NZ619776B2 - Heteroaryl compounds as 5-ht4 receptor ligands - Google Patents
Heteroaryl compounds as 5-ht4 receptor ligands Download PDFInfo
- Publication number
- NZ619776B2 NZ619776B2 NZ619776A NZ61977612A NZ619776B2 NZ 619776 B2 NZ619776 B2 NZ 619776B2 NZ 619776 A NZ619776 A NZ 619776A NZ 61977612 A NZ61977612 A NZ 61977612A NZ 619776 B2 NZ619776 B2 NZ 619776B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- oxadiazolyl
- piperidinyl
- chloro
- isopropyl
- indazole
- Prior art date
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- 108091005523 5-HT4 receptors Proteins 0.000 title claims abstract description 18
- 230000027455 binding Effects 0.000 title abstract description 6
- 239000003446 ligand Substances 0.000 title abstract description 6
- 125000001072 heteroaryl group Chemical group 0.000 title 1
- -1 oxadiazole derivative compounds Chemical class 0.000 claims abstract description 140
- 150000001875 compounds Chemical class 0.000 claims abstract description 102
- 206010057668 Cognitive disease Diseases 0.000 claims abstract description 6
- 206010012289 Dementia Diseases 0.000 claims abstract description 6
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 claims abstract description 5
- 206010003736 Attention deficit/hyperactivity disease Diseases 0.000 claims abstract description 5
- 201000006287 attention deficit hyperactivity disease Diseases 0.000 claims abstract description 5
- 201000000980 schizophrenia Diseases 0.000 claims abstract description 5
- 206010001897 Alzheimer's disease Diseases 0.000 claims abstract description 4
- 238000002360 preparation method Methods 0.000 claims description 82
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 56
- 239000011780 sodium chloride Substances 0.000 claims description 35
- 150000003839 salts Chemical class 0.000 claims description 34
- 150000003891 oxalate salts Chemical class 0.000 claims description 24
- 201000010099 disease Diseases 0.000 claims description 22
- 239000002904 solvent Substances 0.000 claims description 18
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 14
- 150000001412 amines Chemical class 0.000 claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- 239000012024 dehydrating agents Substances 0.000 claims description 6
- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical compound OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 230000001808 coupling Effects 0.000 claims description 4
- 238000010168 coupling process Methods 0.000 claims description 4
- 238000005859 coupling reaction Methods 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- QSXVQVWBNVEVSZ-UHFFFAOYSA-N 2-(2-piperidin-1-ylethyl)-5-(1-propan-2-ylindazol-3-yl)-1,3,4-oxadiazole Chemical compound C12=CC=CC=C2N(C(C)C)N=C1C(O1)=NN=C1CCN1CCCCC1 QSXVQVWBNVEVSZ-UHFFFAOYSA-N 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 150000002500 ions Chemical class 0.000 claims description 3
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- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
- 230000001404 mediated Effects 0.000 claims 1
- YDQDIKYQYPYXMY-UHFFFAOYSA-N oxalic acid;2-(2-piperidin-1-ylethyl)-5-(1-propan-2-ylindazol-3-yl)-1,3,4-oxadiazole Chemical compound OC(=O)C(O)=O.C12=CC=CC=C2N(C(C)C)N=C1C(O1)=NN=C1CCN1CCCCC1 YDQDIKYQYPYXMY-UHFFFAOYSA-N 0.000 abstract description 2
- 208000009025 Nervous System Disease Diseases 0.000 abstract 2
- 206010029305 Neurological disorder Diseases 0.000 abstract 2
- GTUCZTYJFXBSTJ-UHFFFAOYSA-N 6-chloro-8-[5-[1-(2-methoxyethyl)piperidin-4-yl]-1,3,4-oxadiazol-2-yl]-3,4-dihydro-2H-chromen-5-amine Chemical compound C1CN(CCOC)CCC1C1=NN=C(C=2C=3OCCCC=3C(N)=C(Cl)C=2)O1 GTUCZTYJFXBSTJ-UHFFFAOYSA-N 0.000 abstract 1
- 239000011541 reaction mixture Substances 0.000 description 47
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N DMSO-d6 Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 46
- 239000000243 solution Substances 0.000 description 44
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- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 35
- 239000003039 volatile agent Substances 0.000 description 30
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 29
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- 101700067048 CDC13 Proteins 0.000 description 26
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- 239000002253 acid Substances 0.000 description 19
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 19
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- 239000012043 crude product Substances 0.000 description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 12
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 12
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- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 9
- 235000017557 sodium bicarbonate Nutrition 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 8
- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 8
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical class CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 7
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- WPYMKLBDIGXBTP-UHFFFAOYSA-M benzoate Chemical compound [O-]C(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-M 0.000 description 7
- 210000004027 cells Anatomy 0.000 description 7
- 238000002347 injection Methods 0.000 description 7
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- FYSNRJHAOHDILO-UHFFFAOYSA-N Thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
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- 235000006408 oxalic acid Nutrition 0.000 description 5
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- HGUFODBRKLSHSI-UHFFFAOYSA-N 2,3,7,8-tetrachloro-dibenzo-p-dioxin Chemical compound O1C2=CC(Cl)=C(Cl)C=C2OC2=C1C=C(Cl)C(Cl)=C2 HGUFODBRKLSHSI-UHFFFAOYSA-N 0.000 description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Carbodicyclohexylimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
- QRXWMOHMRWLFEY-UHFFFAOYSA-N Isoniazid Chemical compound NNC(=O)C1=CC=NC=C1 QRXWMOHMRWLFEY-UHFFFAOYSA-N 0.000 description 4
- FEWJPZIEWOKRBE-LWMBPPNESA-N L-(+)-Tartaric acid Natural products OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 description 4
- DLYUQMMRRRQYAE-UHFFFAOYSA-N Phosphorus pentoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 4
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- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical compound [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 4
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- 238000010898 silica gel chromatography Methods 0.000 description 4
- AGGHKNBCHLWKHY-UHFFFAOYSA-N sodium;triacetyloxyboron(1-) Chemical compound [Na+].CC(=O)O[B-](OC(C)=O)OC(C)=O AGGHKNBCHLWKHY-UHFFFAOYSA-N 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
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- 150000007942 carboxylates Chemical class 0.000 description 3
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- DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 description 3
- DNUTZBZXLPWRJG-UHFFFAOYSA-N piperidine-1-carboxylic acid Chemical compound OC(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-N 0.000 description 3
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- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
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- RSKCEXWCDKVQQO-UHFFFAOYSA-N 1H-indazole;oxalic acid Chemical compound OC(=O)C(O)=O.C1=CC=C2C=NNC2=C1 RSKCEXWCDKVQQO-UHFFFAOYSA-N 0.000 description 2
- RCSURIYLKXYRRU-UHFFFAOYSA-N 2-(1-cyclobutylpiperidin-4-yl)acetic acid Chemical compound C1CC(CC(=O)O)CCN1C1CCC1 RCSURIYLKXYRRU-UHFFFAOYSA-N 0.000 description 2
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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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4245—Oxadiazoles
-
- 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
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Abstract
Provided are substituted oxadiazole derivative compounds, of the general formula (I), wherein the variables are as defined in the specification. Examples of the compounds include 6-Chloro-8-{5-[1-(2-methoxy-ethyl)-piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-chroman-5-ylamine and 1-Isopropyl-3-[5-(2-piperidin-1-yl-ethyl)-[1,3,4]oxadiazol-2-yl]-1H-indazole oxalate salt. The compounds are 5-HT4 receptor ligands. The compounds may be useful in the treatment of neurological disorders such as attention deficit hyperactivity disorder, Alzheimer’s disease, cognitive disorders, dementia and schizophrenia. idin-1-yl-ethyl)-[1,3,4]oxadiazol-2-yl]-1H-indazole oxalate salt. The compounds are 5-HT4 receptor ligands. The compounds may be useful in the treatment of neurological disorders such as attention deficit hyperactivity disorder, Alzheimer’s disease, cognitive disorders, dementia and schizophrenia.
Description
HETEROARYL‘ COMPOUNDS AS 5-HT4 RECEPTOR LIGANDS
Field of Invention
The present inVention relates to novel compounds of formula (I) and their
pharrnaceutically acceptable salts and compositions containing them, for treatment Of
' various disorders that are related to 5-HT4 receptors.
ound of the Invention
-HT4 receptor has been officially recognized (Humphrey et al., 1993) and
identified in a variety Of tissues across many species (for review see Ford & Clarke,
1993). 5-HT4 or modulators (e.g., Iagonists and antagonists) are found to be useful
for the ent of a variety of diseases such as gastroesophageal reflux disease,
disease, '
gastrointestinal gastric motility disorder, non-ulcer dyspepsia, functional
dyspepsia, irritable bowel syndrome,
_ constipation, dyspepsia, esophagitis,
gastroesophageral disease, nausea, central nervous system diseases, cognitive disorders,
dementia, attention deficit hyperactivity disorder, schizophrenia and cardiovascular
disorders such as cardiac failure and heart arryhthmia (Corsi.M etal., cological
analysis of 5-hydroxytryptamine effects on electrically stimulated human isolated
urinary r, Br;J.Pharmacol. 1991, 104(3), 719-725; Waikar.M.V et al., Evidence
for an inhibitory 5-HT4 receptor in urinary bladder of rhesus and lgus
monkeys, Br.J.Pharrnacol. 1994, 111( 1), 8; Anthony P. D. W. Ford et al., The 5-
HT4 Receptor, Med. Res. Rev. 1993, 13(6), 633-662; Gary W. Gullikson et al.,
Gastrointestinal motility responses to the S and R enantiomers of zacopride a S-HT4
agonist and 5-HT; antagonist, Drug Dev. Res.‘ 1992, 26(4), 405-417; n.A.J et
al., A like or in human right atrium, Naunyn-Schmiedeberg's Arch.‘
Pharmacol. 1991, 344(2), 150-159).,
Patent publications WO97/17345A1, US20060194842, US20080207690,
US20080255113 and 0269211 disclosed some 5-HT4 receptor compounds.
While some 5-HT4 receptor ligands have been disclosed, and there still exists a need
and scope to discover new drugs with novel chemical structures for treatment of
disorders affected by 5-HT4 or. It is an object of the present invention to provide
a novel compound and/or a process for ation of a compound and/or a compound
prepared by said method and/or a pharmaceutical composition and/or use of a
compound in the manufacture of medicament for the treatment of diseases related to 5-
HT4 receptors and/or use of a compound for the manufacture of a medicament for
treatment of a disorder of central nervous system related to or affected by the 5-HT4
receptors. It is a further alternative object to at least provide the public with a useful
choice.
Summary of the Invention
The t ion relates to novel 5-HT4 ligand compounds of the formula
(I),
N n A
N O
wherein,
Ar Cl Y m N
is NH2 or ;
R1 R1 R1
A N N
is , or ;
is point of ment;
R1 is alkyl, R3-O-R3 or p R2;
R2 is cycloalkyl or heterocyclyl, and optionally substituted with en, alkyl
or -CO-OR3;
R3 is alkyl;
“Y” is C or O;
“m” is an integer ranging from 0 to 1; with proviso when m is 0 then R1 is
cycloalkyl or heterocyclyl;
“n” is an integer ranging from 0 to 2;
“p” is an integer ranging from 0 to 1;
or a pharmaceutically acceptable salt thereof.
In one embodiment the compound is ed from the group consisting of:
6-Chloro[5-(1-cyclopropyl-piperidinyl)-[1,3,4]oxadiazolyl]-chroman-
-ylamine;
1-isopropyl{5-[1-(3-methoxy propyl) piperidinyl]-[1,3,4]oxadiazolyl}-
1H-indazole;
3-[5-(1-cyclobutyl-piperidinyl methyl)-[1,3,4]oxadiazolyl]isopropyl-
1H-indazole;
6-chloro[5-(3-cyclobutylaza bicyclo[3.1.0]hexyl)-[1,3,4]oxadiazol
yl] chromanyl amine;
8-Aminochloro-2,3-dihydro benzo[1,4]dioxanyl)-[1,3,4]oxadiazol-
[1,4']bipiperidinyl-1'-carboxylic acid ethyl ester;
-Chloro{5-[1-(tetrahydro pyranyl) piperidinyl]-[1,3,4]oxadiazol
yl}-2,3-dihydro benzofuranyl amine;
6-Chloro[5-(1-cyclopentyl-piperidinylmethyl)-[1,3,4]oxadiazolyl]-
chromanylamine;
6-Chloro[5-(3-isopropylaza-bicyclo[3.1.0]hexyl)-[1,3,4]oxadiazol
yl]-chromanylamine;
6-Chloro[5-(3-cyclobutylmethylaza-bicyclo[3.1.0]hexyl)-
[1,3,4]oxadiazolyl]-chromanylamine;
6-Chloro{5-[1-(tetrahydro-pyranyl)-piperidinyl]-[1,3,4]oxadiazol
yl}-chromanylamine;
6-Chloro{5-[1-(tetrahydro-pyranylmethyl)-piperidinyl]-
[1,3,4]oxadiazolyl}-chromanylamine;
-Chloro[5-(1-cyclopropyl-piperidinyl)-[1,3,4]oxadiazolyl]-2,3-
dihydro-benzofuranylamine;
-Chloro[5-(1-cyclobutyl-piperidinyl)-[1,3,4]oxadiazolyl]-2,3-dihydrobenzofuranylamine
ro[5-(1-cyclopropyl-piperidinyl)-[1,3,4]oxadiazolyl]-2,3-
dihydro-benzo[1,4]dioxinylamine;
ro{5-[1-(tetrahydro-pyranyl)-piperidinyl]-[1,3,4]oxadiazol
yl}-2,3-dihydro-benzo[1,4]dioxinylamine;
6-Chloro{5-[1-(3-methoxy-propyl)-piperidinyl]-[1,3,4]oxadiazolyl}-
2,3-dihydro-benzo[1,4]dioxinylamine;
6-Chloro{5-[1-(tetrahydro-pyranylmethyl)-piperidinyl]-
[1,3,4]oxadiazolyl}-2,3-dihydro-benzo[1,4]dioxinylamine;
-Chloro{5-[1-(tetrahydro-pyranylmethyl)-piperidinyl]-
[1,3,4]oxadiazolyl}-2,3-dihydro-benzofuranylamine;
4-[5-(4-Aminochloro-2,3-dihydro-benzofuranyl)-[1,3,4]oxadiazolyl]-
[1,4']bipiperidinyl-1'-carboxylic acid ethyl ester;
1-Isopropyl{5-[3-(3-methoxy-propyl)aza-bicyclo[3.1.0]hexyl]-
[1,3,4]oxadiazolyl}-1H-indazole;
3-[5-(3-Cyclobutylaza-bicyclo[3.1.0]hexyl)-[1,3,4]oxadiazolyl]
pyl-1H-indazole;
3-[5-(3-Cyclobutylmethylaza-bicyclo[3.1.0]hexyl)-[1,3,4]oxadiazolyl]-
1-isopropyl-1H-indazole;
3-[5-(3-Cyclopropylmethylaza-bicyclo[3.1.0]hexyl)-[1,3,4]oxadiazol
yl]isopropyl-1H-indazole;
1-Isopropyl{5-[1-(tetrahydro-pyranylmethyl)-piperidinyl]-
[1,3,4]oxadiazolyl}-1H-indazole;
1-Isopropyl{5-[1-(tetrahydro-pyranyl)-piperidinyl]-[1,3,4]oxadiazol
yl}-1H-indazole;
1-Isopropyl[5-(2-piperidinyl-ethyl)-[1,3,4]oxadiazolyl]-1H-indazole.
The present invention relates to use of a therapeutically effective amount of
compound of a (I), to manufacture a medicament in the treatment of various
disorders that are related to 5-HT4 receptors.
Specifically, the compounds of this invention are useful in the treatment of
various disorders such as attention t hyperactivity er, alzheimers disease,
cognitive disorders, dementia or schizophrenia.
In another aspect, the ion relates to pharmaceutical compositions
containing a therapeutically effective amount of at least one compound of formula (I),
and their pharmaceutically acceptable salts thereof, in admixture with pharmaceutical
acceptable excipient.
In still another aspect, the invention relates to the methods of treatment by using
compounds of formula (I).
In yet another aspect, the invention further relates to the process for preparing
compounds of a (I) and their pharmaceutically acceptable salts.
Representative compounds of the present invention include those specified
below and their pharmaceutically able salts. The present invention should not be
ued to be limited to them.
6-Chloro[5-(1-cyclopropyl-piperidinyl)-[1,3,4]oxadiazolyl]-chroman
ylamine hemi fumarate;
6-Chloro[5-(1-cyclobutyl piperdinylmethyl)-[1,3,4]oxadiazolyl]-chromanyl
amine L(+)-tartarate salt;
ro[5-(1-cyclobutyl piperdinyl )-[1,3,4]oxadiazolyl]-chromanyl
amine;
1-Isopropyl{5-[1-(3-methoxy propyl) piperidinyl]-[1,3,4]oxadiazolyl}-1H-
indazole oxalate salt;
3-[5-(1-Cyclobutyl-piperidinyl methyl)-[1,3,4]oxadiazolyl]isopropyl-1H-
indazole L(+)-tartarate salt;
6-Chloro[5-(3-cyclobutylaza o[3.1.0]hexyl)-[1,3,4]oxadiazolyl]
chromanylamine oxalate salt;
4-[5-(8-Aminochloro-2,3-dihydro benzo[1,4]dioxanyl)-[1,3,4]oxadiazolyl]-
[1,4']bipiperidinyl-1'-carboxylic acid ethyl ester oxalate salt;
-Chloro{5-[1-(tetrahydro pyranyl) piperidinyl]-[1,3,4]oxadiazolyl}-2,3-
dihydro benzofuranyl amine oxalate salt;
6-Chloro{5-[1-(2-methoxy-ethyl)-piperidinyl]-[1,3,4]oxadiazolyl}-chroman
ylamine;
ro{5-[1-(3-methyl-butyl)-piperidinyl]-[1,3,4]oxadiazolyl}-chroman
ylamine;
6-Chloro[5-(1-cyclobutylmethyl-piperidinyl)-[1,3,4]oxadiazolyl]-chroman
ylamine;
6-Chloro[5-(1-cyclopropylmethyl-piperidinyl)-[1,3,4]oxadiazolyl]-chroman
ylamine;
6-Chloro[5-(1-isopropyl-piperidinyl)-[1,3,4]oxadiazolyl]-chromanylamine;
6-Chloro{5-[1-(3-methoxy-propyl)-piperidinyl]-[1,3,4]oxadiazolyl}-chroman-
-ylamine;
6-Chloro[5-(1-cyclobutyl-piperidinyl)-[1,3,4]oxadiazolyl]-chromanylamine;
6-Chloro[5-(1-cyclobutylmethyl-piperidinyl)-[1,3,4]oxadiazolyl]-2,3-dihydrobenzo
[1,4]dioxinylamine;
6-Chloro[5-(1-cyclobutyl-piperidinyl)-[1,3,4]oxadiazolyl]-2,3-dihydrobenzo
[1,4]dioxinylamine;
6-Chloro[5-(1-cyclopentyl-piperidinyl)-[1,3,4]oxadiazolyl]-chroman
ylamine;
6-Chloro[5-(2-piperidinyl-ethyl)-[1,3,4]oxadiazolyl]-chromanylamine;
4-[5-(5-Aminochloro-chromanyl)-[1,3,4]oxadiazolyl]-[1,4']bipiperidinyl-1'-
carboxylic acid ethyl ester;
6-Chloro[5-(3-piperidinyl-propyl)-[1,3,4]oxadiazolyl]-chromanylamine;
6-Chloro[5-(1-cyclopentyl-piperidinylmethyl)-[1,3,4]oxadiazolyl]-chroman
ylamine oxalate salt;
6-Chloro[5-(3-isopropylaza-bicyclo[3.1.0]hexyl)-[1,3,4]oxadiazolyl]-
chromanylamine e salt;
6-Chloro[5-(3-cyclobutylmethylaza-bicyclo[3.1.0]hexyl)-[1,3,4]oxadiazol
yl]-chromanylamine oxalate salt;
6-Chloro[5-(3-cyclopropylmethylaza-bicyclo[3.1.0]hexyl)-[1,3,4]oxadiazol
yl]-chromanylamine;
ro{5-[1-(tetrahydro-pyranyl)-piperidinyl]-[1,3,4]oxadiazolyl}-
chromanylamine oxalate salt;
6-Chloro{5-[1-(tetrahydro-pyranylmethyl)-piperidinyl]-[1,3,4]oxadiazol
yl}-chromanylamine oxalate salt;
-Chloro[5-(1-cyclopropyl-piperidinyl)-[1,3,4]oxadiazolyl]-2,3-dihydrobenzofuranylamine
oxalate salt;
-Chloro[5-(1-cyclobutyl-piperidinyl)-[1,3,4]oxadiazolyl]-2,3-dihydrobenzofuranylamine
oxalate salt;
6-Chloro[5-(1-cyclopropyl-piperidinyl)-[1,3,4]oxadiazolyl]-2,3-dihydrobenzo
[1,4]dioxinylamine oxalate salt;
ro{5-[1-(tetrahydro-pyranyl)-piperidinyl]-[1,3,4]oxadiazolyl}-2,3-
dihydro-benzo[1,4]dioxinylamine oxalate salt;
6-Chloro{5-[1-(3-methoxy-propyl)-piperidinyl]-[1,3,4]oxadiazolyl}-2,3-
dihydro-benzo[1,4]dioxinylamine oxalate salt;
6-Chloro{5-[1-(tetrahydro-pyranylmethyl)-piperidinyl]-[1,3,4]oxadiazol
3-dihydro-benzo[1,4]dioxinylamine oxalate salt;
-Chloro{5-[1-(tetrahydro-pyranylmethyl)-piperidinyl]-[1,3,4]oxadiazol
yl}-2,3-dihydro-benzofuranylamine oxalate;
4-[5-(4-Aminochloro-2,3-dihydro-benzofuranyl)-[1,3,4]oxadiazolyl]-
[1,4']bipiperidinyl-1'-carboxylic acid ethyl ester oxalate;
3-[5-(1-Cyclobutylmethyl-piperidinyl)-[1,3,4]oxadiazolyl]isopropyl-1H-
indazole;
1-Isopropyl{5-[1-(2-methoxy-ethyl)-piperidinyl]-[1,3,4]oxadiazolyl}-1H-
indazole;
3-[5-(1-Cyclobutyl-piperidinyl)-[1,3,4]oxadiazolyl]isopropyl-1H-indazole;
1-Isopropyl[5-(1-isopropyl-piperidinyl)-[1,3,4]oxadiazolyl]-1H-indazole;
3-[5-(1-Cyclopropylmethyl-piperidinyl)-[1,3,4]oxadiazolyl]isopropyl-1H-
indazole;
ropyl{5-[1-(3-methyl-butyl)-piperidinyl]-[1,3,4]oxadiazolyl}-1H-
indazole;
3-[5-(1-Cyclopropyl-piperidinyl)-[1,3,4]oxadiazolyl]isopropyl-1H-indazole;
3-[5-(1-Cyclopentyl-piperidinyl)-[1,3,4]oxadiazolyl]isopropyl-1H-indazole;
1-Isopropyl{5-[3-(3-methoxy-propyl)aza-bicyclo[3.1.0]hexyl]-
[1,3,4]oxadiazolyl}-1H-indazole oxalate salt;
3-[5-(3-Cyclobutylaza-bicyclo[3.1.0]hexyl)-[1,3,4]oxadiazolyl]isopropyl-
azole oxalate salt;
3-[5-(3-Cyclobutylmethylaza-bicyclo[3.1.0]hexyl)-[1,3,4]oxadiazolyl]
isopropyl-1H-indazole e salt;
3-[5-(3-Cyclopropylmethylaza-bicyclo[3.1.0]hexyl)-[1,3,4]oxadiazolyl]
pyl-1H-indazole oxalate salt;
1-Isopropyl{5-[1-(tetrahydro-pyranylmethyl)-piperidinyl]-[1,3,4]oxadiazol
yl}-1H-indazole oxalate salt;
1-Isopropyl{5-[1-(tetrahydro-pyranyl)-piperidinyl]-[1,3,4]oxadiazolyl}-1H-
indazole oxalate salt;
1-Isopropyl[5-(2-piperidinyl-ethyl)-[1,3,4]oxadiazolyl]-1H-indazole oxalate;
1-cyclobutyl piperidinyl methyl)-[1,3,4]oxadiazolyl]isopropyl-1H-
indazole oxalate salt.
In another aspect the invention relates to the process for preparation of a
nd of formula (I) as defined above, which comprises:
(a) coupling the compound of formula (1) with compound of formula (2)
in presence of dehydrating agent to form a compound of formula (I),
wherein all substitutions are as defined above,
(b) optionally converting the compound of formula (I) to their
pharmaceutically acceptable salts.
In another aspect the invention relates to a compound of a (I) when
prepared by the process above.
In another aspect the invention relates to the process for preparation of a
compound of formula (I) as defined above, which comprises:
- 7A -
(a) coupling the compound of formula (1) with compound of a (2),
in presence of suitable solvent to form a compound of formula (4),
(b) cyclizing the compound of formula (4) to form a compound of formula (I),
wherein all tutions are as defined above,
(c) optionally converting the compound of formula (I) to their pharmaceutically
acceptable salts.
In another aspect the invention relates to a compound of formula (I) when
prepared by the processes above.
In another aspect the invention relates to a pharmaceutical composition
comprising a compound of formula (I) and pharmaceutically acceptable excipients.
In another aspect the invention relates to use of a compound of formula (I) in
the manufacture of medicament for the treatment of diseases related to 5-HT4 receptors.
In another aspect the invention s to use of a nd of formula (I) in
the manufacture of a ment for treatment of a disorder of l nervous system
related to or affected by the 5-HT4 receptors.
Detailed Description of the Invention
Unless otherwise stated, the following terms used in the specification and
claims have the meanings given below:
- 7B -
The term “alkyl” means ht chain or branched hydrocarbon radical
consisting solely of carbon and en atoms, containing no unsaturation, having
from one to three carbon atoms, and which is attached to the rest of the molecule by a
single bond. Exemplary “alkyl” groups include methyl, ethyl, n-propyl, iso-propyl and
the like.
The term “cycloalkyl” means non-aromatic mono cyclic ring of 3 to 8 carbon
atoms. Exemplary “cycloalkyl” groups include cyclopropyl, cyclobutyl, cyclopentyl
and the like.
The term “heterocyclyl” means non-aromatic mono cyclic ring of 2 to 7 carbon
atoms, whose ring structures include 1 to 3 heteroatoms, these additional atoms may be
repeated more than once in ring. Exemplary “heterocyclyl” groups include pyrrolidinyl,
piperidinyl, piperazinyl, morpholinyl and the like.
The phrase "pharmaceutically able salts" tes that the substance or
composition must be compatible chemically and/or toxicologically, with the other
ingredients comprising a formulation, the mammal being treated therewith.
The phrase "therapeutically effective amount" is d as an amount of a
compound of the present invention that (i) treats the particular disease, condition or
disorder (ii) eliminates one or more symptoms of the particular disease, condition or
disorder (iii) delays the onset of one or more symptoms of the particular disease,
condition or disorder bed herein.
Commercial reagents were ed without further purification. Room
temperature refers to 25 - 40 oC. Unless otherwise stated, all mass spectra were d
out using ESI conditions. 1H-NMR spectra were recorded at 400 MHz on a Bruker
instrument. Deuterated chloroform, methanol or ylsulfoxide was used as solvent.
TMS was used as internal reference standard. Chemical shift values are expressed in
parts per million (d) values. The ing abbreviations are used for the multiplicity
for the NMR signals: s=singlet, bs=broad singlet, d=doublet, let, q=quartet,
qui=quintet, h=heptet, ble doublet, dt=double triplet, tt=triplet of triplets,
m=multiplet. tography refers to column chromatography performed using 100 -
200 mesh silica gel and executed under nitrogen pressure (flash chromatography)
conditions.
- 7C -
Unless the context clearly requires ise, throughout the description and the
claims, the words “comprise”, “comprising”, and the like, are to be construed in an
inclusive sense as d to an exclusive or exhaustive sense, that is to say, in the
sense of “including, but not limited to”.
The reference to any prior art in the specification is not, and should not be taken
as, an acknowledgement or any form of suggestion that the prior art forms part of the
common general knowledge in New Zealand.
Pharmaceutical compositions
In order to use the compounds of formula (I) in therapy, they will ly be
formulated into a pharmaceutical ition in accordance with standard
pharmaceutical practice.
The pharmaceutical compositions of the present invention may be formulated in
a conventional manner using one or more pharmaceutically acceptableexcipient. The
ceutically acceptable excipient is carrier or diluent. Thus, the active nds
of the invention may be formulated for oral, intranasal or parenteral (e.g., intravenous,
intramuscular or subcutaneous). Such pharmaceutical compositions and processes for
preparing same are well known in the art (The Science and Practice of Pharmacy, D.B.
Troy, 21st Edition, Williams & Wilkins, 2006).
The dose of the active compounds can vary depending on factors such as the
route of administration, age and weight of patient, nature and severity of the disease to
be treated and r factors. Therefore, any reference herein to a pharmacologically
- 7D -
effective amount of the compounds of general formula (I) refers to the aforementioned
.- factors.
: Methods
of Preparation
The compounds of formula (I) can be prepared by Scheme 1 & Scheme II as
shown below
'SchemeI .-
O N\NH2 /N__. n
7N\ 0
o + HQ > ——~——»
~ 0
(I) (,2) -
In above Scheme I, all symbols are as defined above.
The compound of formula (1) is coupled with nd of formula (2) using
dehydrating agent to form compound of formula (I). The dehydrating agent is ed
from group consisting of aluminium phosphate, calcium oxide, cyanuric chloride, N,N'-
dicyclohexylcarbodiimide, Il) chloride, ormic acid, phosphorus pentoxide
or phosphoryl chloride and more preferably selected dehydrating agent is oryl
chloride.
The compounds of forrnula (l) and formula (2) maytbe prepared'by using
preparations 1 to 9 or commercially available or can be prepared by conventional
methods or by modification, using known process.
WO 42135
Schemell .
H o
o ”\an a H‘
0 N\NH
o 0
(l ) ’
. (4) _1 (2
In above Scheme II, all symbols are as defined above;
The compound of formula (1) is coupled with compound of formula (2) in
suitable solvent to form nd of formula (4). The compound of al(4) is
cyclized in presence of atingflagent to form compound of formula (I).
In the first step of the above preparation, the solvent is selected from group
consisting of ethanol, tetrahydrofuran, dichloromethane, dichloroethane, toluene,
dimethylformamide, yl ide, 1,4-dioxan, tetrahydrofuran, triethylamine,
toluene, pyridine, ethyl acetate, dichloromethane and the like or a mixture thereof and
more preferably selected solvents are dichloromethane and triethylamine.
In the secOnd step of the above preparation, the dehydrating is selected from
group consisting of aluminiumphosphate, calcium oxide, cyanuric chloride, N,N'-
dicyclohexylcarbodiimide, iron(III) chloride, 'orthoformic acid, phosphorus pentoxide
or phosphoryl chloride and more preferably selected dehydrating agent is phosphoryl
chloride.
The compounds of formula (1) and formula (2) may be prepared by using
preparations 1 to 9 or commercially ble or can be prepared by conventional
methods or by modification, using known s.
If necessary, pharmaceutiCally acceptable salts for compounds of formula (I)
may be prepared conventionally by on with the appropriate acid or acid
derivative.
Suitable phannaceutically acceptable salts will be apparent to those d in
the art and include those described in J. Pharm. Sci., 1977, 66, 1-19, such as acid
addition salts formed with inorganic acids 6. g. hydrochloric, hydrobromic, ic,
nitric or phosphoric acid and organic acids e.g., succinic, maleic, acetic, fumaric, citric,
,malic, tartaric, benzoic, p—toluic, p- toluenesulfonic, benzenesulfonic
, acid,
methanesulfonic or naphthalenesulfonic acid. The most red salts of compounds of
formula (I) are oxalate, tartarate,‘ fumarate, methane sulfonate, hydrochloride and
sulfate. Based on the clinical development of the compound we will select the salt form
of the compound and effective dose. e salt is most preferable salt for the free
base compound of Example 3 and Example 4. Fumarate salt is most preferable salt for
the free base nd of Example 1. From free base compounds of Examples 1-74,
the person skilled in art can easily prepare all preferred salts of this invention based on
the clinincal devolpment of the compound.
Examples
The novel compounds of the present invention were prepared according to the
following experimental procedures, using appropriate materials and conditions.
Preparation 1: Preparation of 5-Aminochloro chromancarboxylic acid
hydrazide
Step (i): Preparation of Methyl 4-aminohydroxy benzoate
To a stirred solution of 4-aminosa1icylic acid (50 grams, 326.7 mmol) in
methanol (375 mL) at 0 °C was added trated sulfuric acid (99.7 m_L, 1.87 mmol)
maintaining temperature of the reactiOn below 20°C. The reaction mixture was
gradually heated to reflux and upon tion of the reaction after 6 hours it was
cooled to ice bath temperature and ed with aqueous sodium hydroxide solution
(10.0 N, 2145 _mL). The white precipitate that formed was filtered, washed with water,
ether and dried under vacuum to obtain Methyl 44aminohydroxy benzoate (50.70
grams).
Yield: 93%.
1H - NMR (DMSO-dé): 8 10.76 (bs, 1H), 7.43 (d, J = 8.6 Hz, 1H), 6.13 (bs, 2H), 6.10
(dd, J = 8.6, 2.0 Hz, 1H), 5.99 (d, J =_ 2.0 Hz, 1H), 3.79 (s, 3H);
Mass (m/z): 168 .
Step (ii): Preparation of Methyl 4-acetylamino—2-hydroxy benzoate
A on of Methyl 4-aminohydroxy benzoate (50.7 grams, 303.6, mmol,
ed in above step) in ethyl acetate (750 mL) was added to a stirred solution of
water (250 mL) and sodium bicarbonate (34.9 grams, 415.5 mmol) cooled at 0 °C
followed by acetyl chloride (29.7 mL, 415.5 mmol) over a period of 15 minutes. The
reaction mixture was gradually warmed to room temperature and stirred‘for 2 hours.
The two layers were separated and the organic layer was washed with brine, dried over
anhydrous sodium sulphate and the solvent was removed under reduced re to
obtain methyl ylamino-2—hydroxy benzoate (63.5 grams).
Yield: 99 %.
1H -' NMR (CDCI3): 5 10.86 (bs, 1H), 7.78 (d, J = 8.6 Hz, 1H), 7.23 (s, 1H), 7.16 (bs,
1H), 7.10 (d, J = 8.6 Hz, 1H), 6.13 (bs, 1H), 3.92 (s, 3H), 2.19 (s, 3H);
Mass (m/z): 208 (M—H)+.
Step (iii): Preparation of methyl 4-acetylaminochlorohydroxy benzoate
To a stirred solution of methyl 4—acetylaminohydroxy benzoate (61.4 grams,
294.0 mmol, obtained in above step) in dichloroethane (1.2 ,L) was added N-
chlorosuccinimide (58.8 grams, 441 mmol) and the reaction mixture was refluxed for 3
hours. The volatiles were removed under reduced pressure; the solid compound thus
precipitated was diluted with water (1.0 L) and filtered. The crude product was diluted
with a 1:9 e (methanol and dichloromethane)‘ and washed with brine. The
organic layer was dried over anhydrous sodium. sulphate and the volatiles were
removed under reduced pressure to obtain methyl 4-acetylamino-5jchlorohydroxy
benzoate (67.7 grams).
Yield: 94.6 %.
lH - NMR (DMSO-d5)3 5 10.49 (bs, 1H), 9.47 (s, 1H), 7.75 (s, 1H), 7.72 (s, 1H), 3.85
(s, 3H), 2.16 (s, 3H);
Mass (m/z): 244, 246 (M+H)*.
Step (iv): Preparation of methyl _ 4-Acetylamino-S—chloro-Z-(prop-Z-ynyloxy)
henzoate I
€1.1-
To a stirred solution-of methyl 4-acetylamino—5-chloro—2-hydroxy benzoate (30
grams, 123.2 mmol, obtained in above step) in dimethylformamide (246 mL) was
added potassium carbonate (42.5 grams, 308 mmol). The reaction mixture was cooled
to 0 °C and propargyl bromide (22.3 mL, 150.3 mmol) was added Over a period of 15
minutes. The reaction e was warmed to room ature and stirred for 5 hours
before being dumped in ice cold water. The solids precipitated were filtered and the
crude product was dissolved in a 1:9 mixture.(methanol:dichloromethane) and washed
with brine solution. The organic layer was dried over anhydrous sodium sulphate and
the solvent was removed under reduced pressure to obtain the title compound (25.2
grams).
Yield: 73 %.
1H - NMR (DMSO-de): 8 9.60 (s, 1H), 7.91 (s, 1H), 7.76 (s, 1H), 4.82 (s, .ZH)’ 3.77 (s,
3H), 3.61 (s, 1H), 2.15 (s, 3H);
Mass (m/z): 282, 284 (M+H),+.
Step (v): Preparation of methyl S-acetylamino-6—chloro-2H—chromene—S-
carboxylate
A stirred solution of methyl 4-acetylamino-5—chloro—2—(propynyloxy)
benzoate (25 grams, 88.8 mmol, obtained in above step) in dowtherm A (127 mL) was
heated to 220 °C for 3 hours. The reaction mixture was cooled to 60-70 °C and dumped
- in hexane. The Solids precipitated were filtered and washed with hexane to obtain
methyl 5-acetylamino—6—chloro-2H-chromene-S—carboxylate (16.2 grams).
Yield: 64.8 %. - i
lH - NMR dfi): 8 9.77 (s, 1H), 7.58 (s, 1H), 6.42 (d, J = 10.1 Hz, 1H), 6.04 (m,
1H), 4.83 (s, 2H), 3.78 (s, 3H). 2.06 (s, 3H);
Mass (m/z): 282, 284 (M+H)+.
Step (vi): Preparation of methyl 5—acetylamino—6-ehloro chr0mancarboxylate
To a solution of methyl S-acetylaminochloro-2H-chromenecarboxylate
(20.5 grams, 72.9 mmol, obtained in above step) in ethanol (300 mL) was added Pd/C
(10% w/w, 8.6 grams). The en gas re was applied using balloon pressure.
The reaction mixture was stirred at room temperature for 5 hours and filtered h a
pad of celite. The e was concentrated to dryness to obtain methyl 5-acetylamino-
6V-chloro ncarboxylate (18.88 grams).
Yield; 91.3 %.
1H - NMR (DMSO-dé): 5 9.65 (s, 1H), 7.55 (s, 1H), 4.16 (t, J = 4.5 Hz, 2H), 3.76 (s,
3H), 2.58 (t, J = 6.3 Hz, 2H), 2.05 (s,i 3H), 1.87 (m, 2H);
Mass (m/z): 284, 286 (M+H)+.
Step (vii): Preparation of S-Aminoi6-ch10ro chroman-s-carboxylic acid
To methyl ylamino46fchloro chromancarboxylate (18.88 grams, 66.6
mmol, obtained in above step), aqueous sodium hydroxide solution (1.4 N, 475 mL)
was added and the reaction mixture was refluxed for 6 hours. The reaction mixture was
ed with 2N hydrochloride at 0 °C and the precipitated product was filtered and
dried under vacuum to yield. S-Amino—6-chloro chromancarboxylic acid (14.07
granis).
Ykkt92998
lH - NMR ds): 8 11.8 (bs, 1H), 7.48 (s, 1H), 5.74 (bs, 2H), 4.09 (t, J = 4.6 Hz,
2H), 2.43 (t, J = 6.4 Hz, 2H), 1.91 (m, 2H);
Mass (m/z): 228, 230 (M+H)+.
. Step (viii): Preparation of methyl S-amin-bch10ro chroman-S-carboxylate
To a stirred solution of 5-amino—6-chloro chromancarboxylic' acid (13.5
grams, 59.34 mmol, obtained in above step) in methanol (68 mL) cooled at 0 °C, cenc
sulphuric acid (18.10 mL) was added drop wise. The reaction mixture was gradually
warmed to room ature and stirred for 4 hours; The reaction mixture was cooled
to 0 °C, diluted with water (202 mL) and basified with sodium hydroxide (10 M, 57.9
mL). The product that precipitated was filtered and dried under vacuum to obtain
methyl 5-aminochloro chroman-Si-carboxylate (10.5 .
lI-I - NMR (CDCl3)I 5 7.75 (s, 1H), 4.37 (bs, 2H), 4.24 (t, J = 5.0 Hz, 2H), 3.83 (s, 3H),
2.49 (t, J = 6.6 Hz, 2H), 2.10 (m, 2H);
Mass (m/z): 242, 244 (M+H)+.
Step (ix): Preparation of 5-Aminochloro chroman-S-carboxylic acid hydrazide
To a stirred solution of methyl 5-aminochloro chromancarboxylate (10.0
grams, 41.4 mmol, obtained in above step) in ethanol (82 mL), hydrazine hydrate
(31.05 mL) was added. The reaction temperature was gradually increased to reflux and
the reaction e was stirred at this temperature for 5 hours. The volatiles were
removed under d pressure, the crude mass was dissolved in 10 % methanol in '
Idichloromethane and washed with water, brine, dried over anhydrous sodium sulphate
and the solvent was removed under reduced pressure to obtain 5-Amino—6-chloro-
chroman-8~carboxylic acid hydrazide (9.3 grams).
Yield: 93 %. .
1H - NMR (DMSO‘dé): 5 8.85 (bs, 1H), 7.56 (s, 1H), 5.59 (bs, 2H), 4.43 (bs, 2H), 4.18
(t, J = 4.8sz, 2H), 2.45 (t, J = 6.5 Hz, 2H), 1.93 (m, 2H);
Mass (m/z): 242, 244 (M+H)+.
Preparation 2: ation of methyl l-isopropyl-lH-indazolyl ylate
Step (i): Preparation of methyl lH—indazol-S-yl carboxylate
To a stirredvsolution of indazolecarboxilic acid (80.5 grams, 0.497 mmol,
obtained in above step) in methanol (2 L) cooled at 0 °C was added thionyl chloride
(120 mL, 1.59 mmol) over a period of 1 hour. The reaction temperature'was gradually '
. raised and the reaCtion mixture was refluxed for 5 hours. The volatiles were removed
and the crude mass was d with dichloromethane, washed with aqueous sodium
bicarbonate, dried over anhydrous sodium sulphate and the solvent was removed under
reduced pressure to obtain the title compound (80.2 grams).
Yield: 92 %.
1H - NMR (CDC13): 5 13.2 (bs, 1H), 8.23 (d, J = 8.2 Hz, 1H), 7.86‘(d, J = 8.4 Hz, 1H),
7.48 (t, J = 7.4 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 4.09 (s, 3H);
Mass (m/z): 177 (M+H)+.
Step (ii): Preparation of methyl l-isopropyl-1H—indazolyl ylate
To a d solution of methyl 1H-indazolyl carboxylate (80.0 grams, 0.454
mmol, obtained in above step) in dry‘dimethylformamide (500 mL) at'O °C, sodium
hydride (60 % in l oil, 23.7 grams, 0.592 mmol) was added portion wise over a
period of 30 minutes. The reaction mixture was gradually warmed to room temperature
and stirred for 45’ minutes before cooling it again to 0 °C. To the 'reaction,
isopropyliodide (55 .mL, 0.545 mmol) was added and was stirred atiroom temperature
for 4 hours. The reaction mixture was poured into crushed ice, stirred for 10 minutes
and extracted with ethyl acetate (2x250 mL). The ed organic, layer was washed
with water (2 x 500 mL), brine, dried over anhydrous sodium sulphate and the solvent
was d under reduced pressure to get the crude mass which was purified by silica
gel column to obtain methyl 1-isopropyl-1H-indazol-3—yl ylate (40.0 grams).
Yfiddz409fi
1H - NMR (CDC13)I 5 8.24 (d, J = 8.1 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.43 (t, J = 7.2
Hz, 1H), 7.,31(t J= 7.6Hz, 1H), 4.96(m, 1H), 4.,04(s 3H), l.,66(d J= 6.7Hz, 6H);
Mass (m/z): 219 (M+H).
Step (iii): Preparation of l—isopropyl-lH—indazol—3—yl carboxylic acid hydrazide
To a stirred solution of methyl l-isopropyl-lH-indazolyl carboxylate (40.0
grams, 183.5 mmol, obtained in above step) in ethanol at room temperature hydrazine
hydrate (130 mL, 2.56 mmol) was added. The reaction mixture was refluxed for 2
hours. The volatiles were removed under reduced pressure and the crude mass was
diluted with dichloromethane, washed with water, brine, dried over anhydrous sodium
sulphate and the solvent was removed under reduced re to obtain the title
compound (37.52 grams). ' 3
Yield: 93 %. .
lH - NMR (CDC13)I 5 8.35 (d, J = 8.1 Hz, 1H), 8.16 (bs, 1H), 7.47 (d, J = 8.4 Hz, 1H),
, 7.41 (t, J = 7.0 Hz, 1H), 7.28 (t, J = 7.4Hz, 1H), 4.87 (m, 1H), 4.09 (s, 3H), 1.60 (d, J =
6.6 Hz, 6H);
Mass (m/z): 219 (M+H)+.
Preparation 3: Preparation of o-S-ehloro—2.,3-dihydr0 benzofuran
carboxylic acid hydrazide
Step (i): Preparation of methyl 4-amino—S-chloro-2,3-dihydro Ibenzofu'ran
- carboxylate
To a stirred solution of 4-amino-5—chloro-2,3-dihydr0 benzofuran-74carboxylic
aeid (Chem. Pharm. Bull. 1998, 46(1), 42-52; 3.93 g, 18.4 mmol) in methanol (36.8
mL), cooled at 0 °C, thionyl chloride (6.0 mL) was'added. The reaction mixture was
gradually warmed to room temperature and was heated to reflux for '2 hours. The
volatiles were removed under reduced re; the crude mass was diluted with
s sodium bicarbonate solution and was extracted with ethyl e. The
combined organic layer was dried over anhydrous sodium sulphate and the t was
removed under vacuum to obtain methyl ochloro-2,3-dihydro benzofuran
carboxylate (3.89 grams). Yield: 92.9 %
lH - NMR (DMSO-d5)2 8 7.43 (s, 1H), 6.06 (bs, 2H), 4.60 (t, J = 8.8 HZ, .68 (s,
3H), 2.97 (t, J = 8.8 Hz, 2H); '
Mass (m/z): 228.0, 230.1 (M+H)+.
-15.‘
Step (ii): Preparation of o—5—chloro—2,3-dihydr0 benzofurancarboxylic
acid hydrazide
To a stirred solution of methyl 4-aminochloro-2,3-dihydro benzofiJran
ylate (3.88 grams, 17.07 mmol, obtained in the above step) in ethanol (34.1 mL),
hydrazine hydrate (11.5 mL, 236.2) was added. The reaction temperature was gradually
sed to reflux and the reaction mixture was stirred at this temperature for 5 hours.
The volatiles were removed under reduced pressure, the crude mass was ated with
plenty of ether and pentane to obtain4-Aminochloro—2,3-dihydr0 benzofuran
carboxylic acid hydrazide (3.76 grams).
Yield: 96 %.
lH - NMR (DMSO-da): 5 8.35 (bs, 1H), 7.44 (s, 1H), 5.85 (s, 2H), 4.68 (t, J = 8.7 Hz,
2H), 4.43 (bs, 2H), 3.0 (t, J = 8.7 Hz, 2H);
Mass (m/z): 228.0, 230.1 (M+H)+.
Preparation .4: Preparation of 8-Aminochloro—2,3—dihydro benzo[1,4]dioxane—5—
carboxylic acid ide
Step (i): ation of methyl 8-amin0chlor0-2,3-dihydro benzo[l,4]dioxane-5—
carboxylate
To a stirred solution of 8—Aminochloro—2,3-dihydro-benzo[l,4]d.i0xine—5-
carboxylic acid (Journal of Medicinal Chemistry, 1993, 36, 4121; 2.2 grams, 9.58
mmol) in methanol (38.3 mL), cooled at 0 °C thionyl chloride (2.78 mL) IWas added.
The reaction mixture was gradually warmed to room temperature and then heated to
reflux for 3 hours. The volatiles were removed under reduced pressure; the crude mass
was diluted with aq. sodium bicarbonate solution and extracted with ethyl acetate. The
ed organic layer was dried over anhydrous sodium sulphate and the t was
d under vacuum to obtain the title compound (2.12 grams).
Yiled: 90.9%
‘H - NMR(CDC13): 5 7.52 (s, 1H), 4.47 (bs, 2H), 4.45 - 4.30 (m, 4H), 3.84 (s, 3H).
Mass (m/z): 244.1, 246.1 (M+H)+.
Step (ii): Preparation of 8-Amino-7—chloro-2,3-dihydro benzo[l,4]dioxane
carboxylic acid hydrazide
' To a stirred solution of methyl 8-amino-7—chloro-2,3-dihydrobenzo
[1,4]di0xinecarboxylate (2.1 grams, 8.6 mmol, obtained in the above step) in
ethanol (34.4 mL), hydrazine hydrate (6.2 mL, 129.3 mmol) was added. The reaction
temperature was gradually increased to reflux and the reaction mixture was stirred at
this temperature for 5 hours. The volatiles were removed under reduced pressure, the
crude mass was triturated with plenty of ether and pentane to obtain 8—aminochloro-
2,3-dihydro benzo[1,4]dioxane;5-carboxylic acid hydrazide (2.1 grams).
Yield: 100 %.
1H - NMR (DMSO-de): 5 8.80 (bs, 1H), 7.27 (s, 1H), 5.40 (bs,‘2H), 4.46 (bs, 2H), 4.40-
4.25 (m, 4H); Mass (m/z): 244.1, 246.1 (M+H)+.
Preparation 5: ation of l-cyclopropyl piperidine-4—carbonyl chloride
Step (i): Preparation of opropyl dine—4—carbonitrile ‘
To a stirred solution of 1-cyclopropylpiperidone (Alfa Aesar, 3.0 grams,
21.5 mmol) in a mixture of 1, 2-dimethoxyethane (72 mL) and ethanol (2.2 mL) cooled
at 0 °C, was added p-toluenesulfonylmethylisocyanide (5.45 grams, 27.95 mmol). Solid
ium tertiary butoxide (5.54 grams, 49.45 mmol) was added over a period of 1
hour. The reaction e was stirred at this temperature for additional 1 hour and
. gradually warmed to room temperature. Afier ng for 2 hours at this temperature, it
was cooled to 0 °C, diluted with brine and ethyl acetate. The organic layer was
separated, dried over anhydrous sodium sulphate and the solvent was removed under
reduced pressure to obtain crude product, which was d by slica gel column to
yield opropyl piperidinecarbonitrile (1.32 grams).
Yield: 41.2 %.
‘H — NMR (CDC13): 8 2.82 (m, 2H), 2.63 (m, 1H), 2.49 (m, 2H), 1.98 - 1.78 (m, 4H),
1.70 - 1.58 (m, 1H), 0.50 - 0.40 (m, 2H), 0.40 — 0.35 (m, 2H);
Mass (m/z): 151 (M+H)+.
Step>(ii): Preparation of l-cyclopropyl piperidine-4—carb0xylic acid
A mixture of 1—cyclopropyl piperidinecarbonitrile (1.32 grams, 8.8 mmol,
obtained in the above step) and hydrochloric acid (6 N, 35.2 mL) was refluxed for 3
hours. The volatiles were d under reduced pressure; the traces of water were ’
removed by co distilling with toluene. The crude product thus obtained was triturated
‘ with ether several times and dried under
vacuum to obtained l-cyclopropyl piperidine-
4-carboXylic acid (2.02 grams).
Yield: 100 %.
2012/000011
lH - NMR (DMSO'd6): 5 12.54 (bs, 1H), 10.79 (bs, 1H), 3.50-3.40 (m, 2H), 3.18-30
(m, 2H), 2.—.78265 (m, 1H), 3.55- 3.45 (m: 1H), 2.10- 1.85 (m, 4H), 1.20— 1.10 (m,
2H), 080- 070 (m, 2H);
Mass (m/z): 170 (M+H) .
Step (iii): Preparation of l-cyclopropyl piperidine—4—carbonyl chloride
To a stirred mixture of 1-cyclopropyl piperidinecarboxylic acid (10.0 grams,
48.6 mmol, obtained in above step) in dichloromethane (198 mL) cooled at 0 °C was
added dry dimethyl formamide (2 mL) ed by drop wise addition of oxalyl
chloride (12.5 ‘mL, 145.8- mmol). The on mixture'was lly warmed to room
temperature and stirred for 1 hour. The volatiles were removed under reduced pressure
and the crude l-cyclopropyl piperidine—4-carbonyl ch1oride (11.0 grams). This crude
product was used in the next reaction without purification.
Yeild: 100%.
1H - NMR (DMSO-d6): 8 10.66 (bs, 1H), 3.50 — 3.42 (m, 2H), 3.40 - 3.30 (m, 1H), 3.15
, -30(m 2H), 2.80- 2.65(m, 1H), 2.10- 1.80(m,4H), 115- , 2H), 0.80- 0.70
(m, 2H);
Mass (m/z): 184 .
Preparation 6: Preparation of (l-cyclobutyl piperidinyl) acetic acid
Step (i): Preparation of t-butyl 4-ethoxycarbonylmethylene pipcridine-l-
carboxylate '
To a stirred solution of 1-Boc—4-piperidone (2.0 grams, 10.03 mmol) in benzene—
(40 mL) at room temperature was added Wittig reagent (5.23 grams, 15 mmol). The
reaction mixture was d for 10 hours and the volatiles were removed under
reduced pressure 'to obtain a crude mass Which was purified by silica gel column
chromatography to obtain t—butyl 4-,ethoxycarbonylmethylene piperidine-l—carboxylate
(2.05 grams).
Yield: 76 %.
lH - NMR (CDC13): 8 5.71 (5,1H), 4.16 (q, 2H), 3.55 - 3.45 (m, 4H), 2.94 (t, J = 5.7
Hz, 2H), 2.28 (t, J = 5.6 Hz, 2H), 1.47 (s, 9H), 1.28 (t, J = 7.1 Hz, 3H);
Mass (m/z): 270 (M+H)+.
Step (ii): Preparation of l 4-ethoxycarbonylmethyl piperidine-l-carboxylate
To a stirred solution of t-butyl - 4-ethoxycarbonylmethylene piperidine-l—
carboxylate (2.05 grams, 7.62 mmol, obtained in above step) in ethanol (30 mL) at
-_18-
room temperature was added Pd/C (10 wt %, 600 mg). Hydrogen n pressure was
applied on the reaction for 5 hours. The reaction mixture was d through a pad of
celite and the volatiles were removed under reduced pressure to obtain t-buty1
ethoxycarbonylmethyl piperidine- 1-carboxy1ate (1.98 grams).
Yield: 95.8 %.
‘H - NMR (CDC13): 6 4.20-4.0(m, 4H), 2.83 - 2.65 (m, 2H), 2.23 (d, J = 6.8 Hz, 2H),
2.0 - 1.88 (m, 1H), 1.75 -:1.68 (m, 2H), 1.45 (s, 9H), 1.26 (t, J = 7.0 Hz, 3H), 1.25 -
1.05 (m, 2H);
Mass (ni/z): 272 (M+H)+.
Step (iii): Preparation of piperidin—4-yl acetic acid ethyl ester
To a stirred solution of t—butyl 4-ethoxycarbonylmethyl dine-l-
carboxylate (1.98 grams, 7.3 mmol, obtainedin the above step) in isopropyl alchol (5
mL) cooled at 0 °C_, was added a solution of dry isopropanolic hydrogen chloride (~3
N, 15 mL). The reaction mixture was stirred at room ature for 16 hours. The
volatiles were removed under d pressure and“ the crude product was triturated
with ether several times, dried under vacuum to obtain piperidinyl acetic acid ethyl
ester (1.57 grams)
Yield: 100 %.
1H — NMR (DMSO-ds): 8 4.03 (q, 2H), 3.23 - 3.15 (m, 2H), 2.86- 2.78 (m, 2H), 2.24
(d, J = 6.8 Hz, 2H), 2.0 - 1.85 (m, 1H), 1.81 - 1.72 (m, 2H), 1.40 — 1.25 (m, 2H), 1.14 (t,
J = 6.9 Hz, 3H);
Mass (m/z): 172 (M+H)+. I
Step (iv): Preparation of (l-cyclobutyl piperidin-4—yl) acetic acid ethyl ester
A mixture of cyclobutanone‘(0.3 mL, 3.94 mmol) in acetic acid (0.19 mL, 328
mmol) was added to a d solution of piperidinyl acetic acid ethyl ester (562 mg,
3.28 mmol, obtained in above step) in dichloromethane cooled at 0 °C. Solid sodium
triacetoxyborohydride (1.39 grams, 7.2 mmol) was added portion wise over a period of
minutes. The reaction mixture was gradually warmed to room temperature and
stirred for 16 hours. The reaction mixture was cooled to 0 °C and basified with
ted sodium onate solution (pH:7.5).~ The two layers were separated, the
organic layer was washed with brine, dried over anhydrous sodium sulphate and the
volatiles were removed under reduced pressure to obtain (l-Cyclobutyl piperidinyl)
acetic acid ethyl ester (652mg).
_ 19 _
Yield: 88.3 3%.
lH - NMR (CDC13): 8 4.13 (q, 2H), 2.90 - 2.82 (m, 2H), 2.75 '
- 2.62 (m, 1H), 2.22 (d, J
= 6.9 Hz. 2H), 2.10 .95 (m, 2H), 1.95 - 1.80 (m, 2H), 1.80—1.60 (m, 7H), 1.35 - 1.20
(m, 2H), 1.27 (t, J = 7.1 Hz, 3H);
Mass (m/Z): 226 (M+H)+.
Step (v): Preparation of (l-cyclobutyl piperidin-4—yl) acetic acid
To a stirred mixture of (l-cyclobutyl piperidinyl) acetic acid ethyl ester
(652.9 mg, 2.90 mmol, obtained in above step), tetrahydrofuran (6 mL) and water (6.0
mL) cooled at 0 °C lithium hydroxide drate (133 mg, 3.19 mmol) was added in
a single lot. The reaction mixture was stirred at room temperature for 16 hours. The
reaction mixture was cooled again to 0 °C and acidified with 2N hydrochloric acid to
pH22-3.’The volatiles were removed under d pressure and the traces of water
were removed by azeotropic distillation with e to obtain ( 1-cyclobutyl piperidin-
4-yl) acetic acid (747.9 mg).
Yield: 100 %.
l.H - NMR (DMSO-ds): 5 12.25 (bs, 1H), 10.98 (bs, 1H), 3.56 - 3.45 (m, 1H), 3.30 -
3.20 (m, 2H), 3.1030 (m, 0.5H), 2.90 - 2.82 (m, 0.5H), 2.75 - 2.60 (m, 2H), 2.40 -
2.30 (m, 2H), 2.22 (d, J = 6.9 Hz, 1H), 2.17 (d, J = 6.8 Hz, 1H), 2.15 - 2.08 (m, 2H),
1.95 - 1.75 (m, 2H), 1.74 - 1.65 (m, 2H), 1.65 - 1.50 (m, 2H);
Mass (m/z): 198 (M+H)+.
Preparation 7: Preparation of l—(3—methoxy propyl) din-4—carboxylic acid
Step (i): Preparation of ethyl 1—(3-methoxy propyl) piperidinca‘rb0xylate
To a stirred on of ethyl isonipecotate (22.0 grams, 140 mmol) in
acetonitriie (250 mL) at room temperature was added cesium carbonate (97 grams, 298
mmol) followed by omethoxypropane (20 mL, 154 mmol) and the reaction
mixture was heated to reflux for 4 hours. The reaction mixture was cooled to room
temperature and filtered through a small pad of celite. The volatiles were removed
under reduced pressUre to obtain ethyl 1-(3-methoxy propyl) piperidincarboxylate
(31.0 grams).
Yield: 99%
' 1H
- NMR ): 5 4.12 (q, 2H), 3.41 (t, J = 6.4 H2, 2H), 2.90 — 2.85 (m, 2H), 2.38
(t, J = 7.4VHz,I2H), 2.34 - 2.20 (m, 1H), 2.05 - 1.93 (m, 2H), 1.92 - 1.85 (m, 2H), 1.80 -
- 1.70 (m, 4H), 1.23 (t, J = 7.1 Hz, 3H);
-20_-
Mass (m/z): 230 (M+H)".
Step (ii): Preparation of 1-(3-methoxy propyl) piperidincarboXylic acid
To a stirred mixture of ethyl '1-(3—methoxy propyl) piperidin-4—carboxylate
(33.0 grams, 144.1 mmol, obtained in the above step), tetrahydrofuran (200 mL) and
water (200 mL) was added lithium hydroxide monohydrate (6.1 grams, 144.1 mmol).
The reaction mixture was stirred at room temperature for 16 hours before being diluted
with cetate. The two layers were ted and the aqueous layer was acidified to
pH: 3-4 with concentrated hydrochloric acid and the volatiles were removed under
reduced re to obtain 1—(3-methoxy propyl) piperidincarboxylic acid (35.0
grams).
Yield: 100 %.
- lH — NMR (DMSO-dé): 5 3.30 (t, J = 6.4 Hz, 2H), 3.19 (s, 3H), 2.80 2.70 (m, 2H),
2.25 (t, J = 7.5 Hz, 2H), 2.15 - 2.05 (m, 1H), 1.92 - 1.82 (m, 2H), 1.78 — 1.70 (m, 2H),
1.68 - 1.57 (m, 2H), 1.55 - 1.43 (m, 2H1;
Mass (m/z): 202 (M+H)+.
Preparation 8: ation of 3-cyclobutylaza bicyclo[3.l.0]hexane-6— ~
carboxylic acid
Step (i): Preparation of ethyl ylaza bicyclo[3.1.0]hexanecarboxylate
To a stirred solution of ethyl 3-benzyl-2,4-dioxoaza bicyclo[3.1.0]hexane-6¥
carboxylate (SYNLETT, 1996, 1097; 5.0 grams, 18.3 mmol) in tetrahydrofuran (74 mL)
cooled at 0 °C, BH3-DMS (2N solution in tetrahydrofuran 36 mL, 73.2 mmol) was
added over a period of 30 minutes. The reaction temperature was gradually raised to
reflux for 6 hours. After cooling the reaction mixture to 0 °C, it was quenched by
adding aqueous ammonium chloride solution and was ted with ethyl acetate. The
combined organic layer was dried over anhydrous sodium te and the solvent was
removed under reduced pressure. The crude product was purified by silica gel column
chromatography to obtain ethyl 3-benzylaza o[3.1.0]hexanecarboxylate (2.8
grams)‘ 3
Yield: 62.5% ,
lH - NMR (CDC13)I 5 7.40 - 7.20 (m, 5H), 4.14 (q, 2H), 3.61 '(s, 2H), 3.05 (d, J = 9.0
Hz, 2H), 2.44 (d, J = 8.7 Hz, 2H), 2.14 (t, J = 2.6 Hz, 1H), 1.97 (s, 2H), 1.28 (t, J = 7.1
Hz, 3H);.
Mass (m/z): 246.2 .(M+H)+.
-2]-
Step (ii): Preparation of ethyl 3-aza bicyclo[3.].0]hexane-6Qcarboxylate
To a stirred on of ethyl 3-benzyl-3—aza bicyclo[3.1.0]hexane—6-carboxylate
(2.0 grams, 8.1 mmol, obtained in the above step) in methanol (20 mL), palladium
hydroxide (468 mg) was added. The reaction e was applied with hydrogen
pressure using hydrogen balloon. The reaction mixture was stirred at room temperature
for 2 hours and filtered through a small pad of celitc. The volatiles were removed under
reduced pressure to obtain ethyl 3-aza bicyclo[3.1.0]hexanecarboxy1ate (1.22 grams)
Yhddz96964
lH - NMR (CDC13): 8 4.11 (q, 2H), 3.11 (d, J = 11.6 Hz, 2H), 2.98 (d, J = 11.7 Hz, 2H),
2.02 (s, 2H), 1.49 (t, J = 3.0 Hz, 1H), 1.24 (t, J = 4.2 Hz, 3H);
Mass (m/z): 156.1 .
Step (iii): Preparation of ethyl 3-cyclobutyl—3-aza bicyclo[3.l.0]hexane-6—
‘ I
carboxylate
A mixture of cyclobutanone (157 mg, 2.19 mmol) in acetic acid (0.11 mL, 1.56
mmol) was added to a stirred solution of ethyl 3-aza bicyclo[3.1.0]hexane
carboxylate (243 mg, 1.56 mmol, obtained in the above step) in romethane,
cooled at 0 °C. Solid sodium triacetoxy borohydride (727 mg, 3.43 mmol) was added
portion wise over a period of 15 minutes. The reaction e was gradually warmed
to room temperature and stirred for 16 hours. The reaction mixture was cooled to 0°C
and basified with saturated sodium bicarbonate on (pH:7.5). The two layers were
separated, the organic layer was washed with brine, dried over anhydrous sodium
sulfate and the volatiles were removed under reduced pressure to obtain ethyl 3-
cyclobutylaza bicyclo[3.1.0]hexanecarboxylate (219 mg). i
Ykkk66096
lH - NMR (CDC13): 8 4.11 (q,2H), 3.10-2.90 (m, 3H), 2.34 (d, J = 8.8 Hz, 2H), 2.04 (s,
1H), 1.93 (s, 2H), 2.0 - 1.80 (m, 3H), 1.80- 1.55 (m, 3H), 1.25 (t, J = 7.1, Hz, 3H);
Mass (m/z); 210.2 (M+H)T.
Step (iv): Preparation of 3-cyclobutylaza o[3.1.0]hexanecarboxylic acid
To a stirred mixture of ethyl 3-cyclobutylaza bicyclo[3.1.0]hexane
carboxylate (218 mg, 1.04 mmol, obtained in the above step), tetrahydrofuran (2 mL)
and water (2.0 mL) cooled at 0 °C, lithium ide monohydrate (133 mg, 3.19
mmol) was added in a single lot. The reaction e was stirred at room temperature
for 24 hours. The (reaction mixture .was cooled again to 0 °C and acidified with 2N
hydrochloric acid’ to pH: 2-3. The volatiles were removed.under reduced pressure and
the traces of water were removed by azeotropic distillation with toluene to obtain 3-
cyclobutylaza bicyclo[3.1.0]hexane—6—carboxylic acid (180 mg).
Yield: 92 %.
IH - NMR (DMSO-dg): 5 2.98 - 2.86 (m, 1H), 2.78 (d, J = 8.5 Hz, 2H), 2.20 (d, J = 8.1
Hz, 2H), 1.90 -l.80 (m, 2H), 1.82 - 1.68 (m,- 2H), 1.65 - 1.55 (m, 2H), 1.49 (s, 2H),
1.42 (s, 111);
Mass (m/z): 182.3 (M+H)+.
Preparation 9: atiOn of [l,4']Bipiperidinyl-4,1'-dicarboxy1ic acid -l'-ethyl
ester
Step (i): Preparation of ethyl 4—oxo piperidine—l-carboxylate
To the d‘solution of piperidin—4-one hydrochloride (2.0 g, 14.7 mmol) in
DCM (60 mL) cooled at 0 °C, was added triethylamine (5.15 mL, 36.75 mmol) and
ethylchloroformate (1.59 mL, 16.6 mml). The reaction mixture was stirred at room
temperaturefor 2 hours before being "diluted with water. The two layers were separated,
the organic layer was dried over anhydrous sodium sulfate and the volatiles were
d under reduced pressure to obtain ethyl 4—oxo—piperidine-l-carboxylate (3.14
grams).
Yield: 98 %
IH *- NMR (CDC13): 5 4.22 (q, 2H), 3.79 (t, J = 6.0 Hz, 2H), 2.48 (t, J = 6.0 Hz, 2H),
1.31 (t, J = 7.1 Hz, 3H);
Mass (m/z): 172.1 .
Step (ii): Preparation of [l,4']Bipiperidinyl-4,1'-dicarboxylic- acid diethyl ester
A mixture of ethyl 4-oxo piperidine-l-carboxylate (3.14 grams, 18.3 mmol,
obtained in the above step) in acetic acid (1.05 mL, 18.3 mmol) was added to a stirred
solution of ethyl isonipecotate (2.87 mL, 18.3 mmol) in dichloromethane (10 mL)
cooled at 0 °C. Solid sodium toxy borohydride”(11.6 grams, 54.9-mm'ol) was
added portion wise over a period of 15 minutes. The reaction mixture was gradually
warmed to room temperature and d for 16 hours. The reaction mixture was cooled
to 0 °C and basified with saturated sodium bicarbonate solution (pH 7.5). The two
layers were separated, the c layer was washed with brine, dried over anhydrous
sodium sulfate and the volatiles were removed under reduced pressure. The crude
product’was purified by silica gel column chromatography to obtain [1,4']Bipiperidinyl-
I. 1
4, l'-dicarboxylic acid diethyl ester (5.51 grams).
Yield: 96.3 %.
lH - NMR (CDC13): 8 5.60 - 5.10 (m, 2H), 4.35 - 4.15 (m, 1H), 4.20 - 4.08.(m, 4H),
3.98 - 3.85 (m, 1H), 3.20 - 3.10 (m, 1H), 3.10 - 3.0 (m, 1H), 2.86 - 2.710(m, 2H), 2.60 -
2.50 (m, 1H), 2.48 - 2.35 (m, 1H), 2.10 - 2.0 (m, 2H), 1.98 - 1.85 (m, 4H), 1.60 - 1.43
(m, 2H), 1.32 - 1.22 (m, 6H);
Mass (m/z): 313.2 (M+H)+.
Step (iii): Preparation of [l,4']Bip_iperidinyl-4,1'-dicarboxylic acid 1'-ethyl ester
To a stirred mixture of [l,4']Bipiperidinyl-4,1'-dicarboxylic acid diethyl ester
(5.51 grams, 17.67 mmol), tetrahydrofuran (34 mL) and water (34 mL) cooled at 0 °C,
lithium hydroxide monohydrate (742.0 mg, 17.67 mml) was added. The reaction
mixture was stirred at room temperature for 16 hours, diluted with Ethyl acetate. The
two layers Were separated, the s layer was acidified with 2N hydrochloric acid to
pH: 3-4 '
and the volatiles were d under reduced pressure to obtain
Bipiperidinyl—4,1'-dicarboxylic acid 1'-ethyl ester (5.0 grams).
Yield: 94 %
1H - NMR (DMSO-d6): 5 12.53 (bs,. 1H), 11.16 (bs, 1H), 4.15 - 3.98 (m, 4H), 3.47 -
3.35 (m, 3H), 3.0 -2.90 (m, 2H), 2.90 — 2.65 (m, 2H), 2.60 - 2.50 (m, 1H), 2.18 — 2.08
(m, 2H), 2.05 ~ 1.94 (m, 4H), 1.60 -1.50 (m, 2H), 1.16 (t, J = 7.0 Hz, 3H);
Mass (m/z): 285.1 (M+H)+.
Example 1: ation of 6-Chloro[5-(1-cyclopropyl-piperidinyl)-
[1,3,4]oxadiazolyl]-chroman-S-ylamine hemi fumarate :‘
Step (1): Preparation of N-(l-cyclopropyl piperidine—4-carbonyl)-N’-(5-amino
chloro chroman-S-carbonyl) hydrazine
To a stirred solution of 'S-aminochloro ncarboxylic acid hydrazide
(8.0 grams, 33.1 mmol, ed in preparation 1) in dichloromethane (200 mL) cooled
at 0 °C, was added triethyla’mine (13.9 mL, 99.9 mmol) and 'a solution of l-
cyclopropylpiperidinecarbonyl chloride (11.0 grams) in dichloromethane (200 mL).
The reaction mixture was warmed to room temperature and stirred for 16 hours before
diluting it with water (160 mL). The two layers were separated, the organic layer was
dried over anhydrous sodium te and the les were removed under reduced
pressure to obtain the title compound (10.5 grams).
Yield: 81 %.
]H- NMR (DMSO-dé): 5 10.16 (d, J: 3.2 Hz, 1H), 9.64 (d, J= 3 .2 Hz, 1H), 7.58 (s,
1H), 5.,73(bs 2H), 421 (t, J=4.,7Hz 2H),3.0- 2.88(m, 2H), 2.46(t, J=6.,5Hz 2H),
2.30 220(m,1H),2.18- 2.05 (m, 2H), 20-1.90(m 2H), 170- 1.60(m, 2H), 1.60-
142 (m, 3H), 0.42- 0.35 (m, 2H), 0.30- 0.22 (m, 2H);
Mass (m/z): 393, 395 (M+H).
Step (ii): Preparation of 6-chlorc[5-(l-cy‘clopropyl piperidinyl)-
[1,3,4]oxadiazol—Z-yI]—chroman-5—ylamine
To N—(l—cyclopropyl piperidine—4-carbonyl)-N’-(5-aminochloro chroman-S-
carbonyl) hydrazine (10.5 grams, 26.7 mmol, obtained in the above step) was added
phosphoryl chloride (53.5 mL). The reaction temperature was gradually raised to 120
°C. The on mixture was stirred at this ature for 1h, cooled to room
temperature and triturated with hexanes (3x100 mL). The crude reaction was diluted
with 10% aqueous sodium bicarbonate on and extracted with a 1:9 mixture of
methanol in romethane. The organic layer was dried over anhydrous sodium
sulphate and t was removed under reduced re and the crude product was
purified by silica gel column to obtain 6-Chloro—8-[5-(l-cyclopropyl piperidinyl)-
[1,3,4]oxadiazolyl] chroman-S-yi amine (8.8 grams).
Yield: 87.9 %.
1H — NMR(CDC13): 5 7.66 (s, 1H), 4.35 (bs, '2H), 4.28 (t, J = 5.0 Hz, 2H), 3.18 - 3.10
(m', 2H), 3.08 - 2.93 (m, 1H), 2.53 (t, J = 6.6 Hz, 2H), 2.40 - 2.30 (m, 2H), 2.18 - 2.05
(m, 4H), 20- 187(m 2H), 170 1.60(m, 1H), 0.50 0.,40(m 4H);
Mass (m/z): 375, 377 (M+H).
Step (iii): Preparation of 6-chloro[5-(l-cyclopropyl piperidinyl)—
[1,3,4[0xadiazolyl] chroman-S-yl amine hemi fumarate
A suspension of 6-chloro[5-(l-cycliopropyl‘ piperidinyl)-[l,3,4]0xadiazol-
2-yl] chroman-54yl amine (14 grams, 37.3. mmol, ed in the above step) in ethanol
(280 mL) was heated to reflux until clear solution obtained. The mixture was cooled to
room ature and fumaric acid (4.32 grams, 37.3 mmol) was added. The reaction
mixture was heated to reflux for 1 hour. The volatiles were removed under reduced
pressure and the furmarate salt, thus obtained, was recrystallized from isopropanol to
obtain ro[5-(1-cyclopropy1 piperidinyl)-[1,3,4]oxadiazol—2-yl] chroman-S-
yl amine hemi fumarate (14.0 grams).
Yield: 92.8 %.
j .
lH - NMR (DMSO-dg): 5 7.48 (s, 1H), 6.60 (s, 1H), 5.75 (s, 2H), 4.13 (t, J = 4.8»Hz,
2H), 3.0 - 2.90 (m, 3H), 2.52: - 2.42 (m,‘2H), 2.40 - 2.30 (m, 2H), 2.01 - 1.90 (m, 4H),
2(nn3PD,048-040(nn2PD,035-028(nn2Hx
Mass (m/z): 375, 377 . I,
Example 2: Preparation of ro[5-(l-cyclobutyl piperdin—4~ylmethyl)-
[1,3,4loxadiazol-Z-yll-chroman-S-yl amine L(+)-tartarate salt
Step (i): Preparation of 6-chlor0[5-(1-cyclobutyl piperdin-4—yl methyl)-
[l,3,4]0xadiazol72-yl]-chroman-S-yl amine
To the (l-cyclobutyl piperidin¥4—.yl) acetic acid (725 mg, 3.52 mmol, obtained
in preparation 4) was added phosphoryl chloride (4 mL). The e was d for 15
minutes and 5-Amino—6—chlor0-chromanearboxylic acid hydrazide (500 mg, 2.0
mmol) was added. The reaction mixture was gradually heated to reflux for 30 minutes.
The reaction mixture was cooled to room temperature, triturated with hexanes (2 x 20
mL) and the crude mass was basified with s sodium bicarbonate on. The
basified mixture was extracted with 10% methanol in dichloromethane.'The organic
layer was dried over anhydrous sodium sulphate and the solvent was removed under
reduced pressure and was purified by silica gel column to obtain 6I—chloro[5-(l-
cyclobutyl piperdinylmethy1)—[1,3,4]oxadiazol—2—yl] chroman-S-yi amine (250 mg).
Yield: 30 %.
'H-NMRaxxmy87@(sHQ435®sflfl428mJ=50HL2HL2%
(m, 2H), 2.83 (d, J =_6.9 Hz,:2H), 2.73 — 2.62 (m, 1H), 2.54'(t, J = 6.6 Hz,‘ 2H), 2.20 -
2.10 (m, 2H), 2.08 - 2.0 (m, 2H),1.95 -1.65 (m, 9H), 1.48 - 1.35 (m, 2H);
Mass (m/z): 403, 405 (M+H)+.
Step (ii): Preparation of 6-chloro—8—[5-(l-cyclobutyl piperdin—4—yl methyl)-
[1,3,4]oxadiazolyll-chromanyl amine L(+)-tartarate salt
To a stirred on of 6-chloro-8—[5-(l-cyclobutyl piperdinyi methyl)-
[1,3,4]oxadiazolyl] chroman-S-yl amine (175.7 mg, 0.436 mmoi, obtained in the
above step) in methanol (2 mL), L(+)-tartaric acid (65.4 mg, 0.436 mmol) was added.
The reaction mixture was stirred for 1 hour at room temperature and the volatiles were '
removed under reduced pressure to obtain a crude mass which was triturated several
times with solvent ether to obtain 6-chloro[5-(1-cyclobutyl piperdinyl )~
[.1 ,3,4]oxadiazolyl] chroman-S-yl amine L(+)-tartarate (206.2 mg)
~26-
Yield: 85.5 %
lH - NMR (DMSO'dG): 5 7.46 (s, 1H), 5.79 (bs, 2H), 4.12 (t, J = 4.7 Hz, 2H), 4.06 (bs,
2H), 3.20 - 3.10 (m, 1H), 3.10 = 6.7 Hz, 2H), 2.48 (t, J = 7.6
- 3.0 (m, 2H), 2.84 (d, J
Hz, 2H), 2.33 - 2.15 (m, 2H), 2.10 -2.0 (m, 2H), 2.0 - 1.85 (, 5H), 1.85 - 1.72 (m, 2H),
1.70 — 1.58 (m, 2H), 1.45 - 1.30 (m, 2H);
Mass (m/z); 403, 405 .
Example 3:: Preparation of l-isopropyll{S-[1-(3-methoxy propyl) piperidinyll-
[‘1,3,4]oxadiazolyl}-lH-indazole oxalate salt-
Step (1): Preparation of l-isopropyl{5-[1—(3-methoxy propyl) piperidinyl]-
]oxadiazol-Z-yl}-lH—indazole
To the mixture of l—isopropyl-1H-indazolecarboxylic acid hydrazide (15.0
grams, 68.8 mmol) and 1-(3-Methoxy propyl)-piperidine-4—carboxylic acid
hydrochloride (20.9 grams, 88.2 mmol, ed in preparation 7) cooled at 0 °C was
added phosphoryl chloride (130. mL). The reaction temperature was gradually raised to
100 °C and. stirred was 2 hours. Upon completion of the reaction, it was cooled to 0 °C
and triturated with hexanes (3 x 250 mL). The crude product was basified with aqueous
sodium hydroxide solution and extracted with 5% ol in dichloromethane. The
combined organic layer was dried over’anhydrous sodium sulphate and the solvent was
removed under reduced pressure. The crude product was purified by silica gel column
tography to obtain l-isopropyl{5-[l-(3—methoxy propyl) diny1]-
[1,3,4]oxadiazolyl}-1H-indazole (15.78 grams)
Yield: 59 %‘,
1H - NMR (CDCl3): 5 8.35 (d, J = 8.1 Hz, 1H), 7.53 (d, J = 8.5 Hz, 1H), 7.47 (t, J = 7.0
Hz, 1H), 7.33 (t, J = 7.4 Hz, 1H), 5.05-4.90 (m, 1H), 3.44 (t, J = 6.4 Hz, 2H), 3.35 (s,
3H), 3.15-2.97 (m, 3H), 2.48 (t, J = 7.3 Hz, 2H), 2.26-2.02 (m, 6H), 1.88-1.75 (m, 2H),
1.67 (11,] = 6.7 Hz, 6H);
Mass 384.5 (M+H)+.
Step (ii): Preparation of l-Isopropyl-3—{5—[l-(3-methoxy-propyl)-piperidinyll-
[l,3,4]oxadiazolyl}-lH-indazole oxalate salt '
To a stirred on of 1-isopropyl—3-{5-[1-(3—methoxy propyl) piperidin-4.-yl]-
[l,3,4]oxadiazolyl}-1H-indazole (12.55 grams, 32.7 mmol, obtained in the above
step) in 2-propanol (200 mL); oxalic acid (4.12 grams, 32.7 mmol) was added. After
stirring at room temperature for .1 hour the reaction was further diluted with 2-propanol .
F27-
and refluxed for 2 hours. The crystalline product which was precipitated after cooling
the on mixture to room temperature was filtered, dried under vacuum to obtain 1-
isopropyl{5-{l-(3-methoxy propyl). piperidinyl]-[1,3,4]oxadiazol-2—yl}-1H-
indazole oxalate salt (16.4 grams) '
Yield: 88 %
lH - NMR (DMSO-de): 8 8.18 (d, J =,8.l Hz, 1H), 7.90 (d, J = 8.5 Hz, 1H), 7.54 (t, J;=
7.4 Hz, 1H), 7.38 (t, J = 7.7 Hz, 1H), 5.23 - 5.10 (m, 1H), 3.50 - 3.40 (m, 3H), 3.37 (t,J
= 5.9 Hz, 2H), 3.23 (s, 3H), 3.10 -2.96 (m, 4H), 2.35 - 2.25 (m, 2H), 2.18—2.02 (m, 2H),
1.94 - 1.85 (m, 2H), 1.53 (d, J = 6.6 Hz, 6H);
Mass (m/z): 384.3 (M+H)+.
Example 4: Preparation of 3-[5-(l-cyclobutyl-piperidin-4—yl )-
[1,3,4]oxadiazol—2-yl]—l-isopropyl-'lH-indazole L(+)-tartarate salt
Step (i): Preparation of 3-[5¥(1-cyclobutyl-piperidinyl methyl)-[1,3,4]oxadiazol-
‘ I
2—yl]isopr0pyl—lH—indazole
To the mixture of l-isopropyl—lH-indazolecarboxylic acid hydrazide (120
mg, 0.55 mmol) and lobutyl piperidin-4~yl) acetic acid hydrochloride (147 mg,
0.74 mmol, obtained in preparation 6) cooled at 0 °C, wasadded oryl de
(1.5 mL). The reaction temperature was gradually raised to 100 °C‘and stirred was 2
hours. Upon completion of the reaction, it was cooled to 0 °C and triturated with
hexanes (3 x 25.mL). The crude product was cooled to 0 °C, basified with aqueous
sodium hydroxide solution and extracted with 5% methanol in dichloromethane. The
combined organic layer was dried over anhydrous sodium sulphate and the solvent was
removed under reduced pressure. The crude t was purified by silica gel column
chromatography to obtain 3-[5-(l—cyclobutyl piperidin—4—yl methyl)-[l,3,4]oxadiazol
yl]-l—isopropyl-lH-indazole (62 mg)
Yield: 30 %
‘H - NMR(CDC13): 5 8.37 (d, J = 8.1Hz, 1H), 7.54 (d, J = 8.5 Hz, 1H), 7.48 (t, J = 6.9
Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 5.08-4.92 (m, 1H), 2.93 (d, J = 7.1 Hz, 2H), 2.92-2.87
(m, 2H), 2.74-2.62 (m, 1H), 2.10-1.93 (m, 3H), 1.92-1.82 (m, 4H), 1.80-1.65 (m, 4H),
1.68 (d, J = 6.7 Hz, 6H), 1.52—1.40 (m, 2H);
Mass (m/z): 380.2 (M+H)+.
Step (ii): ation of 3-[5-(1-cyclobutyl piperidin-4—yl methyl)-[l,3,4]oxadiazol—
l-isopropyl—lH-indazole L(+)-tartarate salt
To a stirred solution of 3-[5-(1-cyclobutyl piperidinyl )-
4]oxadiazolyl]isopropyl-1H-indazole (62 mg, 0.16 mmol, obtained inthe
above step). in 2-propanol (5.0 mL), L(+)-tartaric acid (26 mg, 0.16 mmol) was added.
After stirring at room for 1 hour the volatiles were d under reduced pressure
and the crude product was triturated several times with ether to obtain 3-[5-(1-
cyclobutyl piperidinyl )-[1,3,4]oxadiazol-yl]-l-isopropyl-il H-indazole L(+)-
tanannesak(811ng) ‘
Yfiddz9496
1H - NMR ds): 5 8.18 (d, J = 8.1 Hz, 1H), 7.90 (d, J = 8.5 Hz, 1H), 7.54 (t, J =
14H;1HL7380“V=16HL1HL522-SJOUmlH)4Jl($2HL330-3200m
2H), 3.20 - 3.05 (m, 2H), 3.0 (d, J = 6.8 Hz, 2H), 2.45 - 2.30 (m, 1H), 2.10 - 1.90 (m,
4HL190-1800m2HL1J8-165fim2HL150-1400m2Hx
Mass (m/z): 380.2 (M+H)+.
Example 5: Preparation of 6-chloro—8-[5-(3-cyclobutylaza bicyclo[3.].0]hex—6—
yl)—[1,3,4]oxadiazol-2_—yl] nesiylamine oxalic acid
Step (i): Preparation of 6-chloro[5-(3-eyclobutylaza bicyclo[3.].0]hexyl)—
' "
[1,3,4]oxadiazolyl] chroman-S-yl amine
To 3-cyclobutylaza bicyc‘lo[3.1.0]hexane-.6-carboxylic acid (74 mg, 0.40
mmol, obtained in ation 8) was added phosphoryl chloride (1 mL). The mixture
was stirred for 15 minutes and 5-amino—6-chloro chroman-8—carboxylic acid hydrazide
(80 mg, 0.33 mmol) was added. The reaction mixture was gradually heated to reflux for
1 hour. The reaction mixture was cooled to room temperature, triturated with hexanes
(2 x 20 mL) and the crude mass was basified with aqueous sodium bicarbonate
solution. The basified mixture was extracted with 10 % ol in dichloromethane
The organic layer was dried over anhydrous sodium sulphate and the solvent was
removed under reduced pressure and was purified by silica gel column to obtain 6-
. chloro[5-(3-cyclobutylaia bicyclo[3. 1 .0]hexyl)-[ l ,3,4]oxadiazolyl]
chroman-S-yl amine (18 mg).
Yield: 14.0 %.>
1H - NMR‘(CDC13): 6 7.64 (s, 1H), 4.33 (bs,l2H), 4.27 (t, J = 5.3 Hz, 2H), 3.20 - 3.0
mL3HL270-2600m1H)2530“P=64HL2HL248-2350m2H)220-2J0
. (m, 4H), 2.0 - 1.90 (m, 2H), 1.90 - 1.80 (m, 1H), 1.80 - 1.60 (m, 2H), 1.30 — 1.20 (m,
1H) '
WO 42135
Mass (m/z): 387.1, 389.2 (M+H)+
Step (ii): Preparation of 6¥chloro[5-(3-cyclobutyl—3-aza bicyclo[3.l.0]hex-6—yl)-
[1,3,4loxadiazolyl] chroman-S-yl amine e salt
To a stirred solution of 6-ch10ro[5—(3-cyclobutylaza o[3.l.0]hex
yl)-[1,3,4]oxadiazolyl] chroman—5-yl amine (18 mg, 0.05‘mmol, obtained in the
above step) in 2-propanol (3 mL), oxalic acid (6.0 mg, 0.05 mmol) was added. After
stirring at room temperature for 1 hour the reaction was further diluted with 2-propanol
and refluxed for 2 hours. The volatiles were removed under reduced pressure and the
crude product which was obtained was triturated with ether, dried under vacuum to
obtain 6-Chloro—8-[5-(3-cyclobutyl-3 ~aza o[3.1.0]hex—6-yl)—[1,3,4]oxadiazol
yl] chroman-5;y1 amine oxalate salt (21.2 mg)
Yield: 95.6% 7
1H - NMR (DMS'O-da): 5 7.47 (s, 1H), 5.80 (bs, 2H), 4.28 (t, J = 5.3 Hz, 2H), 3.80 -
"3.55 (m, 2H), 3.30—3.20 (m, 1H), 2.70 - 2.60 (m, 1H), 2.60 4 2.40 (m, 4H), 2.30 - 2.05
(m, 4H), 2.0 - 1.90 (m, 3H), 1.90 - 1.70 (m, 2H), 1.30 - 1.20 (m, 1H);
Mass (m/z): 387.1, 389.2 (M+H)+.
Example 6; Preparation of 4—[5-(8-Aminochloro—2,3-dihydro l,4]dioxan-
-yl)~[l,3,4]oxadiazolyl]-[1,4']bipiperidinyl-l'-carb0xylic acid ethyl ester
oxalate salt
Step (i): Preparation of 4-[5-(8-Amino-7—chloro-2,3-dihydro benzo[l,4]dioxan
yl)—[1,3,4]oxadiazolyl]-[1,4']bipiperidinyl—l'-carboxylic acid ethyl ester
To the [1,4']bipiperidiny1—4,1'—dicarboxy1ic acid 1'-ethyl ester (372 mg,'1.02
mmol, obtained in preparation 9) was added phosphoryl chloride (3.2 mL). The mixture
was stirred for 15 minutes and 8-amino—7-chlor0-2,3-dihydro benzo[1,4]dioxane
carboxylic acid ide (200 mg, 0.82 mmol) was added. The reaction mixture was
gradually heated to reflux for 1 hour. The reactiOn mixture was cooled to room
temperature, ated with hexanes (2 x 50 mL) and; the crude mass was basified with
. aqueous sodium bicarbonate solution. The basified mixture was extracted with ethyl
acetate. The organic layer was dried over anhydrous sodium sulphate and the t
was removed under reduced pressure and was purified by silica gel column to obtain 4-
[5-(8-aminochlbro-2,3—dihydro * benzo[l,4]dioxanyl)-[1,3 ,4]oxadiazoly1]—
bipiperidinyl-l'—carboxylic acid ethyl ester (1 10 mg).
Vfidd221598
lH - NMR (CDC13)Z 8 7.42 (s, 1H), 4.50 — 4.36 (m, 6H), 4.33 - 4.20 (m, 2H), 4.12 (q,
2H), 3.03 - 2.92 (m, 3H), 2.83 - 2.70 (m, 2H), 2.55 — 2.42 (m, 1H), 2.42 - 2.30 (m, 2H),
2.15 >
- 2.06 (m, 2H), 2.04 - 1.90 (m, 2H), 1.86 - 1.78 (m, 2H), 1.55 - 1.40 (m, 2H), 1.26
(t, J _= 7.1 112,311); ,
, Mass (m/z): 492.1, 494.3 (M+H)+
Step (ii): Preparation of 4-[5-(8-aminochloro-2,3-dihydro benzo[1,4]dioxin
yl)-[l,3,4]oxadiazoly|]-[l,4']bipiperidinyl-l'~carboxylic acid ethyl ester oxalate
salt
To a stirred solution of 4—[5-(8-aminochloro-2,3-dihydro 1,4]dioxin
yl)-[1,3,4]oxadiazol—2-y1]—[1,4']bipiperidinyl-l'-carboxylic acid ethyl ester (100 mg,
0.20 mmol, obtained-in the above step) in ethanol (3 mL), oxalic acid (23 mg, 0.18
mmol) was added. Afier stirring at room temperature for 1 hour the reaction was further
diluted with 2-propanol and refluxed for 2 hours. The volatiles were removed under
reduced pressure and the crude product obtained was triturated with ether and dried
under vacuum to obtain 4-[5-(8-aminochloro-2,3-dihydro benzo[1,4]dioxiny1)4
[1,3,4]oxadiazol—2-yl]-[1,4']bipiperidinyl-1‘—carboxy1ic acid ethyl ester oxalate salt (115
mg) ..
Yield: 97.4 %
IH - NMR (DMSO-ds): 8 7.29 (s, 1H), 5.66 (bs, 2H), 4.33 (s, 4H), 4.15 - 4.05 (m, 2H),
4.03 (q, 2H), 3.40 - 3.15 (m, 4H), 3.10 - 2.90 (m, 2H), 2.90 - 2.70 (m, 2H), 2.26 - 2.18
(m, 2H), 2.08 - 1.90 (m, 4H), 1.58 -l.42 (m, 2H), 1.17 (t, J = 7.0 Hz, 3H);
Mass (m/z): 492.1, 494.3 (M+H)+.
Example 7: Preparation of 5-Chloro—7-{5-[1-(tetrahydro pyranyl) piperidin
,3,4]oxadia_zolyl}-2,3—dihydro uranyl amine oxalate salt
Step (i): Preparation of 5-Chloro{5-[1-(tetrahydro pyran—4-yl) piperidin-4—yl]-
[l,3,4]oxadiazolyl}-2,3-dihydro uranyl amine
To 1-(tetrahydro pyrany1) piperidinecarboxylic acid (168.2 mg, 0.58
mmol) was added phosphoryl de (1.76 mL). The mixture was stirred for 15
minutes and 4-aminOiS-chlorol-ZJ-dihydro benzofurancarboxylic acid ide
(101.2 mg, 0.0.44 mmol, obtained in preparation 3) was added. The reaction mixture
was gradually heated to reflux for 2 hours. The reaction mixture was cooled to room
temperature, triturated with hexanes (2 x 20 mL) and the crude mass was basified with
s sodium bicarbonate solution. The basified mixture was extracted with 10 %
.'31"
methanol in dichloromethane. The organic layer was dried over anhydrous sodium
sulphate and the t was d under reduced pressure. The residual mass was
purified by silica gel column to obtain 5—chloro—7-{5-[1—(tetrahydro pyranyl) .
din—4-yl]-[l,3,4]oxadiazolyl}-2,3-dihydro benzofuranyl amine (23.5 mg).
Yield: 13.1 %.
Il-l - NMR (CDCls); 8 7.64 (s, 1H), 4.84 (t, J = 8.7 Hz, 2H), 4.31 (bs, 2H), 4.10 - 4.0
(m, 2H), 3.39 (t, J é 11.4 Hz, 2H), 3.10 (t, J '= 8.7 Hz, 2H), 3.10 - 2.95 (m, 3H), 2.62 -
2.50 (m, 1H), 2.45 -, 2.25 (m, 2H), 2.20-1.95 (m, 4H), 1.88 - 1.75 (m, 2H), 1.75 - 1.60
(rh, 2H); '
Mass (m/z): 405.2, 407.4 (M+H)+.
Step (ii): ation of 5-chloro—7-{5--[1--(tetrahydro pyranyl) piperidinyl]-
[1,3,4]oxadiazolyl}--2,3-dihydro benzofuran-4—yl amine oxalate salt
To a stirred solution of 5-chloro {5——[1--(tetrahydro pyran-yl) piperidinyl]-
[1,3,4]oxad1azolyl}-2,3-d1hydro benzofuranylamine (20.4 mg‘, 0.05 mmol) in
l (2 mL), oxalic acid (6.0 mg, 0.05 mmol) was added. After stirring 'at room
temperature for 1 hour the reaction was further diluted with 2-propanol and refluxed for
2 hour; The volatiles were removed under reduced pressure and the crude product
obtained was triturated with ether, dried under vacuum to obtain S-chloro-7—{5-[l-
(tetrahydro pyran~4-yl) piperidinyl]-[l,3,4]oxadiazol—2-yl}—2,3-dihydro benzofuran-
4-ylamine oxalate salt (22.5 mg).
Yield: 90.3 %
1H - NMR dé): 8 7.49 (s, 1H), 6.04 (s, 2H), 4.68 (t, J = 8.7 Hz, 2H), 4.0 53.90
(m, 2H), 3.40 - 3.20 (m, 5H), 3.0 (t, J = 8.7 Hz, 2H),2.35 - 2.20 (m, 3H), 2.10 - 1.90
(m, 5H), 1.70 - 1.57 (m, 3H);
Mass (m/z): 405.1, 407.2 (M+H)+.
Examples 8 - 49:
The compounds of Examples 8:- 49 were prepared by following the procedures
as described in es 1 to 7, with some non-critical variations
6-Chloro—8-{5-[1—(2-methoxy- lH-NMR (DMSO‘dé): 5 9.92 (bs, AlH), 7.49 (s, 1H),
-piperidinyl]- 4.13 (bs, 2H),._3.'70 (t ,J-5.0Hz, 2H), 3.54 (t, J=5.5 Hz,
[1,3,4]0xadiazolyl}-chroman- 2H), 3.38 (s, 3H), 3.10 2.95 (m, 3H), 2.60 (t, J=5.5 Hz,
S—yiamine 2H), 2.54 (t, J=6.6Hz, 2H), 2.30 - 2.13 (m, .3H), 2.15 -
1.85.(m, 5H);
' Mass (m/z): 393.2, 395.3 (M+H)+.
._ ro{5-[1-(3-methyl- (CDC13.): 6 7.67(s, 1H), 4.35 (s, 2H), 4.28 (t,
» butyl)-piperidinyl]- J= 4.8 Hz, 2H), 3.05 - 2.90 (m, 3H), 2.54 (t, J=6.5 Hz,
[l,3,4]oxadiazoly1}-chroman— 2H), 2.40 -2.32 (m, 2H), 2.18 - 2.06 (m, 6H), 2.06 -
-ylamine 1.92 (m, 2H), 1.65 - 1.55 (m, 1H), 1.48 — 1.36(m, 2H),
0.92 (d, J= 6.5 Hz,6H);
Mass (m/z): 405.4, 407.4 (M+H)+.
6-Chloro[5-( l - lH—NMR (DMSO-d5)2 5 7.48 (s, 1H), 5.79.(s, 2H), 4.14
cyclobutylmethyl-piperidin (t, J= 4.8Hz, 2H), 4.12 (5,2H), 3.12 — 2.92 (m, 5H), 2.70
yl)-[l,3,4]oxadiazolyl]- - 2.50 (m, 4H), 2.10 - 2.0 (m,7H), 2.0 - 1.93 (m, 2H),
chroman-S-y13mine 1.90 - 1.75 (m, 4H), .62 (m,2H)
Mass (m/z): 403.3 405.3 (M+H)+.
6-Chloro[5-(1- lH-NMR (DMSO-d6): 5 7.49 (s', 1H), 5.79 (s,- 2H),
cyclopropylmethyl—piperidin 4.13 (t, J=4.8 Hz, 2H), 4.10 (s, 2H), 3.30 - 3.15 (m,2H).
: y1)-[1,3,4]0xadiazoly1]- 3.15 - 3.05 (m, 3H), 2.70 ’- 2.55 (m, 4H), 2.18 - 2.07 (m,
chroman—S-}‘I1am ine 2H), 2.0 - 1.80 (m, 4H), 1.0 - .090 (m,1H), 0.60 - 0.50 .
(m, 2H), 0.25 - 0.16 (m, 2H); _
Mass (m/z): 389.3, 391.4, (M+H)+.
6-Ch10ro[5—(1-isopropy1- 1H—NMR (DMSO-d6): 5 7.49 (s, H), 5.80 (s, 2H), 4.22
piperidin—4-yl)—[1,3,4]oxadiazol— (t, J= 4.8 Hz, 2H), 4.05 (s, 2H), 3.25 - 3.05 (m, 6H),
2-y1]-chr0man—5—ylamine 2.88 - 2.70 (m, 2H),'2.25 - 2.10 (m, 2H), 12.0 - 1.80 (m,
. 4H), 1.12 (d, J= 6.5 Hz, H);
Mass (m/z): 377.3 ,379.5 (M+H)+.
:33-
ro{5-[1-(3-meth0xy- 5 7.48 (s, 1H), 5.79 (s, 2H), 4.13
, (DMSO-d6):
' propyl)-piperidin¥4-yl]- (bs, 4H), 3.34 (t, J=6.0 Hz, 2H), 3.30 - 3.22 (m, 1H),
]oxadiazol-_2-yl}-chroman- 3.21 (s, 3H), 3.20 - 3.0 (m, 4H), 2.70 - 2.60 (m,'2H),
S—ylamine 2.60 - 2.50 (m, 2H), 2.15 - 2.03(m, 2H), 2.0’ - 1.90 (m,
2H), 1.90 - 1.70 (1n, 4H);
Mass (m/z): 407.3, 409.2 .
6—Chloro—8-[5-(1-cyclobutyl- ' 1H-NMR (DMSO-d6): 5 7.48 (s, 1H), 4.14 (s, 2H), 4.13
piperidiny1)-[1,3,4]oxadiazol- (t, J: 4.8 Hz, 2H), 3.10 - 2.90 (m, 4H), 2.47 (t, J: 8.0
2-y1]-chr0man-5—ylamine Hz, 2H), 2.30 - 2.15. (m, 2H), 2.12 — 2.0 (m, 4H), 2.0 —
1.85 (m, 4H), 1.85—1.72 (m, 2H),‘1.70 - 1.58 (m, 2H) ;
Mass (m/z): 389.3, 391.4 (M+H)+.
6-Chloro—8-[5—( l - lH—NMR (DMSO—d6): 5 7.29 (s, 1H), 5.65 (5,211),
cyclobutylmethyl-piperidin-4— 4.33(s,4H), 4.11(s; 2H), 3.15 - 2.95(m,3H), 2.70 -
y1)-[1,3,4]0xadiazoly1]-2,3-' 2.55(m,3H),
dihydrb—benzo[ 1 ,4]dioxin-5 - 2.50-2.30(m,2H), 2.10—2.0(m, 2H);
ylamine Mass (m/Z): 405.3, 407.4 (M-hH)+.
6-Ch10ro[5-(1-cyclobuty1- 'H-NMR (DMSO-d6): 5 7.29 (s, 1H), 5.65(s,2H), 3.10 -
piperidiny1)-[1,3 ,4]oxadiaz01- 3.0(m, 1H), 3.0 - 2.85 (m, 3H), 2.30 - 2.12 (m, 2H),
2-y1]-2,3—dihydro- 2.10 -1.95 (m, 4H), 1.95 - 1.70 (m, 4H), 1.70 - 1.53 (m,
benzo[1,4]dioxin—5—ylamine 2H);
Mass (m/z): 391.4, 393.3 (M+H)+.
6-Chloro-8¥[5-(1-cyclopenty1- IH-NMR (DMSO-d6): 5 7.49 (s, 1H), 5.79 (s, 2H),
piperidiny1)-[1,3,4]oxadiazol- 4.13 (t, J= 4.6 Hz, 2H), 4.0 (s, 2H), 3.25 - 3.08 (m, 3H),
2-y1]-chromanylamine 3.05 - 2.90 (m, 1H), 2.68 - 2.53 (m, 2H), 2.47 (1, J=7.8
tartarate salt Hz, 2H), 2.18 -2.0 (m, 2H), 2.0 - 1.80 (m, 6H), 1.70 -
1.60 (m, 2H), 1.58 -140 (m, 4H);
Mass (m/z): 403.2, 405.7 (M+H)+.
l6-Chloro[5-(2-piperidin-l—yl- 'H—NMR(CDC13): 6 7.69 (s, 1H), 4.35 (bs, 2H), 4.28 0
ethyl)-[ l,3,4]oxadiazolyl]- ,J= 4.5 Hz, 2H), 3.20 - 3.05 (m, 2H), 2.90 - 2.80 (m,
chroman-S-ylamine 2H), 2.80 -2.70 (m, 2H), 2.65 - 2.50 (m, 4H), 2.20 -
2.10 (m, 2H), 2.10 —1.95 (m, 1H), 1.60 - 1.48 (m, 1H),
1.50 - 1.40 (in, 2H);
Mass (m/z):_ 363.2, 365.2. (M+H)*.
4-[5-(5-Aminochloro- ‘H-NMR (DMSO-d6): 8 7.48 (s, 1H), 5.79 (s, 2H),
chromanyl)-[l,3,4]oxadiazol- 4.21 (s, 2H), 4.13 0, J: 4.5 Hz, 2H), 4.10 - 3.95 (m,
[ l ,4']bipiperidinyl- l '- 4H), 3.20 —-3.05 (m, 4H), 2.90 - 2.72 (m, 4H), 2.70 —
carboxylic acid ethyl ester 2.60 (m, 2H), 2.20 - 2.08 (m, 2H), 20-190 (m, 2H),
1.90 - 1.75 (m, 4H), 1.50 - 1.35 (m, 2H), 1.16 0, J= 7.0
Hz, 3H);
Mass (m/z): 490.3, 492.3 (M+H)-+.
.6-Chl0r0-8—[5-(3-piperidin- l ~yl- 'H-NMR d6): 5 7.48 (s, 1H), 5.79 (s, 2H),
propyl)—[ l ,3,4]oxadiazolyl]— 4.13 0, J: 4.8 Hz, 2H), 4.07 (s, 2H), 2.90 0, J=7.2 Hz,
chroman-‘S-ylamine tartarate salt 2H), 2.85-2.70 (m, 6H), 2.47 0, J= 6.5 Hz, 2H), 2.08 —
1.90 (m, 4H), 1.63 - 1.53 (m,4H), 1.50 — 1.38 (m, 2H);
Mass (m/z): 349.2, 351.4 (M+H)+.
6-Chloro[5-( l -cyclopentyl- ‘H-NMR d6)': 5 7.47 (s, 1H), 5.80(s, 2H),
piperidinylmethyl)- 4.130, J=4.8 Hz, 2H), 3.50 - 3.35 (m, 3H),-3.0 - 2.82
[I ,3,4]0xadiazolyl]—chroman- ‘
(m, 4H), 2.47 0, J= 6.7 Hz, 2H), 2.10 -' 1.88 (m, 7H),
-ylamine oxalate salt 1.70-1.40 (m, 8H);
Mass (m/z): 417.3, 419.4 (M+H)*.
6-Chldr0—8—[5-(3-isopropyl lH—NMR (DMSO-d6): 5 7.47 (5,1H), 5.79 (s, 2H),
aza-bicyclo[3. l .O]hexyl)- 4.120, J= 4.6 Hz, 2H), 3.75 - 3.55 (m, 2H), 3.40 - 3.20
[l,3,4]0xadiazolyl]-chroman— (m, 3H), 2.58 (s, 1H), 2.460, I: 6.6 Hz, 2H), 2.42 (s,
-ylamine oxalate salt 2H), 2.0 - 1.90(m, 2H), 1.21 (d, J= 6.0 Hz, 6H);
Mass (m/z): 375.2, 377.2 (M+H)*.
2012/000011
6—Chloro[5-(3- ‘H-NMRI(DMSO-d6): 8 7.46 (s, 1H); 5.79(s, 2H),
cyclobutylmethyl—3—aza- 4.120, I: 4.8 Hz), 3.60-3.45 :(m, 2H), 3.20—1.90 (m,
.bicyclo{3. l .O]hex—6—yl)- 4H), 2.55 (s,1H), 2.46 (1, J= 6.9 Hz, 2H), 2.32 (s, 2H),
[ l,3,4]oxadiazolyl]-Chroman- 2.10 — 2.0(m, 2H), 2.0 -1.90 (m, 3H), 1.90 —,1.80(m,.
-ylamine oxalate salt lH),1.80 - 1.67(m, 3H);
Mass (m/z): 400.9, 403.1 v(M+H)+.
r‘o[5-(3- lH-NMR(CDC13): 6 7.65 (s, 1H), 4.33 (s, 2H), 4.27 (t,
cyclopropylmethyl-3Haza- J: 4.9 Hz, 2H), 3.28 (d, J: 8.0 H), 2.70 — 2.63 (m,
bicyclo[3.l .0]hexyl)- 1H), 2.530, I: 6.5Hz ,2H),2.50-2.42(m, 2H), 2.38 -
]oxadiazol—2—yl]-chroman- 2.30(m, 2H), 2.17 - 2.07 (m, 4H), 0.90 - 0.80(m, 1H),
S-ylamine 0.51 - 0.42(m, 2H), 0.15 — 0.06(m,2H);
Mass (m/z): 387.1, 389.1 (M+H‘)*.
6-Chlor048- { 5 -[ l -(tetrahydro- - 'H-NMR (DMSO—d6): 5 7.49(s, 1H), 5.81 (s, 2H), 4.13
pyran~4~yl)-piperidinyl]— (t, J: 4.5 Hz, 2H), 4.0 - 3.90(m, 2H), 3.60 - 3.40
[-l,3,4]0xadiazolyl}-chroman-‘ (m,4H), 330(1, J: 11.2 Hz, 2H),- 3.20 — 3.10 (m, 2H),
—ylamine oxalate salt 2490, J: 6.7 Hz, 2H), 2.30 — 2.20(m, 2H), 2.10 — 1.88
(m,6H), 1.70 — 1.58(m,2H);
Mass (m/z): 419.2, 421.2 (MJFH)+
6-Chloro{5-[1~(tetrahydro# ‘H—NMR (DMSO-d6): 5 7.49 (s, 1H), 5.81(s, 2H), 4.10
pyran—4-ylmethyl)—piperidin -3.9(m, 2H), 3.90 — 3.80 (m, 2H), 3.27 (1, J= 11.1 Hz,
yl]-[1,3,4]oxadiazol-2—yl}- 2H), 3.15 - 1.90 (m, 5H), 2.49 (t, J: 6.6 Hz, 2H), 2.30 -
chroman-S-ylamine e salt 2.20 (m,2H),'2.18—1.90(m, 4H); .60(m, 2H), 1.30
- l.10(m, 2H); _’
Mass (m/z):43'3.3, 435.2 (M+H)+.
—Chloro[5-( 1 -cyclopropyl- xH-NMR (DMSO-6): 5 7.49 (s, 1H), 6.02 (s, 2H), 4.68
piperidinyl)—[ l ,3,4]oxadiazol- (t, J=8.8‘Hz, 2H), 3.30 — 3.20 (m, 2H), 3.20 — 3.10 (m,
2-yl]-2,3~d,ihydro-benzofuran 2H), 3.05 (t, J=8.8 Hz, 2H), 2.90 -. 2.75 (m, 2H), 2.304
ylamine oxalate salt 2.20 (m, 1H), 2.18-2.07 (m, 2H), 1.90 - 1.77 (m, 2H),»
0.70 - 0.58 (m, 4H);
Mass (m/z): 361.1, 363.1 (M+H)*.
—36.—‘
2012/000011
-Chloro—7-[5-(1-cyclobutyl— lH-NMR (DMSO-dé): 5 7.49 (s, 1H), 6.0 (s, 2H), 4.68
piperidihyl)-[1,3 ,4]oxadiazol- (t, J= 8.8 Hz, 2H), 3.60 - 3.50 (m, 1H), 3.40 - 3.15 (m,
2-yl]-2,3-dihydro—benzofuran 3H), 3.05 (t, J_=18.8 Hz, 2H), 2.90 - 2.70 (m, 2H), 2.30 -
ylamine oxalate salt 2.10 (m,6H), 2.05-1.90 (m, 2H), 1.80 - 1.60(m, 2H);
Mass (m/z): 375.3, 377.0 (M+H)+.
6-Chloro[5-( l -c'yclopropyl- 1H-NMR(DMSO-d6): 5 7.29 (s, 1H), 5.65 (s, 2H), 4.33
piperidinyl)-[1,3,410xadiazol- (s, 4H), 3.35 -'
- 3.25 (m, 2H), 3.25 - 3.13 (m, 1H), 2.93
2—yl]-2,3~dihydr0— 2.82 (m, 2H), 2.37 - 2.28 (m, 1H), 2.20 - 2.10 (m, 2H),
benzo[1,4]dioxinylamine 1.90 - 1.80 (m, 52H), 0.70 - 0.60 (m, 4H);
oxalate salt '
Mass (m/z): 377.1, 379.0 (M+H)*.
6-Chloro{5-[1-(tetrahydro— ‘H-NMR (DMSO-d6): a 7.30 (s, 1H), 5.66 (s, 2H), 4.33
pyranyl)-piperidin—4-yl]- (s, 4H), 4.0 - 3.20(1n, 6H), 3.10 - - 3.90 (m, 2H), 3.40
[1,3,4]oxadiazoly1}—2,3- 3.0(m, 2H), 2.30 - 2.20 (m, 2H), 2.10 - 1.92 (m, 2H),
dihydro-benzo[1,4]dioxin 1.92 - 1.85 (m,2H), 1.70-1.55 (m, 2H) ;
e Oxalate salt Mass (m/z): 421.1, 423.2 (M+H)+.
6—Chloro{5-[1-(3-methoxy- 1H-NMR (DMSO-d6): 5 7.30 (s, 1H), 5.68 (s, 2H),
)—piperidin—4-yl]- 4.33 (s, 4H), 3.50 - 3.40 (m, 2H),, 3.37 (t, J= 5.8 Hz,
[1,3,4]oxadiazol-2—yl}-2,3- 2H), 3.38 - 3.28 (m, 1H), 3.23 (s, 3H), 3.10 - 2.95 (m,
» Idihydro-benzo[1,4]dioxin 4H),'2.30 - 2.20 (m, 2H), 2.10 - 1.92 (m, 2H), 1.90-
ylamine oxalate salt - 1.82 (m, 2H) ;
Mass (m/z): 409.1 411.0 (M+H)+.
ro{5-[l-(tetrahydro- 1, R (DMSO-d6): 8 7.29 (s, 1H), 5.68 (s, 2H), 4.33
pyran-4—ylmethyl)-piperidin (s, 4H), 3.90 - 3.80 (m, 2H), 3.50 - 3.30 (m, 2H), 3.291
yl]-[l,3,4]oxadiazolyl}-2,3— (t, J=l 1 1.4 Hz, 2H), 3.08 - 2.90 (m, 1H), 2.90 - 2.80 (m,
dihydro-benzo[1,4]dioxin 2H), 2.28 -2.16(m, 2H),2.12 - 1.95 (m, 3H), 1.70 — 1.60
ylamlne oxalate salt (m, 2H), 1.28-1.10 (m,2H);
Mass (m/z):435.2, 437.3 (M+H)+.
-Chloro{5-[1-(tetrahydro- .‘H—NMR (CDC13): 5 7.49.(s,.1H), 6.030, 2H),V4.68(t,
pyranylmethyl)—piperidin :J=8.8 Hz, 2H), 3.90 - 3.80 (m, 2H), 3.40 - 3.20 (m, 5H),
yl]-[1,3,4]0xadiazol—2-yl}-2,3- 3.05 0, J= 8.8 Hz, 2H), 3.0 - 2.90 (m, 2H), 2.90 -
dihydro-benzofuranylamine '2.80(m, 2H), 2.25-2.15 (m, 2H), 2.10 — 1.92 (m, 3H),
oxalate 1.70: 1.60 (m, 2H), 1.30-l.l3(m, 2H);
' Mass (m/z): 419.1, 421.2 (Mi-Hf.
4-[5-(43Amino-5 o-2,3- MR (DMSO-d6): a 7.49 (s, 1H), 6.03 (s,2H),
dihydfo-benzofuranyl)- '
4.680, J= 8.7 Hz, 2H), 4.15 — 4.00 (m, 4H), 3.40 -
[1,3,4]0xadiazol-2—yl]— 3.15011, 4H), 3.050, J= 8.7 Hz, 2H), 3.05 - 2.92 (m,
[l,4']bipiperidinyl- 1 '—carboxylic 2H), 2.90 - 2.70011, 2H), 2.30-220 (m,2H), 2.10 —
acid ethyl ester e 1.90011. 4H), 1.60 — 1.42(m,2H), 1.170, J= 7.0 Hz, 3H);
Mass (m/z): 476.1, 478.2 (M+H)+.
3-[5-(l-Cyclobutylmethyl- ‘H-NMR d6): 5 8.17 (d, J= 8.1 Hz, 1H),
piperidin-4—yl)—[ 1 ,3,4]oxadiazol- 7.9001,J=8.56 Hz, 1H), 7.540, J= 7.5 Hz, 1H), 7.38(t,
2-yl]—l —isopropyl-1H-indazole J= 7.6 Hz, 1H), 5.2 1H), 4.12 (s, 2H), 3.3 -
— 5.13(m,
3.2(m, 2H), 3.12 - 3.02(m, 2H), 2.7 — , 2H), 2.6 -
2.55(m, 1H), 2.48 -
.- 2.43(m, 1H), 2.2 - 2.1 (m, 2H), 2.1
2.0 (m, 2H), 1.98—1.87(m, 2H), 1.86 - 1.72 (m, 1H),
1.71 — 1.63 (m, 2H), 1.5401, J= 6.5 Hz, 6H);
_' Mass (m/z): 380 (M+H)+.
' l-Isopropyl{5-[l—(2-meth0xy- <‘H-NMR (CDC13): 8~8.35(d, J=8.1 Hz, 1H), 7.53 (d,
-piperidinyl]— EJ=8.3 Hz, 1H), 7.47 0, J=6.9 Hz,1H), 7.330, J=7.3 Hz,
[1,3,4]oxadiazolyl}-lH- :lH), 5.0 -4.91(m,1H), 3.550, J=5.3 Hz, 2H), 3.380,
indazole 3H), 3.12 -
- 3.1(m, 3H), 2.630, J=5.2Hz, 2H), 2.25‘
2.12 (m,6H), 1.66 (d, J=6.6 Hz, 6H);
Mass (m/z): 370 (M+H)+.
2012/000011
3-[5-(l-Cyclobutyl—piperidin ‘ 1H-NMR(CD.C13): 5 8.33 01, J= 8.2 Hz, 1H), 7.5201, J:
yl)-[l,3,4]oxadiazolyl] 8.5 Hz, 1H), 7.470, J= 7.9 Hz, 1H), 7.330, J=7.5 Hz,
pyl-lH-indazole 1H), 5.0 —4.93(m, 1H), 3.15-3.08(m, 1H), 2.98 -
2.96(m,2H), 2.8 -2.7(m-, 1H), 2.3 - 2.2011, 2H), 2.16 —
2.05 (m, 5H), 2.0 - 1.9 011,311), 1.75 - 1.69 (m, 211),
1.67(d, J= 6.7 Hz, 6H);
Mass (m/z): 366.4 (M+H)+.
l-Isopropyl[5—(l-isopropyl— ‘H-NMR (CDC13): 5 , J: 8.16 Hz, 1H), 7.53» (d,
piperidin-4—yl)-[1,3,4]oxadiazol- I: 8.48 Hz, 1H), 7.47 9t, I: 7.97 Hz, 1H), 7.330, ’1:
2-yl]-1H-indazolc 7.48 Hz, 1H), 5.00 - 4.93011, 1H), 3.06 - 2.96 (m, 3H),
2.8 - 2.75011, 2H), 2.35 - 2.30011, 2H), 2.25 — 2.17 (m,
2H), 2.12 -2.03(m,2H), 1.65(d, 1: 6.8 Hz, 6H), 1.87(d,
J: 6.5 Hz, 6H);
Mass (m/z): 354 (M+H)+.
3-[5-( l -Cyclopropylmethyl- ‘H-NMR (c1303): 58.35 (d, J=8.1‘Hz, 1H), 7.5301,
piperidinyl)-[1,3,4]oxadiazol- J=8.4, Hz, 1H), 7.470, J= 6.7 Hz, 1H),7.33(t, J=7.46 Hz,
2-yl]isopropyl-lH-indazole 1H), 5.03 - 4.95(m, 1H), 3.18 - 315 (m, 2H), 3.15 -
3.07(m,;1H),'2.31(d, J=6.5'Hz, 2H), 2.22 - 2.1(m, 6H),
1.67(d, J=6.68 Hz,6H), 0.98 — 0.91(m,lH), 0.57 — 0.52
(m, 2H), 0.14 -0.11(m, 2H);
Mass (m/z): 366 (M+H)+.
1-[sopropyl{5.-[1—(3-methyl- ‘H-NMR (CDC13): 5 8.35(d, J= 8.1 Hz, 1H), 7.5301, J=
butyl)-piperidinyl]— 8.46 Hz, 1H), 7.470, J= 6.91 Hz, 1H), 7.330, J=7.6 Hz,
[1,3,4]0xadiazolz2—yl}—l H- 1H), 5.0 m,1H), 3.10 — 2.98(m, 3H),-
indazole '1.67(d,J=6.68 Hz, 6H), 1.45 - ,'2H), 0.9201,
J=6.57 Hz, 6H);
Mass (m/z): 382 (M+H)*.
3-[5-(1-Cyclopropyl—piperid,in 1H-NMR(CDC13): 5 8.35(d, J= 8.17 Hz, 1H), 7.53(d,
yl)-[l,3,4]oxadiazolyl]-l- J=8.48 Hz, 1H), 7.47(t, J=6.96 Hz, 1H), 7.33(t, J=_ 7.47
isopropyl-lH-indazole ' HZ, 1H), 5.0 - 4.93(m,1H), 3.16 ‘ 3.05(m, 3H), 2.37 (t,
J: 11.3 HZ,2H), 2.19 — 2.16(m,2H), 2.07-1.98(m, 2H),
1.67(d, J= 6.6 Hz,6H), 1.63 - 1.57 (m, 1H), 051 ~
(m. 4H);
Mass (m/z): 352 (M+H)+.
3-[5-(1—Cyclopentyl-piperidin—4- 1H-NMR (CDCb): 5 8.35 (d, J: 9.39 HZ, 1H), 7.53011,
yl)—[l,3,4]oxadiaz01yl] ' J= 8.49 Hz, 1H), 7.470, J=8.0 Hz, 1H), 7.33 (t, J=7.43
isopropyl-lH-indazole Hz), 5.0-4.93 (m, 1H), 3.15 - 3.05(m, 3H), 2.6 — 2.53(m,
1H), 2.22 - 2.10(m, 6H), 1.98 - 1.90(m, 2H), 1.74 -
, 2H), 1.67(d, Hz, 6H), 1.60—1.55 (m,2H),
1.45 - 1.38 (m, 2H);
Mass (m/z): 380 (M+H)+.
1-Isopropyl{5-[3-(3-methoxy- lH-NMR (DMSO-dé): 5 8.15(d, J=8.2 Hz, 1H), 7.89(d,
propyl)-3—aza—bicyclo[3 .1 .0]hex- J=8.1 Hz, 1H), 753(1, J.=7.5Hz, 1H), 7.36 (t, J = 7.4 Hz,
[l,3,4]0xadiazolyl}-1H- #
1H), 5.20-5.10 (m, 1H), 3.60 - 350 (m, 2H), 3.36 (t, J
indazole oxalate salt 5.8 Hz, 2H), 3.23 (s, 3H), 3.10 - 3.0 (m, 2H), 3.0-2.86
(m, 2H), 2.68 (s, 1H), 2.43 (s, 2H), 1.85-1.72 (m, 2H),
1.53 (d, J = 6.3 Hz, 6H); '
'Mass (m/z): 382.3 (M+H)+.
_ 3-[5-(3-Cyclobutyl—3-aza— 1H-NMR (ch13): 8 8.34 (d, J = 8.1 Hz, 1H), 7.52 (d,-J
o[3.1 .0]hexyl)- = 8.4 Hz, 1H), 7.46 (t, J = 8.0 Hz, 1H), 7.29 (t, J = 7.3
]oxadiazoly11—1— . "Hz, 1H), 5.0 - 4.90 (m, 1H), 3.11 (d, J = 9.0 Hz, 2H),
isopropyi-lH-indazole oxalate 3.10 - 3.0 (m, 1H), 2.73 (s, 1H), 2.41 (d, J = 8.3 Hz,
salt 2.06 - 1.95 1.95—1.80 (m,
. 2H), "2.2 (s, 2H), (m, 2H),
2H), 1.75 - 1.65 (m, 2H), 1.67 (d, J =6.7>Hz, 6H);
Mass (m/z): 364.2 (M+H)+.
3-[5-(3-Cyclobutylmethyl-,3—aza— (DMSO-d6): 5 8.14 (d, J =.8.1 Hz, 1H), 7.89
bicyclo[3.1.0]hexyl)- (d, J = 8.4 Hz, -1 H), 75311, J = 7.4 Hz, 1H), 7.36 (t, J =
‘ [1,3,4]oxadiazo1-2—y11
7.6 Hz, 1H), 5.20 — 5.10 (m, 1H), 3.55 - 3.40 (m, 2H),
isopropyl— 1 H-indazole oxalate 3.10 - 3.0' (m, 2H), 2.95 - 2.85 (m, 2H), 2.67 (s, 1H),
salt 2.60 - 2.50‘(m, 1H), 2.41 (s, 2H), 2.10- 1.98 (m, 2H),
1.90 - 1.80 (m, 1H), 1.85 - 1.65 (m, 3H), 1.52 (d, J =
6.0 Hz, 6H);
Mass (m/z): 378.2 (M+H)+.
3_-[5-(3-Cyclopropylméthyl—3- lH-NMR(CDC13): a 8.34 (d, J = 811 Hz, 1H), 7.52 (d, J
cyclo[3.1.0]hexyl)- = 8.3 Hz, 1H), 7.46 (t, J = 8.1 Hz, 1H), 7.32 (t, J = 7.5
[1,3,4]oxadiazol-29y11 Hz, 1H), 5.0 - 4.90 (tn, 1H), 3.30 (d, J = 8.9 Hz, 2H),
isopropyl—lH-indazolé oxalate 2.77 (s, 1H), 2.48 (d, J = 8.6 Hz, 2H), 2.20 (s, 2H), 1.67
salt (d, J: 6.0 Hz, 6H), 0.90 - 0.80 (m, 1H), 0.50 — 0.40 (m,
2H), 0.18 - 0.08 (m, 2H);
Mass (m/z): 364.1 (M+H)f.
_ 1-Isopropyl-3~{5-[1-(tetrahydro- 1IH—NMR(DMSO-d6): 8 8.18 (d, J = 8.03 Hz, 1H), 7.90
pyranylmethyl)-piperidin—4- '= 8.0 Hz,
(d, J = 8.4 Hz, 1H), 7.54 (t, J 1H), 7.38 (t, J =
’ y'l]-[1,3,4]oxadiazolyl}-1H- 7.3 Hz, 1H), 5.20- 5.14 (m, 1H), 3.90 — 3.80 (m, 2H),
indazole oxalate salt 3.37 — 3.27 (m, 5H), 2.98 - 2.89 (m, 2H), 2.88 - 2.77 (m,
2H), 2.29 — 2.23 (m, 2H), 2.27-2.03 (m, 3H), 1.67 — 1.63
(m, 2H), 1.54 (d, J = 6.4 Hz, 6H), 1.22-1.15 (m, 2H);
Mass (m/z): 410.1 (M+H)+.
l-Isopropyl-3 - { 5-[ l -(tetrahydro- 1H-NMR(DMSO-d6): 88.18 (d, J = 8.1 Hz, 1H), 7.9 (d,
pyranyl)-piperidinyl]- J = 8.5 Hz, 1H), 7.54 (t, J = 7.1 Hz, 1H), 7.38 (t, J = 7.3
[l,3,4]oxadiazolyl}-1H- Hz, 1H), 5.20 — 5.14 (m, 1H), 4.0 — 3.90 (m, 2H), 3.47 —
indazole e salt 3.40 (m, 3H), 3.40 - 3.20 (m, 3H), 3.15 - 3.01 (m, 2H),
2.38 - 2.25 (m, 2H), 2.11 -. 2.06 (m, 2H), 1.95 — 1.86 (m,
2H), 1.66 - 1.60 (m, 2H), 1.54 (d, J = 65 Hz, 6H);
Mass (m/z): 396.2 (M+H)+. j .)
1-Isopropyl[5-(2-piperidin- l- ‘H-NMR (DMSO-d6): 5 8.19(d, J= 8.1 Hz, 1H),
yl-ethyl)-[ l ,3,4]oxadiazol-2—yl]— 7.91(d, J= 8.5 Hz,1H), 7.55(t, J= 7.5 Hz, 1H), 7.38(t,J=
lH-indazole oxalate 7.6 Hz, 1H), 5.21 - 5.14(m, 1H), 3.49-3.41(m,4H), 3.15
- , 4H), 1.76 - l.64(m, 4H), l.54(d, J=6.59 Hz,
6H), 1.54 - , 2H);
Mass (m/z): 340(M+H)+.
ical Assays
Example 50: ination of ECSO values for 5-HT4 receptor:
A stable CHO cell line expressing recombinant human 5-HT4 receptor and
pCRE-Luc reporter system was used for cell-based assay. The assay offers a non-
radioactive based ch to determine binding of a compound to GPCRs. In this
specific assay, the leVel of intracellular cyclic AMP which is modulated by activation
or inhibition of the receptor is measured. The inant cells harbor luciferase
reporter gene under the control of CAMP response element.
The above cells were grown in 96 well clear bottom white plates in‘Hams F12
medium containing 10% fetal bovine serum (FBS). Prior to the addition of compounds
or standard agonist, cells were serum starved overnight. Increasing concentrations of
test compounds were added in OptiMEM medium to the cells. The incubation was
continued at 37 °C in C02 incubator for 4 hours. Medium was removed and cells were
washed with phosphate buffered'saline. The cells Were lysed and luciferase activity was
ed in a Luminometer. Luminescence units were plotted. against the compound
concentrations using Graphpad software. EC50 values of the compounds were defined
as the concentration required in stimulating the luciferase activity by 50 %.
v—Iy—dy—Ao N A
m \l
._.\ ' '204
)—| J} w
H U: . g";-N
h—Ih—d \lO\ . 113.3
. ”‘5"“w
MO. 104
Nl—‘3' '7L2
NN . A00
NU) NO
N9 MN'\IU‘
N9 ._.. as
[\Jfl
NOQ . ._.. C)
N\O 21.5
U) 0 DJ
3L 169
b) w NP.‘
w 4:. u:
U) U! 169-
WW \IO\ 143
-127
w m
bk»CC ,116
WO 42135
Example 51: Rodent Pharmacokinetic Study
Male Wister rats (225 i 25 grams) were used as an experimental animal. Three
to five animals were housed in each cage. Two days prior to dosing day, male wister
rats (225’ - 250 grams) were anesthetized with isoflurane for surgical placement of
jugular vein catheter. Animals were fasted over night before oral dosing (p.o) and food
pellets were allowed 2 hours post , whereas intravenous dosing food and water
were provided as ad libitum. Three rats were dosed with compounds of formula (I) (10
mg/kg) orally and intravenously (05 mg/kg).
_At each time point blood was ted through jugular vein and immediately
replenish with an equivalent volume of normal saline from freely moving rats.
ted blood was transferred into a labeled eppendr off containing 10 ”L of heparin
as anticoagulant. Typically blood‘samples were collected as following time points: Pre
dose, 0.08 (only i.v.), 0.25, 0.5, l, 2, 4, 6, 8, and 24 hours post dose (n=3). Blood was
centrifuged at 4000 rpm for 10 minutes. Plasma was prepared and stored frozen at -20
°C until analysis. The concentrations of the compounds of formula (I) were quantified
in plasma by qualified LC-MS/MS method using suitable extraction technique. The
compounds of a (I) were quantified in the calibration range around 2-2000
ng/mL in plasma. Study samples were analyzed using calibration samples in the batch
and quality l samples spread across the batch.
Phamiacokinetic parameters Cm”, Tmax, AUCt, Ty; and Bioavailability were
ated by non—compartmental model using standard non-compartmental model by
using WinNonLin 5.0.1 or PhOeni-x WinNonlin 6.2'version Software package.
Ekam Strain Dose Vehic Route of Cum Bioavailabi
administrat (ng/m
Numb Gende
‘ g) (%)
Ili-.34i13_'
(gavage) 2 :l: 120,
intravenous 0.0 1117
(bolus) 8 :t 285
oral
(gavage)
intravenous
(bolus)
oral
(gaVage) "
enous
(bolus)
oral 0.96 42 :l: 10
(gavage)
intravenous 783 :1: 0.0 773345 .
(bolus) 1.24 8 d:
oral 1758 :1: 0.5 4814 :1:
e) 264 0 :h 30
- 0.0
intravenous 1858 i 0.0 2373 i
(bolus) 115 8 :1: 90
oral 0.2 790 i
(gavage)
intravenous
(bolus)
oral .553 i 0.4 1490 i
(gavage) 53 2 :t 72
v
WO 42135
intravenous
(bolus)
oral
(gavage)
intravenous
(bolus)
Wistar oral
/ Male (gavage)
intravenous
(bolus)
oral
(gavage)
_47-
Steril intravenous 0 0 1004 :1: 1.44
e (bolus) 8 :t 109
oral . 521'
(gavage) ' l 1 l
Steril intravenous
e (bolus)
Example 52: Rodent Brain Penetration Study
Male Wister rats (225 i 25 grams) Were used as an experimental animal. Three
animals were housed in each cage. Animals were given water and food ad libitum
hout the experiment, and maintained on a 12 hours light/dark cycle.
Brain penetration was determined in te manner in rats. One day prior to
' dosing day, male wistar rats (225
- 250 grams) were acclimatized. Afier acclimatizatidn
the rats were grouped according to the weight in each group, 3 animals were kept in
individual cage and allowed free access to food and water. At each time point (0.50, 1,
and 2 hours) n = 3 s were used.
The compounds of forrnula (I) was suitably preformulated and administered
orally at (free base equivalent) 10 mg/kg. Blood s were removed via, cardiac
puncture by using isoflurane anesthesia the animals were sacrificed to collect brain
tissue. Plasma was separated and Brain samples were homogenized and stored frozen at
-20 °C until analysis. The concentrations of the NCE compound in plasma and Brain
were determined using MS method. '
The compounds of formula (I) were quantified in plasma and brain homogenate
by qualified MS method using suitable extraction technique. The compounds
of formula (I) were quantified in the ation range of 1-500 ng/mL in plasma and
brain homogenates Study samples were analyzed using calibration} samples in the batch
and quality control s spread across the batch. Extent of brain-plasma ratio was
calculated (Cb/C1,).
Strain/ Route of: Single dose Brain
Gender administration Penetration )
Wistar / Male Reagent oral (gavage) 3.88 :1: 0.26
' grade
water
Wistar / Male Sterile intravenous
water for (bolus)
injection
Wistar / Male 10 Reagent oral (gavage) 0.56 £0.08
' grade
water
Wistar / Male Sterile intravenous
water for (bolus) T
injection
Wistar/ Male ‘1 10 Reagent oral (gavage): 2.24 3: 0.09
grade
water
Wistar / Male 5 Sterile intravenous
water for (bolus)
Wistar / Male Reagent oral (gavage) 0.50 :I: 0.07
_ grade
water
Wistar / Male Sterile intravenOus
water for (bolus)
injection
_
Wistar / Male - Reagent oral (gavage) 0.62 d: 0.05
grade
water
Wistar / Male Sterile intravenous .
water for (bolus)
injection-
Wistar / Male oral (gavage) 5.68 d: 1.74
Wistar / Male Sterile intravenous
water for (bolus)
injection
Wistar / Male t oral (gavage) 4.69 :t 0.69
grade
lwater
Wistar / Male Sterile intravenous
water for (bolus)
injection
Wistar / Male l—Re’agent oral e) 3.15 i057
grade
water
Wistar / Male fSterile intravenous
' for
water (bolus)
injection
Wistar / Male Reagent oral (gavage) 2.55 i 0.32
grade _
water
‘ Wistar / Male - Sterile intravenous
water for (bolus)
injection
Example 53: Object Recognition Task Model
'The cognition ing 'properties of compounds of this invention were
estimated by using this model.
Male Wister rats (230 — 280 grams) were used as experimental s. Four
s were housed in each cage; Animals Were kept on 20 % food deprivation before v
one day and given water ad libitum throughout the experiment and maintained on a 12
hours light/dark'cycle. Also the rats were habituated to individual arenas for 1 hour in
the absence ofany objects.
One group of 12 rats received vehicle (1 mL/Kg) orally and’ another set of
animals received nd of the a (I) either orally or i.p.-, before one hour of
the familiar (Tl) and choice trial (T2).
The experiment was carried out in a 50 x 50 x 50 cm open field made up of
acrylic. In the familiarization phase/(Tl), the rats were placed individually in the open
field for 3 minutes, in which two identical objects (plastic bottles, 12.5 cm height x 5.5
cm diameter) covered in yellow masking tape alone (a1 and a2) were positioned in two
adjacent comers, 10‘ cms from the walls. After 24 hours of the (T1) trial for long-term
memory test, the same rats were placed in the same arena as they were placed in T1
trial. Choice phase (T2) rats were allowed to e the open field for 3 s in
presence of one familiar object (a3) and one novel object (b) (Amber color glass bottle,
12 cm high and 5 cm in diameter)- Familiar objects ted similar textures, colors
and sizes. During the Tl and T2 trial, explorations of each object (defined as sniffing,
licking, chewing or having moving, vibrissae whilst directing the nose towards‘the
object at a distance of less than 1 cm) were recorded separately by stopwatch. Sitting on
an object was not regarded as exploratory ty, however, it was rarely observed.
T1 is the total time spent exploring the familiar objects (a1 + a2).
T2 is the total time spent exploring the familiar object and novel object (a3 +b).
‘ The object recognition test was performed as described by Ennaceur, A.,
A new ial test fOr neurobiological studies of memory in rats -
. Delacour, 1., 1988,
Behavioural data, Behavi Brain Res, 31,_47-59.
m.3mg/kg,p.o. 11.21i2.18 l6.47:t1.18 '
2012/000011
- ..
e 54: Radial arm maze
The cognition enhancing properties of compounds of this invention were
estimated by using this model.
Radial arm maze consists of a central hub of 45 cm er. Bach arm was of
dimension 42.5.x 15, x 24 cm. The maze'was elevated to a height of l m above the
ground. The animals were place on a cted diet until they reached approximately 85
% of their free feeding weight. During this diet restriction period animals were
habituated to the novel feed (pellets). Once the rats reached approximately85 % of their
free feeding weight rats were habituated to the maze on the 1St & 2nd day._The animals
that did not eat the pellets were ed from the study. Animals were randomized on
day 2. On the subsequent days the treatment was given as per the allotment. Each
animal was introduced into the maze individually for a period of 10 minutes. The arms
were baited only: once and the animal had to learn. the rule that repeated arm entries
would not be rewarded. The trial ended once the rat had visited 16 arms or 10 minutes
were over or all the pellets were eaten. The arm entries were recorded using the
software. Once the trial was over the rat was removed and the maze was cleaned using
soap water.
Example Reversal of Scopolamine Induced
3. 1 - 3 mg/kg, p.o.
14. 1 --10 mg/kg, p.o.
Claims (18)
1. A compound of the general formula (I): wherein, is or ; is , or ; is point of attachment; R1 is alkyl, R3-O-R3 or ; R2 is cycloalkyl or heterocyclyl, and optionally substituted with hydrogen, alkyl or -CO-OR3; R3 is alkyl; “Y” is C or O; “m” is an r ranging from 0 to 1; with proviso when m is 0 then R1 is cycloalkyl or heterocyclyl; “n” is an integer ranging from 0 to 2; “p” is an integer g from 0 to 1; or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1, which is selected from the group consisting of: ro[5-(1-cyclopropyl-piperidinyl)-[1,3,4]oxadiazolyl]-chromanylamine; 1-isopropyl{5-[1-(3-methoxy propyl) piperidinyl]-[1,3,4]oxadiazolyl}-1H-indazole; 3-[5-(1-cyclobutyl-piperidinyl methyl)-[1,3,4]oxadiazolyl]isopropyl-1H-indazole; 6-chloro[5-(3-cyclobutylaza bicyclo[3.1.0]hexyl)-[1,3,4]oxadiazolyl] n yl amine; 4-[5-(8-Aminochloro-2,3-dihydro benzo[1,4]dioxanyl)-[1,3,4]oxadiazolyl]- [1,4']bipiperidinyl-1'-carboxylic acid ethyl ester; 5-Chloro{5-[1-(tetrahydro pyranyl) piperidinyl]-[1,3,4]oxadiazolyl}-2,3-dihydro benzofuranyl amine; ro[5-(1-cyclopentyl-piperidinylmethyl)-[1,3,4]oxadiazolyl]-chroman ylamine; 6-Chloro[5-(3-isopropylaza-bicyclo[3.1.0]hexyl)-[1,3,4]oxadiazolyl]-chroman ylamine; 6-Chloro[5-(3-cyclobutylmethylaza-bicyclo[3.1.0]hexyl)-[1,3,4]oxadiazolyl]- chromanylamine; ro{5-[1-(tetrahydro-pyranyl)-piperidinyl]-[1,3,4]oxadiazolyl}-chroman ylamine; 6-Chloro{5-[1-(tetrahydro-pyranylmethyl)-piperidinyl]-[1,3,4]oxadiazolyl}- chromanylamine; 5-Chloro[5-(1-cyclopropyl-piperidinyl)-[1,3,4]oxadiazolyl]-2,3-dihydro-benzofuran- 4-ylamine; 5-Chloro[5-(1-cyclobutyl-piperidinyl)-[1,3,4]oxadiazolyl]-2,3-dihydro-benzofuran ylamine; 6-Chloro[5-(1-cyclopropyl-piperidinyl)-[1,3,4]oxadiazolyl]-2,3-dihydrobenzo [1,4]dioxinylamine; 6-Chloro{5-[1-(tetrahydro-pyranyl)-piperidinyl]-[1,3,4]oxadiazolyl}-2,3-dihydrobenzo [1,4]dioxinylamine; 6-Chloro{5-[1-(3-methoxy-propyl)-piperidinyl]-[1,3,4]oxadiazolyl}-2,3-dihydrobenzo [1,4]dioxinylamine; 6-Chloro{5-[1-(tetrahydro-pyranylmethyl)-piperidinyl]-[1,3,4]oxadiazolyl}-2,3- dihydro-benzo[1,4]dioxinylamine; 5-Chloro{5-[1-(tetrahydro-pyranylmethyl)-piperidinyl]-[1,3,4]oxadiazolyl}-2,3- dihydro-benzofuranylamine; 4-[5-(4-Aminochloro-2,3-dihydro-benzofuranyl)-[1,3,4]oxadiazolyl]- [1,4']bipiperidinyl-1'-carboxylic acid ethyl ester; ropyl{5-[3-(3-methoxy-propyl)aza-bicyclo[3.1.0]hexyl]-[1,3,4]oxadiazol -indazole; 3-[5-(3-Cyclobutylaza-bicyclo[3.1.0]hexyl)-[1,3,4]oxadiazolyl]isopropyl-1H- indazole; 3-[5-(3-Cyclobutylmethylaza-bicyclo[3.1.0]hexyl)-[1,3,4]oxadiazolyl]isopropyl- azole; 3-[5-(3-Cyclopropylmethylaza-bicyclo[3.1.0]hexyl)-[1,3,4]oxadiazolyl]isopropyl- 1H-indazole; 1-Isopropyl{5-[1-(tetrahydro-pyranylmethyl)-piperidinyl]-[1,3,4]oxadiazolyl}- 1H-indazole; 1-Isopropyl{5-[1-(tetrahydro-pyranyl)-piperidinyl]-[1,3,4]oxadiazolyl}-1H- indazole; 1-Isopropyl[5-(2-piperidinyl-ethyl)-[1,3,4]oxadiazolyl]-1H-indazole.
3. The compound according to claim 1, which is ed from the group consisting of: 6-Chloro[5-(1-cyclopropyl-piperidinyl)-[1,3,4]oxadiazolyl]-chromanylamine hemi fumarate; 6-Chloro[5-(1-cyclobutyl piperdinylmethyl)-[1,3,4]oxadiazolyl]-chromanyl amine L(+) tartarate salt; 6-Chloro[5-(1-cyclobutyl piperdinyl methyl)-[1,3,4]oxadiazolyl]-chromanyl amine; 1-Isopropyl{5-[1-(3-methoxy propyl) piperidinyl]-[1,3,4]oxadiazolyl}-1H-indazole oxalate salt; 1-Cyclobutyl-piperidinyl methyl)-[1,3,4]oxadiazolyl]isopropyl-1H-indazole L(+)- tartarate salt; 6-Chloro[5-(3-cyclobutylaza bicyclo[3.1.0]hexyl)-[1,3,4]oxadiazolyl] chroman ylamine oxalate salt; 4-[5-(8-Aminochloro-2,3-dihydro benzo[1,4]dioxanyl)-[1,3,4]oxadiazolyl]- [1,4']bipiperidinyl-1'-carboxylic acid ethyl ester oxalate salt; 5-Chloro{5-[1-(tetrahydro pyranyl) piperidinyl]-[1,3,4]oxadiazolyl}-2,3-dihydro benzofuranyl amine oxalate salt; 6-Chloro{5-[1-(2-methoxy-ethyl)-piperidinyl]-[1,3,4]oxadiazolyl}-chromanylamine; 6-Chloro{5-[1-(3-methyl-butyl)-piperidinyl]-[1,3,4]oxadiazolyl}-chroman ylamine; 6-Chloro[5-(1-cyclobutylmethyl-piperidinyl)-[1,3,4]oxadiazolyl]-chromanylamine; 6-Chloro[5-(1-cyclopropylmethyl-piperidinyl)-[1,3,4]oxadiazolyl]-chromanylamine; 6-Chloro[5-(1-isopropyl-piperidinyl)-[1,3,4]oxadiazolyl]-chromanylamine; 6-Chloro{5-[1-(3-methoxy-propyl)-piperidinyl]-[1,3,4]oxadiazolyl}-chromanylamine; 6-Chloro[5-(1-cyclobutyl-piperidinyl)-[1,3,4]oxadiazolyl]-chromanylamine; 6-Chloro[5-(1-cyclobutylmethyl-piperidinyl)-[1,3,4]oxadiazolyl]-2,3-dihydrobenzo ioxinylamine; 6-Chloro[5-(1-cyclobutyl-piperidinyl)-[1,3,4]oxadiazolyl]-2,3-dihydro-benzo[1,4]dioxin- 5-ylamine; 6-Chloro[5-(1-cyclopentyl-piperidinyl)-[1,3,4]oxadiazolyl]-chromanylamine; 6-Chloro[5-(2-piperidinyl-ethyl)-[1,3,4]oxadiazolyl]-chromanylamine; 4-[5-(5-Aminochloro-chromanyl)-[1,3,4]oxadiazolyl]-[1,4']bipiperidinyl-1'-carboxylic acid ethyl ester; 6-Chloro[5-(3-piperidinyl-propyl)-[1,3,4]oxadiazolyl]-chromanylamine; 6-Chloro[5-(1-cyclopentyl-piperidinylmethyl)-[1,3,4]oxadiazolyl]-chromanylamine oxalate salt; 6-Chloro[5-(3-isopropylaza-bicyclo[3.1.0]hexyl)-[1,3,4]oxadiazolyl]-chroman e oxalate salt; 6-Chloro[5-(3-cyclobutylmethylaza-bicyclo[3.1.0]hexyl)-[1,3,4]oxadiazolyl]-chroman- 5-ylamine oxalate salt; 6-Chloro[5-(3-cyclopropylmethylaza-bicyclo[3.1.0]hexyl)-[1,3,4]oxadiazolyl]- chromanylamine; 6-Chloro{5-[1-(tetrahydro-pyranyl)-piperidinyl]-[1,3,4]oxadiazolyl}-chroman ylamine oxalate salt; 6-Chloro{5-[1-(tetrahydro-pyranylmethyl)-piperidinyl]-[1,3,4]oxadiazolyl}-chroman- 5-ylamine oxalate salt; 5-Chloro[5-(1-cyclopropyl-piperidinyl)-[1,3,4]oxadiazolyl]-2,3-dihydro-benzofuran ylamine oxalate salt; 5-Chloro[5-(1-cyclobutyl-piperidinyl)-[1,3,4]oxadiazolyl]-2,3-dihydro-benzofuran ylamine e salt; 6-Chloro[5-(1-cyclopropyl-piperidinyl)-[1,3,4]oxadiazolyl]-2,3-dihydrobenzo [1,4]dioxinylamine oxalate salt; 6-Chloro{5-[1-(tetrahydro-pyranyl)-piperidinyl]-[1,3,4]oxadiazolyl}-2,3- dihydro-benzo[1,4]dioxinylamine oxalate salt; 6-Chloro{5-[1-(3-methoxy-propyl)-piperidinyl]-[1,3,4]oxadiazolyl}-2,3-dihydrobenzo [1,4]dioxinylamine e salt; 6-Chloro{5-[1-(tetrahydro-pyranylmethyl)-piperidinyl]-[1,3,4]oxadiazolyl}-2,3- dihydro-benzo[1,4]dioxinylamine oxalate salt; 5-Chloro{5-[1-(tetrahydro-pyranylmethyl)-piperidinyl]-[1,3,4]oxadiazolyl}-2,3- dihydro-benzofuranylamine oxalate; 4-[5-(4-Aminochloro-2,3-dihydro-benzofuranyl)-[1,3,4]oxadiazolyl]-[1,4']bipiperidinyl- 1'-carboxylic acid ethyl ester oxalate; 1-Cyclobutylmethyl-piperidinyl)-[1,3,4]oxadiazolyl]isopropyl-1H-indazole; 1-Isopropyl{5-[1-(2-methoxy-ethyl)-piperidinyl]-[1,3,4]oxadiazolyl}-1H-indazole; 3-[5-(1-Cyclobutyl-piperidinyl)-[1,3,4]oxadiazolyl]isopropyl-1H-indazole; 1-Isopropyl[5-(1-isopropyl-piperidinyl)-[1,3,4]oxadiazolyl]-1H-indazole; 3-[5-(1-Cyclopropylmethyl-piperidinyl)-[1,3,4]oxadiazolyl]isopropyl-1H-indazole; 1-Isopropyl{5-[1-(3-methyl-butyl)-piperidinyl]-[1,3,4]oxadiazolyl}-1H-indazole; 3-[5-(1-Cyclopropyl-piperidinyl)-[1,3,4]oxadiazolyl]isopropyl-1H-indazole; 3-[5-(1-Cyclopentyl-piperidinyl)-[1,3,4]oxadiazolyl]isopropyl-1H-indazole; 1-Isopropyl{5-[3-(3-methoxy-propyl)aza-bicyclo[3.1.0]hexyl]-[1,3,4]oxadiazolyl}-1H- indazole oxalate salt; 3-[5-(3-Cyclobutylaza-bicyclo[3.1.0]hexyl)-[1,3,4]oxadiazolyl]isopropyl-1H-indazole e salt; 3-[5-(3-Cyclobutylmethylaza-bicyclo[3.1.0]hexyl)-[1,3,4]oxadiazolyl]isopropyl-1H- le oxalate salt; 3-[5-(3-Cyclopropylmethylaza-bicyclo[3.1.0]hexyl)-[1,3,4]oxadiazolyl]isopropyl-1H- indazole oxalate salt; 1-Isopropyl{5-[1-(tetrahydro-pyranylmethyl)-piperidinyl]-[1,3,4]oxadiazolyl}-1H- indazole oxalate salt; 1-Isopropyl{5-[1-(tetrahydro-pyranyl)-piperidinyl]-[1,3,4]oxadiazolyl}-1H-indazole oxalate salt; 1-Isopropyl[5-(2-piperidinyl-ethyl)-[1,3,4]oxadiazolyl]-1H-indazole e salt and 3-[5-(1-cyclobutyl piperidinyl methyl)-[1,3,4]oxadiazolyl]isopropyl-1H-indazole oxalate salt; or their pharmaceutically acceptable salts.
4. The process for preparation of a compound of formula (I) as claimed in claim 1, which comprises: (a) coupling the compound of formula (1) with compound of formula (2) in presence of dehydrating agent to form a nd of formula (I), wherein all substitutions are as defined in claim 1, (b) optionally converting the compound of formula (I) to their pharmaceutically able salts.
5. The process for preparation of a compound of formula (I) as claimed in claim 1, which comprises: (a) coupling the compound of formula (1) with compound of formula (2) in ce of suitable solvent to form a compound of formula (4), (b) cyclizing the compound of formula (4) to form a compound of formula (I), wherein all substitutions are as defined in claim 1, (c) optionally converting the compound of formula (I) to their pharmaceutically acceptable salts.
6. A pharmaceutical composition comprising a compound according to any of claims 1 to 3 and pharmaceutically acceptable excipients.
7. The pharmaceutical composition according to claim 6, for the treatment of clinical conditions mediated through 5-HT4 receptors such as attention deficit hyperactivity disorder, mers disease, cognitive disorders, dementia or schizophrenia.
8. Use of a compound according to any one of the claims 1 to 3 in the manufacture of medicament for the ent of diseases related to 5-HT4 receptors.
9. The use of compound according to the claim 8, for the treatment of clinical ions such as attention deficit hyperactivity disorder, alzheimers disease, cognitive disorders, dementia or phrenia.
10. Use of a nd of formula (I) as d in claim 1, in the manufacture of a medicament for treatment of a disorder of central nervous system related to or affected by the 5-HT4 ors.
11. A compound of formula (I) when prepared by the s of claim 4.
12. A compound of formula (I) when prepared by the s of claim 5.
13. A compound of the general formula (I) as claimed in claim 1, substantially as hereinbefore described with particular reference to any one of the Examples.
14. The process for preparation of a compound of formula (I) as claimed in claim 4, substantially as hereinbefore described with particular reference to any one of the Examples.
15. The process for preparation of a compound of formula (I) as claimed in claim 5, substantially as hereinbefore described with particular nce to any one of the Examples.
16. A pharmaceutical composition as d in claim 6, substantially as hereinbefore described with particular reference to any one of the Examples.
17. Use of a compound as d in claim 8, substantially as hereinbefore described with particular reference to any one of the Examples.
18. Use of a compound as claimed in claim 10, substantially as hereinbefore described with particular reference to any one of the Examples.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN3203/CHE/2011 | 2011-09-19 | ||
| IN3203CH2011 | 2011-09-19 | ||
| PCT/IN2012/000011 WO2013042135A1 (en) | 2011-09-19 | 2012-01-05 | Heteroaryl compounds as 5-ht4 receptor ligands |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| NZ619776A NZ619776A (en) | 2015-04-24 |
| NZ619776B2 true NZ619776B2 (en) | 2015-07-28 |
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