US20020019533A1 - Piperidine derivatives and anti-platelet agents containing the same - Google Patents
Piperidine derivatives and anti-platelet agents containing the same Download PDFInfo
- Publication number
- US20020019533A1 US20020019533A1 US09/245,846 US24584699A US2002019533A1 US 20020019533 A1 US20020019533 A1 US 20020019533A1 US 24584699 A US24584699 A US 24584699A US 2002019533 A1 US2002019533 A1 US 2002019533A1
- Authority
- US
- United States
- Prior art keywords
- cyclohepten
- ylidene
- dibenzo
- 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
Links
- WCKITLGQGJSRBV-UHFFFAOYSA-N CC1CCN(C=O)CC1 Chemical compound CC1CCN(C=O)CC1 WCKITLGQGJSRBV-UHFFFAOYSA-N 0.000 description 6
- 0 C*(CC1)CCC1=C1c(cc(*)cc2)c2Nc2ccccc12 Chemical compound C*(CC1)CCC1=C1c(cc(*)cc2)c2Nc2ccccc12 0.000 description 5
- GETQZCLCWQTVFV-UHFFFAOYSA-N CN(C)C Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 4
- YOKRXNOGVCDZOM-UHFFFAOYSA-N CCCCN1CCC(=C2C3=C(C=CC=C3)CC3=C2C=C(C)C=C3)CC1 Chemical compound CCCCN1CCC(=C2C3=C(C=CC=C3)CC3=C2C=C(C)C=C3)CC1 YOKRXNOGVCDZOM-UHFFFAOYSA-N 0.000 description 3
- JJCFRYNCJDLXIK-UHFFFAOYSA-N CN(CC1)CCC1=C1c(cccc2)c2C=Cc2ccccc12 Chemical compound CN(CC1)CCC1=C1c(cccc2)c2C=Cc2ccccc12 JJCFRYNCJDLXIK-UHFFFAOYSA-N 0.000 description 3
- PAMIQIKDUOTOBW-UHFFFAOYSA-N CN1CCCCC1 Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 3
- KSMVBYPXNKCPAJ-UHFFFAOYSA-N CC1CCC(N)CC1 Chemical compound CC1CCC(N)CC1 KSMVBYPXNKCPAJ-UHFFFAOYSA-N 0.000 description 2
- TVSMLBGFGKLKOO-UHFFFAOYSA-N CC1CCN(C)CC1 Chemical compound CC1CCN(C)CC1 TVSMLBGFGKLKOO-UHFFFAOYSA-N 0.000 description 2
- BDDVMGBYHAKHGS-UHFFFAOYSA-N CCCCN1CCC(=C2C3=C(C=CC=C3)CC3=C2C=C(C)C=C3)CC1.II Chemical compound CCCCN1CCC(=C2C3=C(C=CC=C3)CC3=C2C=C(C)C=C3)CC1.II BDDVMGBYHAKHGS-UHFFFAOYSA-N 0.000 description 2
- YDQASHZTPVYCIQ-UHFFFAOYSA-N C.CC(C)(C)OC(=O)NCCN1CCC(=C2C3=C(C=CC=C3)C=CC3=C2C=CC=C3)CC1.Cl.Cl[C]=S=[W].NCCN1CCC(=C2C3=C(C=CC=C3)C=CC3=C2C=CC=C3)CC1.[H]C(=O)N1CCC(C(=O)NCCN2CCC(=C3C4=C(C=CC=C4)C=CC4=C3C=CC=C4)CC2)CC1.[H]C(=O)N1CCC(C(=O)O)CC1 Chemical compound C.CC(C)(C)OC(=O)NCCN1CCC(=C2C3=C(C=CC=C3)C=CC3=C2C=CC=C3)CC1.Cl.Cl[C]=S=[W].NCCN1CCC(=C2C3=C(C=CC=C3)C=CC3=C2C=CC=C3)CC1.[H]C(=O)N1CCC(C(=O)NCCN2CCC(=C3C4=C(C=CC=C4)C=CC4=C3C=CC=C4)CC2)CC1.[H]C(=O)N1CCC(C(=O)O)CC1 YDQASHZTPVYCIQ-UHFFFAOYSA-N 0.000 description 1
- VRUAYSHSMSZNON-UHFFFAOYSA-N C1=CC2=C(C=C1)C(=C1CCNCC1)C1=C(C=CC=C1)C=C2.CC(C)(C)OC(=O)NCCBr.CC(C)(C)OC(=O)NCCN1CCC(=C2C3=C(C=CC=C3)C=CC3=C2C=CC=C3)CC1 Chemical compound C1=CC2=C(C=C1)C(=C1CCNCC1)C1=C(C=CC=C1)C=C2.CC(C)(C)OC(=O)NCCBr.CC(C)(C)OC(=O)NCCN1CCC(=C2C3=C(C=CC=C3)C=CC3=C2C=CC=C3)CC1 VRUAYSHSMSZNON-UHFFFAOYSA-N 0.000 description 1
- ZXNNVOLXHKFKMT-UHFFFAOYSA-N CC(=O)NC1(C)CCCCC1 Chemical compound CC(=O)NC1(C)CCCCC1 ZXNNVOLXHKFKMT-UHFFFAOYSA-N 0.000 description 1
- JHLVEBNWCCKSGY-UHFFFAOYSA-N CC(C)(C)OC(NC)=O Chemical compound CC(C)(C)OC(NC)=O JHLVEBNWCCKSGY-UHFFFAOYSA-N 0.000 description 1
- XQTJTHKSACPHCW-UHFFFAOYSA-N CC(CC1)CCN1N=C=O Chemical compound CC(CC1)CCN1N=C=O XQTJTHKSACPHCW-UHFFFAOYSA-N 0.000 description 1
- YDBHSDRXUCPTQQ-UHFFFAOYSA-N CC1(N)CCCCC1 Chemical compound CC1(N)CCCCC1 YDBHSDRXUCPTQQ-UHFFFAOYSA-N 0.000 description 1
- WYRGXXSBMISUCJ-UHFFFAOYSA-N CC1(NC(=O)OC(C)(C)C)CCCCC1 Chemical compound CC1(NC(=O)OC(C)(C)C)CCCCC1 WYRGXXSBMISUCJ-UHFFFAOYSA-N 0.000 description 1
- VYSXSWBSWQZKSY-UHFFFAOYSA-N CC1(NC=O)CCCCC1 Chemical compound CC1(NC=O)CCCCC1 VYSXSWBSWQZKSY-UHFFFAOYSA-N 0.000 description 1
- FKNQCJSGGFJEIZ-UHFFFAOYSA-N CC1=CC=NC=C1 Chemical compound CC1=CC=NC=C1 FKNQCJSGGFJEIZ-UHFFFAOYSA-N 0.000 description 1
- QRMPKOFEUHIBNM-UHFFFAOYSA-N CC1CCC(C)CC1 Chemical compound CC1CCC(C)CC1 QRMPKOFEUHIBNM-UHFFFAOYSA-N 0.000 description 1
- IPKRGTICIXXWNG-UHFFFAOYSA-N CC1CCC(C)CC1.N=C=O Chemical compound CC1CCC(C)CC1.N=C=O IPKRGTICIXXWNG-UHFFFAOYSA-N 0.000 description 1
- JWCUUEGMURPVTK-UHFFFAOYSA-N CC1CCCCN1C.[C-]#[O+] Chemical compound CC1CCCCN1C.[C-]#[O+] JWCUUEGMURPVTK-UHFFFAOYSA-N 0.000 description 1
- VNWKCRHDPZTSEK-UHFFFAOYSA-N CC1CCN(C)CC1.CN=C=O Chemical compound CC1CCN(C)CC1.CN=C=O VNWKCRHDPZTSEK-UHFFFAOYSA-N 0.000 description 1
- UALBKBSRPRQRKO-UHFFFAOYSA-N CC1CCN(C)CC1.[C-]#[O+] Chemical compound CC1CCN(C)CC1.[C-]#[O+] UALBKBSRPRQRKO-UHFFFAOYSA-N 0.000 description 1
- JUKGIMHWIZVPKI-UHFFFAOYSA-N CC1CCN(N)CC1.[C-]#[O+] Chemical compound CC1CCN(N)CC1.[C-]#[O+] JUKGIMHWIZVPKI-UHFFFAOYSA-N 0.000 description 1
- LXJMRZYJPOVLET-UHFFFAOYSA-N CN(C)C(=O)NC1(C)CCCCC1 Chemical compound CN(C)C(=O)NC1(C)CCCCC1 LXJMRZYJPOVLET-UHFFFAOYSA-N 0.000 description 1
- JQTMGOLZSBTZMS-UHFFFAOYSA-N CN1CCN(C=O)CC1 Chemical compound CN1CCN(C=O)CC1 JQTMGOLZSBTZMS-UHFFFAOYSA-N 0.000 description 1
- SJRJJKPEHAURKC-UHFFFAOYSA-N CN1CCOCC1 Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 1
- KDTVWEHAAISPNW-UHFFFAOYSA-N CN1CCSCC1 Chemical compound CN1CCSCC1 KDTVWEHAAISPNW-UHFFFAOYSA-N 0.000 description 1
- OHDBUCQDUSMFSO-UHFFFAOYSA-N CNC(C(CC1)CCN1C=O)=O Chemical compound CNC(C(CC1)CCN1C=O)=O OHDBUCQDUSMFSO-UHFFFAOYSA-N 0.000 description 1
- IZNTWTMLHCGAJU-UHFFFAOYSA-N OC(C(CC1)CCN1C=O)=O Chemical compound OC(C(CC1)CCN1C=O)=O IZNTWTMLHCGAJU-UHFFFAOYSA-N 0.000 description 1
- UZOFELREXGAFOI-UHFFFAOYSA-N [H]N1CCC(C)CC1 Chemical compound [H]N1CCC(C)CC1 UZOFELREXGAFOI-UHFFFAOYSA-N 0.000 description 1
- NNWUEBIEOFQMSS-UHFFFAOYSA-N [H]N1CCCCC1C Chemical compound [H]N1CCCCC1C NNWUEBIEOFQMSS-UHFFFAOYSA-N 0.000 description 1
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
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- 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
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- 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
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- 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
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- 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
-
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- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- 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
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- 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
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- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P9/06—Antiarrhythmics
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- A—HUMAN NECESSITIES
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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
-
- 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
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
- 1. Field of the Invention
- 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.
- 2. Discussion of the Background
- 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.
- 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 (5HT2) 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.
- 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.
- This and objects which will become apparent hereinafter have been achieved with the following novel serotonin agents.
-
- 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 represents a hydrogen atom or a halogen atom selected from the group consisting of bromine, chlorine, flourine and iodine,
- Y1represents one of the following organic groups:
- —CONH—, —NHCO—, —CONHCH2—, —(CH2)n— or —COO—,
- wherein n is an integer of from 0 to 4, and
- Z1 represents one of the following organic groups:
- —CH═CH—, —S—CH2—, —S— or —CH2—CH2—,
- or a salt thereof.
- Preferred substituents for A1 in the above general formula (I) include:
-
- 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.
- Illustrative examples of such preferred substituents of A1 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 Y1 in the general formula (I) include a group —CONH—.
- Preferred examples of Z1 include —CH═CH—.
-
- wherein
- A2 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 A2 has a substituent, the substituent is one of the following groups.
-
- 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, or an acylaminoalkyl group, and
- R5 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
- X2, Y2, and Z2, respectively, have the same meanings as X1, Y1, and Z1.
- Preferred substituents for A2 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, Y2 is a group —CONH—.
- Preferably, Z2 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.
- 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
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- This application is based on Japanese Patent Application No. 081499/1944, the text of which is incorporated herein by reference.
- 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.
- 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%
- 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%
- 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).
- 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%
- 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%
- N-(2-(4-(5H-Dibenzo[a,d] cyclohepten-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%
- The compounds shown in Table 1 were produced by the similar manner as described in Preparation procedure A.
A Y X Z pKi pIC50 1 —CONH— H —CH═CH— 8.2 7.5 2 8.6 7.3 3 8.4 7.2 4 8.5 7.2 5 8.0 6.5 6 — 6.9 7 8.5 6.7 8 7.9 6.6 9 7.8 7.1 10 8.8 — 11 8.8 7.0 12 8.6 6.6 13 9.3 — 14 — — 15 — — 16 CH3CH2O— — 7.6 17 (CH3)3CO— — 7.0 18 8.9 7.3 19 8.3 6.4 20 8.0 6.3 21 7.8 6.5 22 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— 9.2 6.9 28 CH3NH(CH2)3— — 6.6 29 (CH3)3COCON(CH2)3—CH3 — 7.1 30 —CONHCH2— 8.3 6.4 31 (CH3)3CO— 8.8 — 32 H2N— —CH2— — — 33 —COO— 8.3 7.4 34 H2N— — —CH2—CH2— — — 35 (CH3)3CO— —CONH— 8.3 — 36 8.9 5.8 37 H2N— — —S— 8.4 5.0 38 (CH3)3CO— —CONH— 9.1 7.3 39 9.2 7.1 40 F —S—CH2— 7.1 5.6 - 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%
- 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%
-
-
- In the equation, Ki indicates the dissociation constant and [L] indicates the concentration of [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.
- 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 5×108 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.
- 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 5×108 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.
- 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 weight: 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.
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.
- 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.
Claims (13)
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:
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—
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:
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—.
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:
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—
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.
R5 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-(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-ethoxycarbonyl-amino)ethyl)piperidine,
4-(5H-dibenzo[a,d] cyclohepten-5-ylidene-1-(2-t-butoxy-carbonylamino)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.
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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 |
US10/658,322 US20040063701A1 (en) | 1994-04-20 | 2003-09-10 | Piperidine derivatives and anti-platelet agents containing the same |
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JP0814991994 | 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 |
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Application Number | Title | Priority Date | Filing Date |
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US08/917,180 Continuation US5932593A (en) | 1994-04-20 | 1997-08-25 | Piperidine derivatives and anti-platelet agents containing the same |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/101,980 Division US20020147195A1 (en) | 1994-04-20 | 2002-03-21 | Piperidine derivatives and anti-platelet agents containing the same |
Publications (1)
Publication Number | Publication Date |
---|---|
US20020019533A1 true US20020019533A1 (en) | 2002-02-14 |
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 (1)
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 |
Family Applications After (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
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 |
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) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20200083094A (en) | 2018-12-28 | 2020-07-08 | 강원대학교산학협력단 | Cyproheptadine derivatives, process for preparing the same and composition for promoting appetite comprising the same |
Families Citing this family (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TW366343B (en) * | 1994-04-20 | 1999-08-11 | Ajinomoto Kk | Piperidine derivatives and anti-platelet agents containing the same |
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 |
EP1008348A4 (en) * | 1997-02-27 | 2001-04-04 | Ajinomoto Kk | Thrombolytic agent |
KR20010006165A (en) | 1997-04-09 | 2001-01-26 | 에가시라 구니오 | Process for producing piperidinecarboxylic acid amides |
EP0991633A1 (en) | 1997-06-25 | 2000-04-12 | 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) |
EP3559568B1 (en) | 2016-12-23 | 2024-02-07 | Unilever IP Holdings B.V. | Freezer cabinet and method for adapting a freezer cabinet |
WO2018114374A1 (en) | 2016-12-23 | 2018-06-28 | Unilever Plc | Freezer cabinet and method for adapting a freezer cabinet |
Family Cites Families (9)
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 |
US5393890A (en) * | 1988-06-02 | 1995-02-28 | Ajinomoto Co., Inc. | Piperidine derivatives and hypotensives containing the same |
US5250681A (en) * | 1988-06-02 | 1993-10-05 | 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 |
AU620996B2 (en) * | 1989-07-04 | 1992-02-27 | Hokuriku Pharmaceutical Co. Ltd. | 4-{(dibenzocycloheptene) or (dibenzoxepin)}-1-substituted piperidines |
US5229400A (en) * | 1990-10-05 | 1993-07-20 | Ajinomoto Co., Inc. | Piperidine compounds 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 |
TW366343B (en) * | 1994-04-20 | 1999-08-11 | Ajinomoto Kk | Piperidine derivatives and anti-platelet agents containing the same |
-
1995
- 1995-04-19 TW TW084103844A patent/TW366343B/en active
- 1995-04-19 KR KR1019950009172A patent/KR100351012B1/en not_active IP Right Cessation
- 1995-04-20 CA CA002147429A patent/CA2147429A1/en not_active Abandoned
- 1995-04-20 AT AT95302647T patent/ATE204566T1/en not_active IP Right Cessation
- 1995-04-20 EP EP01103999A patent/EP1103544A3/en not_active Withdrawn
- 1995-04-20 CN CN95104192A patent/CN1056143C/en not_active Expired - Fee Related
- 1995-04-20 PT PT95302647T patent/PT682015E/en unknown
- 1995-04-20 ES ES95302647T patent/ES2161828T3/en not_active Expired - Lifetime
- 1995-04-20 DE DE69522257T patent/DE69522257T2/en not_active Expired - Fee Related
- 1995-04-20 DK DK95302647T patent/DK0682015T3/en active
- 1995-04-20 EP EP95302647A patent/EP0682015B1/en not_active Expired - Lifetime
-
1997
- 1997-08-25 US US08/917,180 patent/US5932593A/en not_active Expired - Fee Related
-
1999
- 1999-02-08 US US09/245,846 patent/US20020019533A1/en not_active Abandoned
-
2000
- 2000-06-12 JP JP2000175490A patent/JP2001002571A/en active Pending
-
2002
- 2002-03-21 US US10/101,980 patent/US20020147195A1/en not_active Abandoned
-
2003
- 2003-09-10 US US10/658,322 patent/US20040063701A1/en not_active Abandoned
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20200083094A (en) | 2018-12-28 | 2020-07-08 | 강원대학교산학협력단 | Cyproheptadine derivatives, process for preparing the same and composition for promoting appetite comprising the same |
Also Published As
Publication number | Publication date |
---|---|
EP1103544A3 (en) | 2001-06-06 |
US5932593A (en) | 1999-08-03 |
CN1056143C (en) | 2000-09-06 |
CA2147429A1 (en) | 1995-10-21 |
EP1103544A2 (en) | 2001-05-30 |
DK0682015T3 (en) | 2003-01-27 |
EP0682015A1 (en) | 1995-11-15 |
DE69522257T2 (en) | 2002-06-13 |
PT682015E (en) | 2002-01-30 |
US20040063701A1 (en) | 2004-04-01 |
TW366343B (en) | 1999-08-11 |
DE69522257D1 (en) | 2001-09-27 |
JP2001002571A (en) | 2001-01-09 |
KR950031071A (en) | 1995-12-18 |
ATE204566T1 (en) | 2001-09-15 |
CN1112560A (en) | 1995-11-29 |
KR100351012B1 (en) | 2002-12-26 |
EP0682015B1 (en) | 2001-08-22 |
ES2161828T3 (en) | 2001-12-16 |
US20020147195A1 (en) | 2002-10-10 |
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