-04-20 2003-09-10 Piperidine derivatives and anti-platelet agents containing the same

Publications (1)

Publication Number Publication Date
US20020147195A1 true US20020147195A1 (en) 2002-10-10

Family

ID=13748073

Family Applications (4)

Application Number Title Priority Date Filing Date
US08/917,180 Expired - Fee Related US5932593A (en) 1994-04-20 1997-08-25 Piperidine derivatives and anti-platelet agents containing the same
US09/245,846 Abandoned US20020019533A1 (en) 1994-04-20 1999-02-08 Piperidine derivatives and anti-platelet agents containing the same
US10/101,980 Abandoned US20020147195A1 (en) 1994-04-20 2002-03-21 Piperidine derivatives and anti-platelet agents containing the same
US10/658,322 Abandoned US20040063701A1 (en) 1994-04-20 2003-09-10 Piperidine derivatives and anti-platelet agents containing the same

Family Applications Before (2)

Application Number Title Priority Date Filing Date
US08/917,180 Expired - Fee Related US5932593A (en) 1994-04-20 1997-08-25 Piperidine derivatives and anti-platelet agents containing the same
US09/245,846 Abandoned US20020019533A1 (en) 1994-04-20 1999-02-08 Piperidine derivatives and anti-platelet agents containing the same

Family Applications After (1)

Application Number Title Priority Date Filing Date
US10/658,322 Abandoned US20040063701A1 (en) 1994-04-20 2003-09-10 Piperidine derivatives and anti-platelet agents containing the same

Country Status (12)

Country Link
US (4) US5932593A (en)
EP (2) EP1103544A3 (en)
JP (1) JP2001002571A (en)
KR (1) KR100351012B1 (en)
CN (1) CN1056143C (en)
AT (1) ATE204566T1 (en)
CA (1) CA2147429A1 (en)
DE (1) DE69522257T2 (en)
DK (1) DK0682015T3 (en)
ES (1) ES2161828T3 (en)
PT (1) PT682015E (en)
TW (1) TW366343B (en)

Families Citing this family (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100351012B1 (en) * 1994-04-20 2002-12-26 아지노모토 가부시키가이샤 Piperidine derivatives and antiplatelet agents containing them
US5801175A (en) * 1995-04-07 1998-09-01 Schering Corporation Tricyclic compounds useful for inhibition of G-protein function and for treatment of proliferative diseases
JP3779349B2 (en) * 1995-04-24 2006-05-24 興和株式会社 Piperidine derivatives
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
AU6230398A (en) * 1997-02-27 1998-09-18 Ajinomoto Co., Inc. Thrombolytic agent
WO1998045264A1 (en) * 1997-04-09 1998-10-15 Ajinomoto Co., Inc. Process for producing piperidinecarboxylic acid amides
WO1999000376A1 (en) * 1997-06-25 1999-01-07 Novo Nordisk A/S Novel heterocyclic compounds
JP2000247882A (en) 1999-02-26 2000-09-12 Ajinomoto Co Inc Intermittent claudication-treating agent
US6262076B1 (en) * 2000-01-28 2001-07-17 Ajinomoto Co., Inc. Pharmaceutical composition for use in the treatment of diabetic neuropathy
WO2003018538A1 (en) 2001-08-31 2003-03-06 Ajinomoto Co., Inc. Novel diarylalkene derivatives and novel diarylalkane derivatives
JP2005298340A (en) * 2002-03-13 2005-10-27 Ajinomoto Co Inc Treating agent of pain
WO2005102335A2 (en) * 2004-04-23 2005-11-03 Hypnion, Inc. Methods of treating sleep disorders
US9533973B2 (en) 2011-12-08 2017-01-03 The Board Of Regents Of The University Of Texas System Allosteric modulators of 5-hydroxytryptamine 2C receptor (5-HT2CR)
CN110100138B (en) 2016-12-23 2021-08-13 荷兰联合利华有限公司 Freezer and method for retrofitting a freezer
CN110140018B (en) 2016-12-23 2021-06-25 荷兰联合利华有限公司 Freezer and method for retrofitting a freezer
KR102236857B1 (en) 2018-12-28 2021-04-06 강원대학교산학협력단 Cyproheptadine derivatives, process for preparing the same and composition for promoting appetite comprising the same

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1322527A (en) * 1961-05-06 1963-03-29 Sandoz Sa New thiaxanthene derivatives and their preparation
FR2620121B1 (en) * 1987-09-09 1990-01-05 Synthelabo ((PYRIMIDINYL-2) -AMINOALKYL) -1 PIPERIDINES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION
US5250681A (en) * 1988-06-02 1993-10-05 Ajinomoto Co., Inc. Piperidine derivatives and hypotensives containing the same
US5393890A (en) * 1988-06-02 1995-02-28 Ajinomoto Co., Inc. Piperidine derivatives and hypotensives containing the same
CA2004211A1 (en) * 1988-11-30 1990-05-31 Masataka Syoji Piperidine derivatives and hyportensives containing the same
US5095022A (en) * 1989-07-04 1992-03-10 Hokuriku Pharmaceutical Co., Ltd. Piperidine derivatives and pharmaceutical compositions comprising the same
EP0479601B1 (en) * 1990-10-05 1999-12-15 Ajinomoto Co., Inc. Piperidine derivatives and their use as antiarrhythmic agents
JP2961995B2 (en) * 1991-10-08 1999-10-12 味の素株式会社 Piperidine derivatives and antiarrhythmic drugs containing the same
KR100351012B1 (en) * 1994-04-20 2002-12-26 아지노모토 가부시키가이샤 Piperidine derivatives and antiplatelet agents containing them

Also Published As

Publication number Publication date
EP1103544A2 (en) 2001-05-30
DK0682015T3 (en) 2003-01-27
CA2147429A1 (en) 1995-10-21
US20040063701A1 (en) 2004-04-01
KR100351012B1 (en) 2002-12-26
KR950031071A (en) 1995-12-18
ES2161828T3 (en) 2001-12-16
PT682015E (en) 2002-01-30
DE69522257D1 (en) 2001-09-27
EP1103544A3 (en) 2001-06-06
CN1056143C (en) 2000-09-06
TW366343B (en) 1999-08-11
JP2001002571A (en) 2001-01-09
ATE204566T1 (en) 2001-09-15
US5932593A (en) 1999-08-03
DE69522257T2 (en) 2002-06-13
EP0682015A1 (en) 1995-11-15
CN1112560A (en) 1995-11-29
EP0682015B1 (en) 2001-08-22
US20020019533A1 (en) 2002-02-14

Similar Documents

Publication Publication Date Title
US20020147195A1 (en) Piperidine derivatives and anti-platelet agents containing the same
KR100263414B1 (en) Thieno [3,2-b] pyridine derivatives
DE69104615T2 (en) DIPHENYLPIPERAZINE DERIVATIVE.
DE69311165T2 (en) Condensed heterocyclic ketone derivatives, their preparation and their use
US4097481A (en) Tertiary amide derivatives of pyrrolidine and piperidine
US4575508A (en) 2-Substituted 1-(3'-aminoalkyl)-1,2,3,4-tetrahydro-β-carbolines, and their use as antiarrhythmic agents
WO1998017646A1 (en) 1-(4-piperdinyl)-piperidinylene as aggregation inhibitor
ES2208947T3 (en) DERIVATIVES OF PIPERAZINO AS ANTAGONISTS OF NEUROQUININA.
EP1176144B1 (en) N-triazolylmethyl-piperazine derivatives as neurokinine receptor-antagonists
IL90309A (en) Derivatives of 6-phenyl-3-(piperazinylalkyl)-2,4(1h,3h)-pyrimidinedione their preparation and pharmaceutical compositions containing them
JPH021439A (en) Diamine compound, its manufacture, and medicine containing it and used in treatment for hyperpiesia and inflammation
DE69232981T2 (en) pyrroloazepine
DE69612753T2 (en) (R) -5-BROMO-N- (1-ETHYL-4-METHYLHEXAHYDRO-1H-1,4-DIAZEPIN-6-YL) -2-METHOXY-6-METHYLAMINO-3-PYRIDINE-CARBOXAMIDE, METHOD FOR THE PRODUCTION THEREOF AND THE CONTAINER THEREOF MEDICAL PREPARATION
BRPI0807829A2 (en) "Soluble EPOXIDE HYDROLASE INHIBITORS FOR TREATMENT OF METABOLIC SYNDROME AND RELATED DISORDERS".
JP2962186B2 (en) Piperidine derivative and serotonin antagonist containing the same
DE69232980T2 (en) PYRROLOAZEPINDERIVATE
JPH0368574A (en) Pharmaceutically active aminoimidazopyridine
US5641772A (en) Condensed diazepinones, processes for preparing them and agents containing these compounds for treating diseases of the central nervous system and for promoting cerebral blood circulation
US4855308A (en) Method of treating senile cognitive decline with N'-substituted aminopyridine adrenergic agents
JP3215676B2 (en) Piperidine derivative
EP0388081B1 (en) Agent for the treatment of disorders of the cerebral neurotransmitter system
US4822778A (en) Membrane stabilizing phenoxy-piperidine compounds and pharmaceutical compositions employing such compounds
US3833578A (en) Pyrazinoylalkylbenzenesulfonylureas and process for their preparation
DE19618970A1 (en) New thiazolopyridines
US5610155A (en) Condensed diazepinones, processes for preparing them and agents containing these compounds for treating diseases of the central nervous system and for promoting cerebral blood circulation

Legal Events

Date Code Title Description
STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION