HRP990188A2 - Diaza-spiro /3,5/ nonane derivatives - Google Patents
Diaza-spiro /3,5/ nonane derivatives Download PDFInfo
- Publication number
- HRP990188A2 HRP990188A2 HR98110804.6A HRP990188A HRP990188A2 HR P990188 A2 HRP990188 A2 HR P990188A2 HR P990188 A HRP990188 A HR P990188A HR P990188 A2 HRP990188 A2 HR P990188A2
- Authority
- HR
- Croatia
- Prior art keywords
- phenyl
- spiro
- diaza
- nonan
- naphthalen
- Prior art date
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- BKIMMITUMNQMOS-UHFFFAOYSA-N nonane Chemical class CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims description 102
- 239000000203 mixture Substances 0.000 claims description 35
- -1 bicyclo[3.3.1]non-9-yl Chemical group 0.000 claims description 24
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- 238000000034 method Methods 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 17
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- PULGYDLMFSFVBL-SMFNREODSA-N nociceptin Chemical compound C([C@@H](C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O)[C@@H](C)O)NC(=O)CNC(=O)CNC(=O)[C@@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 PULGYDLMFSFVBL-SMFNREODSA-N 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- TYBCSQFBSWACAA-UHFFFAOYSA-N Nonan-4-one Chemical compound CCCCCC(=O)CCC TYBCSQFBSWACAA-UHFFFAOYSA-N 0.000 claims description 6
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- 230000001154 acute effect Effects 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 5
- 229940079593 drug Drugs 0.000 claims description 5
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- GSUUINFTNAGZDH-UHFFFAOYSA-N 7-cyclooctyl-1-phenyl-1,7-diazaspiro[3.5]nonan-2-one Chemical compound C=1C=CC=CC=1N1C(=O)CC1(CC1)CCN1C1CCCCCCC1 GSUUINFTNAGZDH-UHFFFAOYSA-N 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 238000006268 reductive amination reaction Methods 0.000 claims description 3
- AJYMZRDFCFFPPR-UHFFFAOYSA-N 7-(1,2,3,4,4a,5,6,7,8,8a-decahydronaphthalen-2-yl)-1-phenyl-1,7-diazaspiro[3.5]nonan-2-one Chemical compound O=C1CC2(CCN(CC2)C2CC3CCCCC3CC2)N1C1=CC=CC=C1 AJYMZRDFCFFPPR-UHFFFAOYSA-N 0.000 claims description 2
- YNQHGZPSSJWKSX-UHFFFAOYSA-N 7-cycloheptyl-1-phenyl-1,7-diazaspiro[3.5]nonan-2-one Chemical compound C=1C=CC=CC=1N1C(=O)CC1(CC1)CCN1C1CCCCCC1 YNQHGZPSSJWKSX-UHFFFAOYSA-N 0.000 claims description 2
- XFUQQZWGUPWDLW-UHFFFAOYSA-N 7-cyclononyl-1-phenyl-1,7-diazaspiro[3.5]nonan-2-one Chemical compound C=1C=CC=CC=1N1C(=O)CC1(CC1)CCN1C1CCCCCCCC1 XFUQQZWGUPWDLW-UHFFFAOYSA-N 0.000 claims description 2
- VITXVCYZJIGRMI-UHFFFAOYSA-N 7-cyclononyl-1-phenyl-1,7-diazaspiro[3.5]nonane Chemical compound C=1C=CC=CC=1N1CCC1(CC1)CCN1C1CCCCCCCC1 VITXVCYZJIGRMI-UHFFFAOYSA-N 0.000 claims description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 2
- YOMSZEJVVGTTDO-KDURUIRLSA-N CC(C)[C@H]1CC[C@H](CC1)N1CCC2(CC(=O)N2c2ccccc2)CC1 Chemical compound CC(C)[C@H]1CC[C@H](CC1)N1CCC2(CC(=O)N2c2ccccc2)CC1 YOMSZEJVVGTTDO-KDURUIRLSA-N 0.000 claims description 2
- MEBVZOCGRFHLIS-BGYRXZFFSA-N CC(C)[C@H]1CC[C@H](CC1)N1CCC2(CCN2c2ccccc2)CC1 Chemical compound CC(C)[C@H]1CC[C@H](CC1)N1CCC2(CCN2c2ccccc2)CC1 MEBVZOCGRFHLIS-BGYRXZFFSA-N 0.000 claims description 2
- 125000004094 acenaphthen-1-yl group Chemical group [H]C1=C([H])C2=C3C(=C([H])C([H])=C([H])C3=C1[H])C([H])([H])C2([H])* 0.000 claims description 2
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000004129 indan-1-yl group Chemical group [H]C1=C([H])C([H])=C2C(=C1[H])C([H])([H])C([H])([H])C2([H])* 0.000 claims description 2
- 125000004130 indan-2-yl group Chemical group [H]C1=C([H])C([H])=C2C(=C1[H])C([H])([H])C([H])(*)C2([H])[H] 0.000 claims description 2
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- 238000007429 general method Methods 0.000 description 51
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- 238000002844 melting Methods 0.000 description 21
- 230000008018 melting Effects 0.000 description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
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- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
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- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
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- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
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- 125000000753 cycloalkyl group Chemical group 0.000 description 1
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- JMNJYGMAUMANNW-FIXZTSJVSA-N dynorphin a Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O)NC(=O)CNC(=O)CNC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=CC=C1 JMNJYGMAUMANNW-FIXZTSJVSA-N 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
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- 150000002081 enamines Chemical class 0.000 description 1
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- 238000005516 engineering process Methods 0.000 description 1
- CCGKOQOJPYTBIH-UHFFFAOYSA-N ethenone Chemical compound C=C=O CCGKOQOJPYTBIH-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 1
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- 229910052731 fluorine Inorganic materials 0.000 description 1
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- 229960004903 invert sugar Drugs 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 230000003137 locomotive effect Effects 0.000 description 1
- 230000006742 locomotor activity Effects 0.000 description 1
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- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
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- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003399 opiate peptide Substances 0.000 description 1
- 239000008012 organic excipient Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002400 pro-nociceptive effect Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000002731 protein assay Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
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- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 235000013599 spices Nutrition 0.000 description 1
- NRNKZKFTQBNHBT-UHFFFAOYSA-N spiro[3.5]nonan-2-one Chemical compound C1C(=O)CC21CCCCC2 NRNKZKFTQBNHBT-UHFFFAOYSA-N 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
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- 150000003890 succinate salts Chemical class 0.000 description 1
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- 238000003786 synthesis reaction Methods 0.000 description 1
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- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
-
- 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
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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
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- 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
- A61P25/08—Antiepileptics; Anticonvulsants
-
- 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
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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
- A61P25/22—Anxiolytics
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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
- A61P25/24—Antidepressants
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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
- A61P25/28—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
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Addiction (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Hospice & Palliative Care (AREA)
- Heart & Thoracic Surgery (AREA)
- Urology & Nephrology (AREA)
- Child & Adolescent Psychology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Hydrogenated Pyridines (AREA)
Description
Predloženi izum odnosi se na spojeve opće formule
[image]
u kojoj
R1 predstavlja (C6-12) -cikloalkil, po potrebi supstituiran s nižim alkilom ili C(O)O nižim alkilom, indan-1-il ili indan-2-il, po potrebi supstituiran s nižim alkilom; acenaften-1-il; biciklo[3.3.l]non-9-il, oktahidro-inden-2-il; 2,3–dihidro-lH-fenalen-1-il; 2,3,3a,4,5,6-heksahidro-1H-fenalen-1-il, dekahidro-azulen-2-il; biciklo-[6.2.0]dec-9-il; dekahidro-naftalen-1-il; dekahidro-naftalen-2-il; tetrahidro-naftalen-1-il, tetrahidro-naftalen-2-il ili 2-okso-1,2-difenil-etil;
R2 je =0 ili vodik;
R3 je vodik, izoindolil-1,3-dion, niži alkoksi, niži alkil, amino, benziloksi, -CH2OR5 ili CH2(R5)2;
R4 je vodik ili –CH2OR5;
R5 vodik ili niži alkil;
[image] je cikloheksil ili fenil, po potrebi supstituiran s nižim alkilom, halogenim ili alkoksi, i na njihove farmaceutski prihvatljive kiselinske adicijske soli.
Spojevi formule 1 i njihove soli odlikuju se dragocjenim terapeutskim svojstvima. Iznenađujuće je pronađeno da su spojevi predloženog izuma agonisti i/ili antagonisti orfanin FQ (OFQ) receptora. Zbog toga se oni mogu upotrijebiti za liječenje psihijatrijskih, neuroloških i fizioloških poremećaja, posebno, ali ne i isključivo za ublažavanje simptoma anksioznosti i stresnih poremećaja, depresije, traume, gubitka pamćenja zbog Alzheimerove bolesti ili drugih demencija, epilepsije i konvulzija, akutnih i/ili kroničnih stanja bola, simptoma odvikavanja ovisnosti o drogama, kontrole ravnoteže vode, izlučivanja Na+ poremećaja arterijskog krvnog tlaka i metaboličkih poremećaja kao što je debljina.
Ove indikacije bile su opisane u slijedećim publikacijama:
- Nociceptin/orfanin FQ i opioid receptoru sličan ORL1 receptor, Eur. J. Pharmacol., 340: 1-15, 1997;
- Orfan opioid receptor i njegov endofenozni ligand ociceptin/orfanin FQ, Trends Pharmacol. Sci., 18: 293-300, 1997;
- Orfanin FQ je funkcionalni anti-opioid peptid, Neuroscience, 75:333-337, 1996;
- Orfanin FQ/nociceptinski nedostatak anti-nociceptivnog, hiperalgezijskog ili alodinijskog učinaka u akutnim toplinskim ili mehaničkim ispitivanjima, nakon intraceiebroventrikularnog ili intratekalnog davanja miševima ili štakorima, Eur. J. pain, 2: 267-280, 1998;
- Orfanin FQ djeluje kao anksiolitik prema smanjenim odgovorima ponašanja na stres, Proc. Natl- Acad. Sci., USA, 94: 14854-14858, 1997;
- Orfanin FQ, agonist orfan opioid receptora ORLl, stimulira uzimanje hrane kod štakora, Neuroreport, 8: 369-371, 1996;
- Olakšavanje dugotrajne potencijacije i pamćenja u miševima s nedostatkom nociceptin receptora, Nature, 394: 577-581, 1998;
- Razdioba nociceptin/orfanin FQ receptorskog transkripta u ljudskom središnjem živčanom sustavu i imunin stanicama, J. Neuroimmuno, 81: 184-192, 1998;
- Orfamin FQ ima ulogu kod sepsa, Prog, Clin. Biol. Res. (1998), 397, 315-325.
OFQ, heptadeka-peptid, izoliran je iz mozga štakora i on je prirodni ligand za na G-proteinski povezan receptor (OFQ-R), nađen u visokim razinama u tkivu mozga. OFQ pokazuje agonističko djelovanje prema OFQ-R in vitro i in vivo.
Julius (Nature 377, 476, [1995] raspravlja o otkriću OFQ i piše da taj peptid dijeli najveću sekvencu istovrsnosti s dinorfinom A, dokazanim endogenim ligandom za receptore opioida. OFQ inhibira adenilat ciklazu u CHO (LC 132+) stanicama u kulturi i inducira hiperalgeziju ako se mišu dade intra-cerebroventrikularno- Oblik posljedica pokazuje da je taj heptadekapeptid endogeni agonist LC 132 receptora i izgleda da ima pro-nociceptivna svojstva. Opisano je da ako se mišu ubrizga intra-cerebroventrikularno, OFQ usporava lokomotornu aktivnost i inducira hiperalgeziju i zaključeno je da OFQ može djelovati kao moždani neurotransmiter za moduliranje nociceptivnog i lokomotornog ponašanja.
Predmet predloženog izuma su spojevi formule 1 i njihove farmaceutski prihvatljive adicijske soli, racemične smjese i njihovi odgovarajući enantiomeri, pripravljanje gore navedenih spojeva, lijekova koji ih sadrže i njihova proizvodnja, kao i upotreba gore spomenutih spojeva za suzbijanje ili prevenciju bolesti, posebno bolesti i poremećaja ranije spomenute vrste, ili za proizvodnju odgovarajućih lijekova.
Slijedeće definicije općih pojmova upotrijebljene u predloženom opisu primjenjuju se neovisno da li se dotični pojam koristi sam ili u kombinaciji, kao niži alkil i niži alkoksi.
Kako se ovdje rabi, pojam "niži alkil" označava ravnu ili razgranatu alkilnu skupinu koja ima od 1 do 6 ugljikovih atoma, na primjer metil, etil, propil, izopropil, n-butil, i-butil, 2-butil, t-butil i slično. Prednosne niže alkilne skupine su skupine koje imaju 1-4 ugljikova atoma.
Pojam "cikloalkila" označava zasićenu karbocikličku skupinu koja ima od 6 do 12 ugljikovih atoma, a to su ponajprije cikloheksil, ciklooktil, ciklononil i ciklodecil.
Pojam "halogen" označava klor, jod, fluor i brom.
Pojam "farmaceutski prihvatljive kiselinske adicijske soli" obuhvaća soli s anorganskim i organskim kiselinama koje su dobro poznate u struci za farmaceutske svrhe, kao klorovodična kiselina, dušiČna kiselina, sumporna kiselina, fosforna kiselina, limunska kiselina, mravlja kiselina, fumarna kiselina, maleinska kiselina, octena kiselina, sukcinska kiselina, vinska kiselina, metan-sulfonska kiselina, p-toluensulfonska kiselina i slično.
Prednosni spojevi predloženog izuma su oni spojevi formule 1 u kojoj R1 predstavlja (C6-9)-cikloalkil ili dekahidro-naftalen-2-il, na primjer slijedeći spojevi:
3,3-bis-hidroksimetil-7-(cis-4-izopropil-cikloheksil)-1-fenil-1,7-diaza-spiro[3.5]nonan-4-on;
7-(cis-4-izppropil-cikloheksil)-1-fenil-1,7-diaza-spiro[3.5]nonan-2-on;
7-(cis-4-izopropil-cikloheksil)-1-fenil-1,7-diaza-spiro[3.5]nonan;
7-ciklononil-1-fenil-1,7-diaza-spiro[3. 5]nonan-2-on;
7-ciklononil-1-fenil-1,7-diaza-spiro[3.5]nonan;
7-ciklooktil-1-fenil-1,7-diaza-spiro[3.5]nonan-2-on;
7-cikloheptil-1-fenil-1,7-diaza-spiro[3.5]nonan-2-on i
(2RS,4aSR,8aRS)-7-(dekahidro-naftalen-2-il)-1-fenil-1,7-diaza-spiro[3.5]nonan-2-on.
Predloženi spojevi formule 1 i njihove farmaceutski prihvatljive soli mogu se proizvesti metodama poznatim u struci, na primjer dolje opisanim postupcima, koji uključuju
a) reduktivno aminiranje spoja formule
[image]
sa spojem formule
[image]
pri čemu R1, R2, R3 i R4 i (F) imaju gore navedena značenja, ili
b) kondenzaciju imina formule
[image]
s derivatom karboksilne kiseline formule
[image]
čime se dobije spoj formule
[image]
u kojoj R1, R3, R4 i (F) imaju gore navedena značenja, i X je halogen, ili
c) kondenzaciju 4-fenilamino-4~piperidinokarbonitrila ili 4-cikloheksil-amino-4-piperidinokerbonitrila formule
[image]
s metilbromacetatom u prisutnosti metala, čime se dobije spoj formule
[image]
u kojoj R1 i (F) imaju gore data značenja, ili
d) redukciju spoja formule
[image]
u azetidin formule
[image]
u kojoj R1, R3, R4 i [image] imaju gore navedena značenja, ili
e) hidrogeniranje spoja formule I, u kojoj (F) predstavlja fenol, u spoj formule 1 u kojoj[image] predstavlja cikloheksil, i po želji,
pretvorbu racemične smjese u njene enantiomerne komponente, čime se dobiju optički čisti spojevi, i/ili,
pretvorbu dobivenih spojeva u farmaceutski prihvatljive kiselinske adicijsku soli.
U skladu s inačicom a) postupka reduktivno aminiranje keto spoja formule II s aminom formule III provodi se miješanjem sa sredstvom za dehidrataciju u prisutnosti molekulskih sita (4A) , u inertnom otapalu kao što je toluen ili tetrahidrofuran (THF), pri temperaturi refluksa. Alternativna metoda je dehidratacija u prisutnosti kiselog katalizatora s odstranjivanjem vode, npr. azeotropnim odstranjivanjem vode, ili s tetraizopropil-ortotitanatom u THF-u.
Dobiveni intermedijarni enamin ili imin se zatim reducira s redukcijskim sredstvom, kao što su metalni hidridi ili vodik u prisutnosti katalizatora hidrogeniranja, prednosno s natrijevim cijanobrohidridom u protonskom otapalu, na primjer u mješavini THF-a i etanola u kiselom području pH.
Primjeri odgovarajućih keto spojeva formule II jesu slijedeći:
2-indanon, 1,3-dihidro-4-metil-2H-inden-2-on, 4-(1-metiletil)-cikloheksanon, cis-oktahidro-inden-2-on, ciklooktanon, ciklodekanon, dekahidro-azulen-2-on, ciklononanon, cikloundekanon, cikloheptanon, ciklododekanon, biciklo[6.2.0]dec-9-on ili 1,3-dihidro-2H-inden-2-on.
Kondenzacija imina formule IV s ketenom formule V u sladu s inačicom b) provodi se u prisutnosti baze kao što je trietilamin. Reakcija se provodi pri 0°C i zatim se miješa pribl. 24 sata pri sobnoj temperaturi.
U skladu s inačicom c) postupka, 4-fenil- ili 4-cikloheksil-4-piperidinokarbonitril formule VI kondenzira se s metilbromacetatom u prisutnosti metala kao cinka. Reakcija se provodi u internom otapalu, na primjer THF-u. Smjesu se grije otprilike 1 1/2 sata, faze se odvoje i izolira se dobiveni spoj formule 1-2.
Redukcija spoja formule 1-1 u azetidin formule 1-3 u skladu s inačicom d) postupka provodi se s redukcijskim sredstvom, ponajprije s metalnim hidridom kao što je litij-aluminijev hidrid metodama koje su poznate u struci. Mješavinu aluminijevog triklorida i metalnog hidrida pomiješa se sa spojem formule 1-1 u THF-u, čime se dobije spoj formule 1-3.
Inačica e) postupka odnosi se na hidrogeniranje spoja formule 1 u kojoj [image] predstavlja fenil. Željeni cikloheksilni prsten se dobije u protonskom otapalu, kao metanolu i u prisutnosti katalizatora hidrogeniranja, na primjer u prisutnosti oksida platine. Reakcija se provodi pod tlakom vodika između 1 i 50 bara.
Racemične smjese mogu se pretvoriti u svoje enantiomerne komponente na uobičajen način, na primjer preparativnom HPLC.
Tvorba soli vrši se pri sobnoj temperaturi po metodama koje su kao takove poznate svakom stručnjaku. U obzir dolaze kako soli s anorganskim, tako također i soli s organskim kiselinama. Primjeri takovih soli jesu hidrokloridi, hidrobromidi, sulfati, nitrati, citrati, acetati, maleati, sukcinati, metansulfonati, p-toluen-sulfonati i slično.
Spojevi formula II, III, IV, V i VI, koji se upotrebljavaju kao polazni materijali, su poznati spojevi ili se mogu proizvesti poznatim metodama.
Slijedeća shema 1 opisuje ciklizaciju (kondenzaciju) spojeva formula IV i V ili II i III-l u spoj formule 1-1. U shemi 2 prikazana je ciklizacija (kondenzacija) spojeva formule VI s metilbromacetatom u spojeve formule 1-2.
Shema 1
[image]
u kojoj R1, R3, R4 i[image] imaju gore navedena značenja, i X je halogen.
Shema 2
[image]
Kako je ranije spomenuto, spojevi formule 1 i njihove farmaceutski prihvatljive kiselinske adicijske soli imaju dragocjena farmakodinamička svojstva. Nađeno je da su spojevi predloženog izuma agonisti i/ili antagonisti OFQ receptora i pokazuju učinke u životinjskim modelima psihijatrijskih, neuroloških i fizioloških poremećaja, kao što je anksioznost, stresni poremećaji, depresija, trauma, gubitak pamćenja zbog Alzheimerove bolesti ili drugih demencija, epilepsije i konvulzija, akutna i/ili kronična stanja bola, simptomi odvikavanja ovisnosti o drogama, kontrola ravnoteže vode, izlučivanje Na\ poremećaji arterijskog krvnog tlaka i metabolički poremećaji kao debljina.
Farmakološko djelovanje spojeva ispitano je dolje metodama opisanim u nastavku.
Metode ispitivanja vezanja OFQ-R
Stanična kultura
Stanice HEK-293, prilagođene za rast u suspenziji (293s), uzgajane su u HL mediju plus 28% FBS-a. Stanice su transfektirane sa OFQ receptorskom cDNA štakora (LC132), FEBS Lett., 347, 284-288, 1994, kloniranom u vektor ekspresije pCEP4 (Invitrogen, San Diego, CA, USA) upotrebom lipofektina (Life Technologeis, Bethesda, MD, USA). Transfektirane stanice su selektirane u prisutnosti higromicina (1000 U/ml) (Calbiochem, San Diego, CA, USA). Skupljene rezistentne stanice su ispitane s obzirom na ekspresiju OFQ-R vezanjem [3H]-OFO (Amersham PLC, Buckinghamshire, Engleska). Te stanice (293s-OFQ-R) su ekspandirane u kulturi velikog raspona i pripravku membrana. Priprava membrana
Stanice 293s-OFQ-R skupljene su centrifugiranjem, isprane 3 puta s fosfatno puferiranom otopinom soli (PBS) prije ponovne suspenzije u puferu A (50 mM tris-HCl, pH 7,8, 5 mM MgCl2, 1 mM EGTA) i raskinute s homogenizatorom za tkivo (30 sekundi, namješteno 4, Pt 20, Kinematica, Kriens, Luzern, Švicarska). Ukupna membranska frakcija dobivena je centrifugiranjem pri 49.000 x g i pri 4°C. Taj je postupak ponovljen dva puta i talog je ponovno suspendiran u puferu A. Alikvoti su odloženi pri -70°C i koncentracije proteina su određene upotrebom pokusnog proteinskog reagenta BCATM. Protein Assay Reagenta (Pierce, Rockford, IL), prema uputama proizvođača. Ispitivanja vezanja
Proučavanja kompeticije [3H]-OFQ provedena su sa 77 μg membranskog proteina u krajnjem ispitnom volumenu od 0,5 ml pufera plus 0,1% BSA i 0,01% bacitracina (Boehringer, Mannheim, Njemačka) tijekom 1 sata pri sobnoj temperaturi. Za određivanje nespecifičnog vezanja upotrijebljeno je 50 nM neobilježenog OFQ. Ispitivanja su prekinuta filtracijom kroz Whatman GF/C filtre (Unifilter-96, Canberra Packard S.A., Zürich, Švicarska), koji su prethodno obrađeni s 0,3%-tnim polietileniminom (Sigma, St. Lous, MO, USA) i 0,1 %-tnim BSA (Sigma) tijekom 1 sata. Filtri su isprani 6 puta s 1 ml ledeno hladne 50 mM tris-HCl, pH 7,5. Zadržana radioaktivnost zbrojena je na Packardovoj Top-Count mikroploči scintilacijskog brojača nakon dodatka 40 μl Microscinta 40 (Canberra Packard). Učinci spojeva određeni su upotrebom najmanje 6 koncentracija u triplikatu, i određivanje je provedeno dva puta. 1050 vrijednosti određene su izradom krivulja i te su vrijednosti preračunate u Ki vrijednosti metodom Chenga i Prusoffa, Bichem. Pharmacol., 22, 3099, 1973.
Afinitet prema OFQ--receptoru, izražen kao ppq, je u rasponu od 6,5 do 9,3.
Pripravljanje slijedećih spojeva opisano je u primjerima 1-54:
[image]
[image]
[image]
[image]
[image]
[image]
Spojevi formule I, kao i njihove farmaceutski upotrebljive kiselinske adicijske soli, mogu se upotrijebiti kao lijekovi, npr. u obliku farmaceutskih pripravaka. Farmaceutski pripravci mogu se dati oralno, npr. u obliku tableta, prevučenih tableta, dražeja, kapsula od tvrde i meke želatine, otopina, emulzija ili suspenzija. Međutim, davanje se može izvršiti i rektalno, npr. u obliku čepića, ili parenteralno, npr. u obliku injekcijskih otopina.
Spojevi formule 1 i farmaceutski upotrebljive kiselinske adicijske soli mogu se preraditi s farmaceutski inertnim, anorganskim ili organskim pomoćnim tvarima za proizvodnju tableta, prevučenih tableta, dražeja i kapsula od tvrde želatine. Kao takove pomoćne tvari, npr. za tablete, dražeje i kapsule od tvrde želatine, mogu se upotrijebiti laktoza, kukuruzni škrob ili njihovi derivati, talk, stearinska kiselina ili njene soli itd.
Prikladne pomoćne tvari za kapsule od meke želatine jesu, na primjer, biljna ulja, voskovi, masti, polukruti i tekući polioli itd.
Prikladne pomoćne tvari za proizvodnju otopina i t sirupa jesu, na primjer, voda, polioli, saharoza, invertni šećer, glukoza itd.
Prikladne pomoćne tvari za injekcijske otopine jesu, na primjer, voda, alkoholi, polioli, glicerol, biljna ulja itd. Prikladne pomoćne tvari za čepiće jesu, na primjer, prirodna ili otvrdnuta ulja, voskovi, masti, polu-tekući ili tekući polioli itd.
Osim toga farmaceutski pripravci mogu sadržavati konzervanse, sredstva za pospješivanje otapanja, stabilizatore, sredstva za kvašenje, emulgatore, zaslađivače, bojila, začine, soli za podešavanje osmotskog tlaka, pufere, sredstva za maskiranje ili antioksidante. Oni također mogu sadržavati i druge terapeutski korisne tvari.
Doziranje se može mijenjati u širokim granicama i usklađuje se, naravno, prema individualnim potrebama u svakom pojedinom slučaju. Općenito, učinkovito doziranje za oralno ili parenteralno davanje je 0,01-20 mg/kg/dnevno, ponajprije kao doziranje od 0,1-10 mg/kg/dnevno za sve opisane indikacije- Dnevna doza za odraslu osobu težine 70 kg je stoga između 0,7 i 1400 mg/dnevno, ponajprije 7-700 mg/dnevno, iako se gornju granicu može prekoračiti ako je potrebno.
Slijedeći primjeri prikazuju izum bez njegovog ograničenja. Sve su temperature navedene u stupnjevima Celzija.
Primjer 1
7-indan-2-il-1-fenil-1,7-diaza-spiro[3.5]nonan-2-onhidroklorid (1:1)
2-indanon (2,3 mmola) otopi se u toluenu i doda se 1-fenil-1,7-diaza-spiro[3.5]nonan-2-on (2,3 mmola) i molekulska sita (4A, 2,5 g) . Smjesu se refluktira 16 sati uz miješanje, profiltrira i filtrat se ispari. Ostatak se otopi u THF/etanolu (25 ml, 9:1), doda se natrijev cijano-borhidrid (2,3 mmola) i pH se namjesti na 4. Smjesu se miješa 3 sata pri sobnoj temperaturi. Doda se led-vodu (30 ml) i otopinu kalijevog karbonata (50%, 30 ml). Mješavinu se ekstrahira dva puta s metilen kloridom, organsku fazu se skupi, osuši s MgS04 i zgusne. Kromatografijom na silika gelu (etil acetat/n-heksan, 1:1) dobije se željeni proizvod koji kristalizira kao njegova HCl sol iz etanol/etila acetata. Dobiveno je 0,47 g (55%) 7-indan-2-il-1-fenil-1,7-diaza-spiro[3.5]nonan-2-on hidroklorida (1:1) kao bezbojne krute tvari, talište >250°C i MS: m/e = 332,5 (M+).
Primjer 2
(RS)-7-(4-metil-indan-2-il)-1-fenil-1,7-diaza-spiro[3.5]-nonan-2-on hidroklorid (1:1)
Naslovni spoj, talište >250°C i MS: m/e = 347,4 (M+H+), proizveden je u skladu s općom metodom opisanom u primjeru 1 iz 1,3-dihidro-4-metil-2H-inden-2-ona i l-fenil-1,7-diaza-spiro[3.5]nonan-2-ona.
Primjer 3
cis-7-(4-izopropil-cikloheksil)-1-fenil-1,7-diaza-spiro-[3.5]-nonan-2-on hidroklorid (1:1)
Naslovni spoj, talište >250°C i MS: m/e = 341,3 (M+H+) , proizveden je u skladu s općom metodom opisanom u primjeru 1 iz 4-(1-metiletil) -cikloheksanona i 1-fenil-1,7-diaza-spiro[3.5]nonan-4-ona.
Primjer 4
(RS)-7-(4-metil-indan-2-il)-1-fenil-1,7-diaza-spiro[3.5]-nonan hidroklorid (1:1)
Mješavinu aluminijevog triklorida (3 mmola) i litij-aluminijevog hidrida (3 mmola) u dietil eteru (5 ml) grije se 1 sat. Zatim se otopinu doda k mješavini (RS)-7-(4-metil-indan-2-il)-1-fenil-1,7-diaza-spiro[3.5]nonan-2-ona (1 mmol) u THF-u (20 ml). Grije se 4 sata. Doda se vodu (50 ml) i metilen klorid (100 ml) , faze se odvoje i osuše s Na2SO4 i zgusnu, Čime se dobije željeni proizvod koji iz etanol/etil acetata kristalizira kao njegova HCl sol. Dobiveno je 80 mg (20%) (RS)-7-(4-metil-indan-2-il)-1-fenil-1,7-diaza-spiro[3.5]nonan hidroklorida (1:1) kao bezbojne krute tvari, talište >219°C (rasp.) i MS: m/e = 333,3 (M+H+') .
Primjer 5
cis-7-(4-izopropil-cikloheksil)-1-fenil-1,7-diaza-spiro-[3.5]nonan hidroklorid (1:1)
Naslovni spoj, talište >207°C i MS: m/e == 327,4 (M+H+) , proizveden je u skladu s općom metodom opisanom u primjeru 4 iz cis-7-(4-izopropil-cikloheksil)-1-fenil-1,7-diaza-spiro[3.5]nonkan-2-ona.
Primjer 6
trans-7-(4-izopropil-cikloheksil)-1-fenil-1,7-diaza-spiro[3 . 5]nonan hidroklorid (1:1)
Naslovni spoj, talište >229°C i MS: m/e = 327,4 (M+H+), proizveden je u skladu s općom metodom opisanom u primjeru 4 iz trans-7-(4-izopropil-cikloheksil)-1-fenil-1,7-diaza-spiro[3 .5]nonan-2-ona.
Primjer 7
trans-7-(4-izopropil-cikloheksil)-1-fenil-1,7-diaza-spiro-[3.5]nonan-2-on hidroklorid (1:1)
Naslovni spoj, talište >250°C i MS: m/e = 341,3 (M+H+), proizveden je u skladu s općom metodom opisanom u primjeru 1 iz 4-(1-metiletil)-cikloheksanona i 1-fenil-1,7-diaza-spiro[3.5]nonan-2-ona.
Primjer 8
(RS)-7-acenaften-1-il-1-fenil-1,7-diaza-spiro[3 - 5]nonan-2-on hidroklorid (1:1)
Naslovni spoj, bijela kruta tvar, talište 245°C (rasp.) i MS: m/e == 369,3 (M+H+), proizveden je u skladu s općom metodom opisanom u primjeru aa iz (RS)-4-fenilamino-1- (acenaften-1-il)-1-piperidin-4-karbonitrila.
Primjer 9
(RS)-7-acenaften-1-il-1-fenil-l,7~diaza~spiro[3 . 5]nonan hidroklorid (1:1)
Naslovni spoj, bijela kruta tvar, talište 184°C (rasp.) i MS: m/e = 355,3 (M+H+), proizveden je u skladu s općom metodom opisanom u primjeru 4 iz (RS)-7-acenaften-1-il-1-fenil-1,7-diaza-spiro[3.5]nonan-2-ona.
Primjer 10
7-biciklo[3.3.1]non-9-il-1-fenil-1,7-diaza-spiro[3.5]nonan-2-on hidroklorid (1:1)
Naslovni spoj, bijela kruta tvar, talište 292°C i MS: m/e = 339,3 (M+H+), proizveden je u skladu s općom metodom opisanom u primjeru aa iz 1-biciklo[3.3. l]non-9-il-1-fenil-aminopiperidin-4-karbonitrila.
Primjer 11
7-biciklo[3.3.1]non-9-il-1-fenil-1,7-diaza-spiro[3.5]nonan hidroklorid (1:1)
Naslovni spoj, bijela kruta tvar, talište 178°C i MS: m/e = 325,4 (M+H+), proizveden je u skladu s općom metodom opisanom u primjeru 4 iz 7-biciklo[3.3.1]non-9-il-1-fenil-1,7-diaza-spiro[3.5]nonan-2--ona.
Primjer 12
(RS)-7-(oktahidro-inden-2-il)-1-fenil-1,7-diaza~spiro[3.5]-nonan-2-on hidroklorid (1:1)
Naslovni spoj, talište 312°C (rasp.) i MS: m/e == 339,3 (M+H+), proizveden je u skladu s općom metodom opisanom u primjeru 1 iz cis-oktahidro-inden-2-ona i l-fenil-1,7-diaza-spiro[3.5]nonan-2-ona.
Primjer 13
(RS)-7-(oktahidro-inden-2~il)-1-fenil-1,7-diaza-spiro[3 . 5]-nonan hidroklorid (1:1)
Naslovni spoj, bijela kruta tvar, talište 184°C (rasp.) i MS: m/e = 325,4 (M+H+), proizveden je u skladu s općom metodom opisanom u primjeru 4 iz (RS)-7-(oktahidro-inden-2-il)-1-fenil-1,7-diaza-spiro[3.5]nonan-2-ona.
Primjer 14
7-ciklooktil-1-fenil-1,7-diaza-spiro[3.5]nonan-2-on hidroklorid (1:1)
Naslovni spoj, talište 294°C (rasp.) i MS: m/e = 327,3 (M+H+), proizveden je u skladu s općom metodom opisanom u
primjeru 1 iz ciklooktanona i 1-fenil-1,7-diaza-spiro[3.5]-nonan-2-ona.
Primjer 15
7-ciklooktil-1-fenil-1,7-diaza-spiro[3 .5]nonan hidroklorid (1:1)
Naslovni spoj, bijela kruta tvar, talište 186°C (rasp.) i MS: m/e = 313,3 (M+H+), proizveden je u skladu s općom metodom opisanom u primjeru 4 iz 7-ciklooktil-1-fenil-1,7-diaza-spiro[3.5]nonan-2-ona.
Primjer 16
(RS)-7-(2,3-dihidro-1H-fenalen-1-il)-1-fenil-1,7-diaza-spiro[3.5]nonan-2-on hidroklorid (1:1)
Naslovni spoj, blijedo smeđa kruta tvar, talište 203°C (rasp.) i MS: m/e = 383,2 (M+H+), proizveden je u skladu s općom metodom opisanom u primjeru aa iz (RS)-7-(2,3-dihidro-1H-fenalen-1-il)-piperidin-4-karbonitrila.
Primjer 17
7-ciklodecil-1-fenil-1,7-diaza-spiro[3.5]nonan~2-on hidroklorid (1:1)
Naslovni spoj, talište 260°C (rasp.) i MS: m/e = 355,4 (M+H+) , proizveden je u skladu s općom metodom opisanom u primjeru 1 iz ciklodekanona i 1-fenil-1,7-diaza-spiro[3.5]-nonan-2-ona.
Primjer 18
(IRS,3aRS)-7-(2,3,3a,4,5,6-heksahidro-lH-fenalen-1-il)-1-fenil-1,7-diaza-spiro[3. 5]nonan-2-on hidroklorid (1:1)
Naslovni spoj, bijela kruta tvar, talište 232°C (rasp.) i MS: m/e = 387,3 (M+H+), proizveden je u skladu s općom metodom opisanom u primjeru aa iz (IRS,3aRS)-7-(2,3,3a,4,5,6-heksahidro-1H-fenalen-1-il)-piperidin-4-karbonitrila.
Primjer 19
(IRS,3aSR)-7-(2,3,3a,4,5,6-heksahidro-1H-fenalen-1-il)-1-fenil-1,7-diaza-spiro[3.5Jnonan-2-on hidroklorid (1:1)
Naslovni spoj, bijela kruta tvar, talište 162°C (rasp.) i MS: m/e = 387,3 (M+H+), proizveden je u skladu s općom metodom opisanom u primjeru aa iz (IRS,3aSR)-7-(2,3,3a,4,5,6~heksahidro~lH-fenalen-1-il)-piperidin-4-karbonitrila.
Primjer 20
7-(dekahidro-azulen-2-il)-1-fenil-1,7-diaza-spiro[3.5]nonan-2-on hidroklorid (1:1) (smjesa diastereoizomera)
Naslovni spoj, bijela kruta tvar, talište 334°C (rasp.) i MS: m/e == 353,4 (M-H^) , proizveden je u skladu s općom metodom opisanom u primjeru 1 iz dekahidro-azulen-2-ona i 1-fenil-1,7-diaza~spiro[3 . 5]nonan-2-ona.
Primjer 21
7-ciklononil-1-fenil-1,7-diaza-spiro[3.5]nonan-2-on hidroklorid (1:1)
Naslovni spoj, bijela kruta tvar, talište 249°C (rasp.) i MS: m/e == 341,3 (M+H+), proizveden je u skladu s općom metodom opisanom u primjeru 1 iz cikloheksanona i 1-fenil-1,7-diaza-spiro[3.5]nonan-2-ona.
Primjer 22
7-(dekahidro-azulen-2-il)-1-fenil-1,7-diaza-spiro[3.5]nonan hidroklorid (1:1) (smjesa diastereoizomera)
Naslovni spoj, bijela kruta tvar, talište 212°C (rasp.) i MS: m/e = 369,3 (M+H+), proizveden je u skladu s općom metodom opisanom u primjeru 4 iz 7-(dekahidro-azulen-2-il)-1-fenil-1,7-diaza-spiro[3.5]nonan-2-ona (smjese diastereoizomera).
Primjer 23
7-ciklononil-1-fenil-1,7-diaza-spiro[3.5]nonanon fumarat (1:2,25)
Naslovni spoj dobiven je redukcijom 7-ciklononil-1-fenil-1,7-diaza-spiro[3.5]nonan-2-ona u skladu s općom metodom opisanom u primjeru 4 i obradom baze s fumarnom kiselinom u dietil eteru. Bijela kruta tvar, talište 138°C (rasp.) i MS: m/e = 327,4 (M+H+).
Primjer 24
7-ciklodecil-1-fenil-1,7-diaza-spiro[3.5]nonanonfumarat (1:3,1)
Naslovni spoj dobiven je redukcijom 7-ciklodecil-1-fenil-1,7-diaza-spiro[3.5]nonan-2-ona u skladu s općom metodom opisanom u primjeru 4 i obradom baze s fumarnom kiselinom u dietil eteru. Bijela kruta tvar, talište 141°C (rasp.) i MS: m./e = 341,3 (M+H+).
Primjer 25
7-cikloudecil-1-fenil-1,7-diaza~spiro[3.5]nonan-2-on hidroklorid (1:1)
Naslovni spoj, bijela kruta tvar, talište 279°C (rasp.) i MS: m/e = 369,4 (M+H+) proizveden je u skladu s općom metodom opisanom u primjeru 1 iz cikloundekanona i 1-fenil-1,7-diaza-spiro[3.5]nonan-2-ona.
Primjer 26
7-cikloundecil-1-fenil-1,7-diaza-spiro[3.5]nonanonfumarat (1:0,78)
Naslovni spoj dobiven je redukcijom 7-cikloundecil-1-fenil-1, 7-diaza-spiro[3.5]-nonan-2-ona u skladu s općom metodom opisanom u primjeru 4 i obradom baze s fumarnom kiselinom u dietil eteru. Bijela kruta tvar, talište 174°C (rasp.) i MS: m/e = 355,4 (M+H+).
Primjer 27
(IRS,3aSR)~7-(2,3,3a,4,5,6-heksahidro-lH-fenalen-1-il)-1-fenil-1,7-diaza-spiro[3 . 5]nonan fumarat (1:1)
Naslovni spoj dobiven je redukcijom (IRS,3aSR)-7-(2,3,3a,4,5,6-heksahidro-1H-fenalen-1-il)-1-fenil-1,7-diaza-spiro[3.5]nonan-2-ona u skladu s općom metodom opisanom u primjeru 4 i obradom baze s fumarnom kiselinom u dietil eteru. Bijela kruta tvar, talište 136°C i MS: m/e = 373,4 (M+H).
Primjer 28
(IRS,3aRS)-7-(2,3,3a,4,5,6-heksahidro-lH-fenalen-1-il)-1-fenil-1,7-diaza-spiro[3.5]nonan fumarat (1:1)
Naslovni spoj dobiven je redukcijom (IRS,3aRS)-7-(2,3,3a,4,5,6-heksahidro~lH-fenalen-1-il)-1-fenil-1,7-diaza-spiro[3.5]nonan-2-ona u skladu s općom metodom opisanom u primjeru 4 i obradom baze s fumarnom kiselinom u dietil eteru. Bijela kruta tvar, talište 175°C i MS: m/e = 373,4 (M+H+).
Primjer 29
7-cikloheptil-1-fenil-1,7-diaza-spiro[3.5]nonan-2-onhidroklorid (1:1)
Naslovni spoj, bijela kruta tvar, talište 289°C (rasp.) i MS: m/e = 313,2 (M+H+), proizveden je u skladu s općom metodom opisanom u primjeru 1 iz cikloheptanona i 1-fenil-1,7-diaza-spiro[3.5]nonan-2-ona.
Primjer 30
7-cikloheptil-1-fenil-1,7-diaza-spiro[3.5Jnonanonfumarat (1:1)
Naslovni spoj dobiven je redukcijom 7-cikloheptil-1-fenil-1,7-diaza-spiro[3.5]nonan~2~ona u skladu s općom metodom opisanom u primjeru 4 i obradom baze s fumarnom kiselinom u dietil eteru. Bijela kruta tvar, talište 190°C (rasp.) i MS: m/e == 299,4 (M+H+).
Primjer 31
7-ciklododecil-1-fenil-1,7-diaza-spiro[3.5]nonan-2-on hidroklorid (1:1)
Naslovni spoj, bijela kruta tvar, talište 279°C (rasp.) i MS: m/e = 383,3 (M+H+) , proizveden je u skladu s općom metodom opisanom u primjeru 1 iz ciklododekanona i 1-fenil-1,7-diaza~spiro[3.5]nonan-2-ona.
Primjer 32
(RS)-7-acenaftalen-1-il-1-p-tolil-1,7-diaza-spiro[3.5]nonan-2-on fumarat (1:1)
Naslovni spoj dobiven je reakcijom (RS)-4-(p-tolil-amino)-1-(acenaften-1-il)-piperidin-4-karbonitrila u skladu s općom metodom opisanom u primjeru aa i obradom baze s fumarnom kiselinom u dietil eteru. Bijela kruta tvar, talište 209°C i MS: m/e = 383,3 (M+H+).
Primjer 33
7-ciklododecil-1-fenil-1,7-diaza-spiro[3.5]nonanonfumarat (1:1)
Naslovni spoj dobiven je redukcijom 7-ciklododecil-1-fenil-1,7-diaza-spiro[3.5]nonan-2-ona u skladu s općom metodom opisanom u primjeru 4 i obradom baze s fumarnom kiselinom u dietil eteru. Bijela kruta tvar, talište 179°C i MS: m/e = 369,4 (M+H4").
Primjer 34
(IRS,8RS,9SR)-7-biciklo[6.2.0]dec-9-il-1-fenil-1,7-diaza-spiro[3.5]nonan-2-on fumarat (1:1,5)
Naslovni spoj dobiven je reakcijom (1RS,8RS)-biciklo[6.2.0]dec-9-ona i 1-fenil-1,7-diaza-spiro[3.5]nonan-2-ona u skladu s općom metodom opisanom u primjeru 1 i obradom baze s fumarnom kiselinom u dietil eteru. Bijela kruta tvar, talište 203°C i MS: m/e = 353,4 (M+H+).
Primjer 35
(1RS.8RS,9RS)-7-biciklo[6.2.0]dec-9-il-1-fenil-1,7-diaza-spiro[3.5]nonan-2-on fumarat (1:1,3)
Naslovni spoj dobiven je reakcijom (IRS,8RS)-biciklo-[6.2. 0]dec-9-ona i 1-fenil-1,7-diaza-spiro[3.5]nonan-2-ona u skladu s općom metodom opisanom u primjeru 1 i obradom baze s fumarnom kiselinom u dietil eteru. Blijedo smeda kruta tvar, talište 158°C i MS: m/e = 353,4 (M+H+).
Primjer 36
(IRS,8RS,9RS)-7-biciklo[6.2.0]dec-9-il-1-fenil-1,7-diaza-spiro[3.5]nonan--2~on fumarat (1:1)
Naslovni spoj dobiven je redukcijom (IRS,8RS,9RS)-7-biciklo[6.2.0]dec-9-il-1-fenil-1,7-diaza-spiro[3.5]nonan-2-ona u skladu s općom metodom opisanom u primjeru 4 i obradom baze s fumarnom kiselinom u dietil eteru. Bijela kruta tvar, talište 144°C i MS: m/e = 339,4 (M+H+).
Primjer 37
(IRS)-2-[7-(cis-izopropil-cikloheksil)-2-okso-1-fenil-1,7-diaza-spiro[3.5]non-3-il]izoindol-1,3-dion fumarat (1:1)
cis-[l-(4-izopropil-cikloheksil)-piperidin-4-iliden]-fenil-amin (1,00 g, 3,35 mmola) i trietilamin (678 mg, 6,70 mmolova) otopi se u 50 ml dietil etera i doda se 1,3-dihidro-1,3-diokso-2H-izoindol-2-acetil klorid (1,5 g, 6,7 mmola) u 10 ml tetrahidrofurana pri 0°C. Reakcijsku smjesu se miješa 24 sata pri sobnoj temperaturi. Trietilamonijev klorid se odfiltrira, filtrat se ispere s vodom, osuši s MgSO4 i zgusne. Kromatografijom na silika gelu (heksan/etil acetat/trietilamin 40:10:1) dobiveno je 551 mg (34%) željenog proizvoda koji je iz etera istaložen kao njegova fumaratna sol, talište 208°C i MS: m/e = 486,3 (M+H+).
Primjer 38
(3RS)-7-(cis-4-izopropil-cikloheksil)-3-metoksi-1-fenil-1,7-diaza-spiro[3.5]nonan-2-on fumarat (1:1)
Naslovni spoj, talište 148°C i MS: m/e = 371,3 (M+H+) , proizveden je u skladu s općom metodom opisanom u primjeru 37 iz cis-[l-(4-izopropil-cikloheksil)-piperidin-4-iliden]-fenil-amina i metoksi acetil klorida.
Primjer 39
(3RS)-3-benziloksi-7-(cis-4-izopropil-cikloheksil)-1-fenil-1,7-diaza-spiro[3.5]nonan-2-on fumarat (1:1)
Naslovni spoj, talište 138°C i MS: m/e = 447,3 (M+H+) , proizveden je u skladu s općom metodom opisanom u primjeru 37 iz cis-[1-(4-izopropil-cikloheksil)-piperidin-4-iliden]-fenil-amina i benziloksi acetil klorida.
Primjer 40
(3RS)-3,3-bis-hidroksimetil-7-(4-metil-indan-2-il)-1-fenil-1,7-diaza-spiro[3.5]nonan-2-on hidroklorid (1:1)
Naslovni spoj, talište >250°C i MS: m/e = 407,4 (M+H+), proizveden je u skladu s općom metodom opisanom u primjeru 1 iz 1,3-dihidro-4-metil-2H-indena-2-ona i 3,3-bis-hidroksimetil-1-fenil-1,7-diaza-spiro[3.5]nonan-2-ona.
Primjer 41
3,3-bis-hidroksimetil-7-indan-2-il-1-fenil-1,7-diaza-spiro[3.5]nonan-2-on hidroklorid (1:1)
Naslovni spoj, talište >250°C i MS: m/e = 393,3 (M+H+), proizveden je u skladu s općom metodom opisanom u primjeru 1 iz 1,3~dihidro-2H-indena-2-ona i 3,3-bis-hidroksimetil-1-fenil-1,7-diaza-spiro[3.5]nonan-2-ona.
Primjer 42
(2RS,4aSR,8aRS)-1-(dekahidro-naftalen-2-il)-1-il)-1-fenil-1,7-diaza-spiro[3.5]nonan-2-on hidroklorid (1:1)
Naslovni spoj, talište >250°C i MS: m/e = 353,3 (M+H4), proizveden je u skladu s općom metodom opisanom u primjeru aa 1 iz (2RS,4aSR,8aRS)-1-(dekahidro-naftalen-2-il)-4-fenilamino-piperidin-4-karbonitrila, koji je proizveden iz (2RS,4aSR,8aRS)-dekahidro-naftalen-2-ilamina u skladu s općim metodama opisanim u primjerima ac i ad.
Primjer 43
(2RS,4aSR,8aRS)-7-(dekahidro-naftalen-2-il)-1-il)-1-fenil-1,7-diaza-spiro[3.5]nonan hidroklorid (1:1)
Naslovni spoj, talište 195-196°C i MS: m/e = 339,4 (M+H+), proizveden je u skladu s općom metodom opisanom u primjeru 4 iz (2RS,4aSR,8aRS)-7-(dekahidro-naftalen-2-il)-1-il)-1-fenil-1,7-diaza-spiro[3.5]nonan-2-ona.
Primjer 44
(3-hidroksimetil)-7-indan-2-il-1-fenil-1,7-diaza-spiro[3.5]-non-3-il)-metanol hidroklorid (1:1)
3,3-bis-hidroksimetil-7-indan-2-il-1-fenil-1,7-diaza-spiro[3.5]nonan-2-on, dobiven u primjeru 41, (110 mg, 0,28 mmola) otopi se u dietil eteru (6 ml) i tetrahidrofuran (8 ml) doda se pri sobnoj temperaturi k mješavini litij-aluminijevog hidrida (55 mg) i aluminijevog triklorida (190 mg) u dietil eteru (20 ml) . Smjesu se kuha 1 sat uz miješanje, ohladi se i pogasi s vodom (7 ml). Ekstrakcijom s diklormetanom, sušenjem s Na2SO4 i isparavanjem otapala dobiveno je 55 mg (52%) naslovnog spoja koji iz etil acetata kristalizira kao njegova HCl sol, talište >140°C (rasp.), MS: m/e = 379,4 (M+H+).
Primjer 45
3,3-bis-hidroksimetil-7-(cis-4-izopropil-cikloheksil)-3-fenil-1,7-diaza-spiro[3.5]nonan-2-on hldroklorid (1:1)
Naslovni spoj, talište >245°C i MS: m/e = 401,5 (M+H+) , proizveden je u skladu s općom metodom opisanom u primjeru 1 iz 4-izopropil-cikloheksanona i 3,3-bis-hidroksimetil-1-fenil-1,7-diaza-spiro[3.5]nonan-2-ona i odvojen je od trans-stereoizomera kromatografijom na silika gelu s diklormetan/ metanolom 6%.
Primjer 46
(RS)-7-(2-okso-1,2-difenil-etil)-1-fenil-1,7-diaza-spiro-[3.5]nonan-2-on
Suspenziju 2-klor-1,2-difenil-etanona (0,23 g, 1 mmol), 1-fenil-l, 7-diaza-spiro[3.5]nonan-2-ona (0,2 g, 0,9 mmola) i natrijevog bikarbonata (0,23 g) u 2-butanonu kuha se 4 sata uz miješanje. Smjesu se ohladi, otapalo se odstrani u vakuumu i ostatak se očisti kromatografijom na silika gelu s etil acetat/heksanom (1:2), čime se dobije 0,33 g (87%) naslovnog spoja. MS: m/e = 411,3 (M+H+).
Primjer 47
Mješavina [3-hidroksimetil-7-(cis- i (trans-4-izopropil-cikloheksil)-1-fenil-l,7-diaza-spiro[3.5]non-3-il]-metanol
hidroklorid (1:1)
Naslovni spoj, talište >126°C (rasp.) i MS: m/e = 387,3 (M+H+) , proizveden je u skladu s općom metodom opisanom u primjeru 44 iz 3,3-bis-hidroksimetil-7-(cis-4-izopropil-cikloheksil)-1-fenil-1,7-diaza-spiro[3.5]nonan-2-ona.
Primjer 48
(RS)-[3-hidroksimetil-7-(4-metil-2-indan-2-il)-1-fenil-1,7-diaza-spiro[3.5]non-3-il]-metanol hidroklorid (1:1)
Naslovni spoj, talište >154°C (rasp.) i MS: m/e = 393,3 (M-t-H4') , proizveden je u skladu s općom metodom opisanom u primjeru 44 iz 3,3-bis-hidroksimetil-7-(4~metil-indan-2-il)-1-fenil-1,7-diaza-spiro[3 . 5]nonan-2-ona.
Primjer 49
Mješavina (RS)- i (SR) -3-hidroksimetil-7-[(RS)-4-metil-indan-2-il]-1-fenil-1,7-diaza-spiro[3.5]nonan-on hidroklorida (1:1)
Naslovni spoj, talište >250°C (rasp.) i MS: m/e = 377,3 (M+H+), proizveden je u skladu s općom metodom opisanom u primjeru 1 iz 4-metil-indan-2-ona i 3-hidroksi-metil-1-fenil-1,7-diaza-spiro[3.5]nonan-2-ona.
Primjer 50
(SR)-3-hidroksimetil-7-(trans-4-izopropil-cikloheksil) 1-fenil-1,7-diaza-spiro[3.5]nonan-on hidroklorid (1:1)
Naslovni spoj, talište >218-222°C i MS: m/e = 371,3 (M+H+), proizveden je u skladu s općom metodom opisanom u primjeru 1 iz 4-izopropil-cikloheksanona i 3-hidroksimetil-1-fenil-1,7-diaza-spiro[3.5]nonan-ona i odvojen od cis-steroizomera kromatografijom na silika gelu s diklormetan/ metanolom 2%.
Primjer 51
(RS)-7-acenaften-1-il-1-(3-fluor-fenil-1,7-diaza-spiro[3.5]-nonan-2-on fumarat (1:1)
Naslovni spoj, bijela kruta tvar, talište 230°C i MS: m/e = 387,3 (M+H+), dobiven je reakcijom (RS)-4-(3-fluor-fenilamino)-1-(acenaften-1-il)-piperidin-4-karbonitrila u skladu s općom metodom opisanom u primjeru 1 i obradom baze s fumarnom kiselinom u dietil eteru.
Primjer 52
(RS)-7-acenaften-1-il-1-(4-klor-fenil-1,7-diaza-spiro[3.5]-nonan-2-on fumarat (1:0,75)
Naslovni spoj, blijedo smeđa kruta tvar, talište 196°C i MS: m/e = 403,3 (M+H+) , dobiven je reakcijom (RS)-4-(4-klor-fenilamino)-1-(acenaften-1-il)-piperidin-4-karbonitrila u skladu s općom metodom opisanom u primjeru 1 i obradom baze s fumarnom kiselinom u dietil eteru.
Primjer 53
(RS)-7-acenaften-1-il-1- (3-klor--fenil-l, 7-diaza-spiro[3.5]-nonan-2-on fumarat (1:1)
Naslovni spoj, bijela kruta tvar, talište 214°C i MS: m/e == 403,4 (M+H+) , dobiven je reakcijom (RS)-4-(3-klor-fenilamino)-1-(acenaften-1-il)-piperidin-4-karbonitrila u skladu s općom metodom opisanom u primjeru 1 i obradom baze s fumarnom kiselinom u dietil eteru.
Primjer 54
(RS)-7-acenaften-1-il-1-(4-fluor-fenil-1,7-diaza-spiro[3.5]-nonan-2-on fumarat (1:1)
Naslovni spoj, bijela kruta tvar, talište 210°C i MS m/e = 387,2 (M+H+) , dobiven je reakcijom (RS)-4-(4-fluor-fenilamino)-1-(acenaften-1-il)-piperidin-4-karbonitrila u skladu s općom metodom opisanom u primjeru 1 i obradom baze s fumarnom kiselinom u dietil eteru.
SINTEZA INTERMEDIJATA
Primjer aa
7-benzil-1-fenil-1,7-diaza-spiro[3 . 5]nonan-2-on hidroklorid (1:1)
Metil bromacetat (136 mmolova) doda se kap po kap k suspenziji 4-(fenilamino)-1-(fenilmetil)-4-piperidinkarbo-nitrila (34 mmola) i cinka (170 mmolova), prethodno zagrijanoj do refluksa. Po završenom dodavanju smjesu se grije 1 1/2 sata. ohladi i doda se otopinu kalijevog karbonata (50%, 45 ml) . Dvofaznu mješavinu se profiltrira kroz Celite®, faze se odvoje i vodenu fazu se ekstrahira s THF-om. Organske faze se skupe, osuše s MgSO4 i zgusnu. Filtracijom kroz silika gel (metilen klorid/metanol 98:2) dobiven je željeni proizvod (9,1 g, 87%) koji iz etil acetat/etanola kristalizira kao njegova HCl sol. 7-benzil-1-fenil-l, 7-diaza-spiro[3.5]nonan--2-on hidroklorid (1:1) izoliran je kao bezbojna kruta tvar, talište >250°C i MS: m/e = 307,2 (M+H+).
Primjer ab
1-fenil-1,7-diaza-spiro[3 . 5]nonan-2-on hidroklorid (1:1)
7-benzil-1-fenil-1,7-diaza-spiro[3 . 5]nonan~2-on (17 mmolova) otopi se u metanolu (300 ml) . Doda se paladij na ugljenu (10%, 0,3 g) i smjesu se hidrogenira pri sobnoj temperaturi i pod normalnim tlakom. Filtracijom i isparavanjem dobiven je željeni proizvod koji iz etil acetat/etanola kristalizira kao njegova HCl sol. Dobiveno je 3,5 g (81%) 1-fenil-1,7-diaza-spiro[3.5]nonan-2-on hidroklorida (1:1) kao bezbojne krute tvari, talište >250°C i MS: m/e = 216 (M+).
Primjer ac
1-biciklo-[3.3.1]non-9-il-piperidin-4-on
1-biciklo-[3.3.1]non-9-ilamin (2,26 g, 16,2 mmolova) otopi se u etanolu (40 ml). Doda se kalijev karbonat (224 mg, 1,62 mmola) i l-etil-1-metil-4-okso-piperidinijev jodid (6 g, 22,4 mmola) otopljen u vodi (15 ml) i smjesu se refluktira 75 minuta. Doda se vodu (100 ml), etanol se odstrani u vakuumu i ostatak se ekstrahira s etil acetatom (2 x 100 ml). Sjedinjene organske faze se isperu sa zasićenom otopinom NaCl (100 ml) , osuše (MgSO4) i ispare. Kromatografijom na stupcu silika gela (toluen/etil acetat 4:1) dobiven je željeni proizvod (2,99 g, 83%) kao blijedo žuto ulje, i MS: m/e = 221 (M+).
Primjer ad
1-biciklo-[3.3.1]non-9-il-4-fenilamino-piperidin-4-karbonitril
1-biciklo-[3.3.1]non-9-il-piperidin-4-on (2,99 g, 13,5 mmolova) otopi se u octenoj kiselini (15 ml) . Doda se anilin (1,36 ml, 14,9 mmolova) i trimetilsililcijanid (1,44 ml, 13.5 mmolova) pri 0°C i smjesu se miješa 17 sati pri sobnoj temperaturi. Reakcijsku smjesu se prelije u hladnu otopinu amonijaka (voda/28% amonijak, 30 ml/50 ml) i ekstrahira se s diklormetanom (2 x 100 ml). Sjedinjene organske faze se isperu sa zasićenom otopinom NaCl (100 ml), osuše (MgSO4) i zgusnu. Kromatografijom na stupcu silika gela (toluen/etil acetat 4:1) dobiven je željeni proizvod (3,18 g, 73%) kao blijedo žuta kruta tvar, talište 168°C i MS: m/e = 324,4 (M+).
Primjer ae
cis-[1-(4-izopropil-cikloheksil) -piperidin-4-iliden]fenil-amin
cis-1-(4-izopropil-cikloheksil)-piperidin-4-on (5,0 g, 23,4 mmola), piridin (3,3 g, 35,3 mmola) i molekulska sita (20 g, 4A) u 100 ml pentana miješaju se 6 dana pri sobnoj temperaturi. Molekulska sita se odfiltriraju i otapalo se ispari. Sirov proizvod se upotrebljava za daljnje stupnjeve bez ikakvog daljnjeg čišćenja.
Primjer af
7~benzil-3,3-bis-hidroksimetil-1-fenil-l,7~diaza-spiro[3 . 5]-nonan-2-on hidroklorid (1:1)
Otopinu 7-benzil-1-fenil-1,7-diaza-spiro[3 . 5]nonan-2-ona (0,7 mmola) u THF~u (4 ml) doda se k litijevom diizopropilamidu (2 mmola) i N,N,N',N'-tetrametiletilen-diaminu (2 mmola) u THF-u (5 ml) pri -75°C. Smjesu se miješa 1 sat pri -78°C, kroz smjesu se 5 minuta propušta plinoviti formaldehid i nastavi se miješati još jedan sat. Reakcijsku smjesu se pogasi sa zasićenom otopinom natrijevog bikarbonata (30 ml) i ekstrahira s diklor-metanom. Organske faze se skupe, osuše s NasSC^ i zgusnu. Kromatografijom na silika gelu (diklormetan/metanol 50:1) dobiven je željeni proizvod koji kristalizira iz etanol/ etil acetata kao njegova HCl sol. Dobiveno je 65 mg (25%) 7-benzil-3,3-bis-hidroksimetil-1-fenil-1,7-diaza-spiro[3 . 5]-nonan-2-on hidroklorida (1:1) kao bezbojna kruta tvar, taliŠte >250°C i MS: m/e = 367,2 (1^+H) .
Primjer ag
(RS)-7-benzil-3-hidroksimetil-l~fenil-1,7-diaza-spiro[3.5]-nonan-2-on hidroklorid (1:1)
Nalovni spoj, talište >117°C i MS: m/e == 337,2 (M++R) proizveden je kao sporedni proizvod u primjeru af. Dobiveno je 60 mg (25%) (RS)-7-benzil-3-hidroksimetil-1-fenil-1,7-diaza-spiro[3.5]nonan-2-on hidroklorida (1:1) kao bezbojna kruta tvar, talište >117°C (rasp.) i MS: m/e = 337,2 (M++H).
Primjer ah
3,3-bis-hidroksimetil-1-fenil-1,7-diaza-spiro[3.5]nonan-2-on hidroklorid (1:1)
Naslovni spoj, talište >250°C i MS: m/e = 277,2 (M++H) proizveden je u skladu s općom metodom opisanom u primjeru ab iz 7-benzil-3,3-bis-hidroksimetil-1-fenil-1,7-diaza-spiro[3.5]nonan-2-ona.
Primjer ai
(RS)-3-hidroksimetil-1-fenil-1,7-dia2a~spiro[3 . 5]nonan-2-on
Nalovni spoj, žuto ulje, MS: m/e = 247,3 (M++H) proizveden je u skladu s općom metodom opisanom u primjeru ah iz (RS)-7-benzil-3-hidroksimetil-1-fenil-1,7-diaza-spiro[3.5]nonan-2-ona.
Primjer A
Tablete slijedećeg sastava proizvedene su na uobičajen način:
mg/tableti
aktivna tvar 5
laktoza 45
kukuruzni škrob 15
mikrokristalinična celuloza 34
magnezijev stearat 1
masa tablete 100
Primjer B
Proizvedene su kapsule slijedećeg sastava:
mg/kapsuli
aktivna 10
laktoza 155
kukuruzni škrob 30
talk 5
masa punjenja kapsule 200
Najprije se u mješalici pomiješaju aktivna tvar, laktoza i kukuruzni škrob i zatim se miješaju u mlinu. Smjesu se vrati u mješalicu, doda se talk i temeljito se promiješa. Sa smjesom se strojno pune kapsule od tvrde želatine.
Primjer C
Proizvedeni su čepići slijedećeg sastava:
mg/čepiću
aktivna tvar 15
masa za čepiće 1285
ukupno 1300
Masa za čepiće se rastali u staklenoj ili čeličnoj posudi, temeljito se promiješa i ohladi na 54°C. Zatim se k tome doda praškastu aktivnu tvar i miješa se do potpune disperzije. Smjesu se prelije u kalupe za čepiće prikladne veličine, pusti se ohladiti, zatim se Čepići izvade iz kalupa i pojedinačno pakiraju u voštani papir ili metalnu foliju.
Claims (9)
1. Spojevi opće formule
[image]
naznačeni time, da
R1 predstavlja (C6-10)-cikloalkil, po potrebi supstituiran s nižim alkilom ili C(O)O nižim alkilom, indan-1-il ili indan-2-il, po potrebi supstituiran s nižim alkilom; acenaften-1-il; biciklo[3.3.1]non-9-il, oktahidro-inden-2-il; 2,3-dihidro-1H-fenalen-1-il; 2,3,3a,4,5,6-heksahidro-1H--fenalen-1-il, dekahidro-azulen-2-il; biciklo-[6.2.0]dec-9-il; dekahidro-naftalen-1-il, dekahidro-naftalen-2-il; tetrahidro-naftalen-1-il, tetrahidro-naftalen-2-il ili 2-okso-l,2-difenil-etil;
R2 je =O ili vodik;
R3 je vodik, izoindolil-1,3-dion, niži alkoksi, niži alkil, amino, benziloksi, -CH2OR5 ili CH2N(R5)2;
R4 je vodik ili –CH2OR5;
R5 vodik ili niži alkil;
[image]
cikloheksil ili fenil, po potrebi supstituiran s nižim alkilom, halogenim ili alkoksi;
racemičke smjese i njihovi odgovarajući enantiomeri i njihove farmaceutski prihvatljive kiselinske adicijske soli .
2. Spoj prema zahtjevu 1, naznačen time, da R1 predstavlja (C6-9)-cikloalkil ili dekahidro-naftalen-2-il.
3. Spoj prema zahtjevu 2, naznačen time, da je to:
3,3-bis-hidroksimetil-7-(cis-4-izopropil-cikloheksil)-1-fenil-1,7-diaza-spiro[3.5]nonan-4-on;
7-(cis-4-izopropil-cikloheksil)-1-fenil-1,7-diaza-spiro[3.5]nonan-2-on;
7-(cis-4-izopropil-cikloheksil)-1-fenil-1,7-diaza-spiro[3.5]nonan;
7-ciklononil-1-fenil-1,7-diaza-spiro[3.5]nonan-2-on;
7-ciklononil-1-fenil-1,7-diaza-spiro[3.5]nonan;
7-ciklooktil-1-fenil-1,7-diaza-spiro[3.5]nonan-2-on;
7-cikloheptil-1-fenil-1,7-diaza-spiro[3.5]nonan-2-on i
(2RS,4aSR,8aRS)-7-(dekahidro-naftalen-2-il)-1-fenil-1,7-diaza-spiro[3.5]nonan-2-on.
4. Lijek, naznačen time, da sadrži jedan ili više spojeva prema bilo kojem zahtjevu od 1 do 3 i farmaceutski prihvatljiva pomoćna sredstva.
5. Lijek prema zahtjevu 4, naznačen time, da se upotrebljava za liječenje bolesti koje su povezane s orfanin FQ (OFQ) receptorom, koje uključuju psihijatrijske, neurološke i fiziološke poremećaje, kao anksioznost i stresne poremećaje, depresiju, traumu, gubitak pamćenja zbog Alzheimerove bolesti ili drugih demencija, epilepsiju i konvulzije, akutna i/ili kronična stanja bola, i simptome odvikavanja ovisnosti o drogama, kontrolu ravnoteže vode, izlučivanje Na+, poremećaje arterijskog krvnog tlaka i metaboličke poremećaje kao debljinu.
6. Postupak za proizvodnju spoja formule 1 kako je definiran u zahtjevu 1, naznačen time, da uključuje
a) reduktivno aminiranje spoja formule
[image]
sa spojem formule
[image]
pri čemu R1, R2, R3 i R4 i
[image]
imaju značenja navedena u zahtjevu 1, i po želji,
pretvorbu racemične smjese u njene enantiomerne komponente čime se dobiju optički čisti spojevi, i/ili, po želji,
pretvorbu dobivenih spojeva u farmaceutski prihvatljive kiselinske adicijsku soli.
7. Spoj prema bilo kojem od zahtjeva 1-3, naznačen time, da je proizveden u skladu s postupkom definiranim u zahtjevu 6 ili njemu ekvivalentnom metodom.
8. Upotreba spoja prema bilo kojem od zahtjeva 1-3, naznačena time, da se on koristi za liječenje bolesti povezanih s orfanin FQ (OFQ) receptorom, koje uključuju psihijatrijske, neurološke i fiziološke poremećaje, kao što su anksioznost i stresni poremećaji, depresija, trauma, gubitak pamćenja zbog Alzheimerove bolesti ili druge demencije, epilepsiju i konvulzije, akutna i/ili kronična stanja bola, i simptome odvikavanja ovisnosti o drogama, kontrolu ravnoteže vode, izlučivanje Na+, poremećaje arterijskog krvnog tlaka i metaboličke poremećaje kao što je debljina, ili za proizvodnju lijeka koji se može upotrijebiti za liječenje tih bolesti.
9. Izum, naznačen time, da je u skladu s gornjim opisom.
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WO2003004034A1 (en) * | 2001-07-02 | 2003-01-16 | Omeros Corporation | Method for inducing analgesia comprising administration alternatively of an opioid receptor agonist and an opioid receptor like receptor 1 agonist for and an implantable infusion pump |
US20030040479A1 (en) * | 2001-07-02 | 2003-02-27 | Omeros Corporation | Rotational intrathecal analgesia method and device |
ES2392340T3 (es) * | 2002-03-29 | 2012-12-07 | Mitsubishi Tanabe Pharma Corporation | Remedio para los trastornos del sueño |
JP2005289816A (ja) | 2002-05-14 | 2005-10-20 | Banyu Pharmaceut Co Ltd | ベンズイミダゾール誘導体 |
SI1519939T1 (sl) | 2002-07-05 | 2010-04-30 | Targacept Inc | N-aril diazaspiracikliŽŤne spojine in postopki za njihovo pripravo in njihova uporaba |
BR0306309A (pt) * | 2002-09-09 | 2004-10-19 | Janssen Pharmaceutica Nv | Derivados de 1,3,8-triazaespiro[4.5]decan-4-ona substituìda com hidroxialquila úteis para o tratamento de distúrbios mediados pelo receptor orl-1 |
GB0323204D0 (en) * | 2003-10-03 | 2003-11-05 | Novartis Ag | Organic compounds |
WO2005060947A2 (en) * | 2003-12-19 | 2005-07-07 | Sri International | Agonist and antagonist ligands of the nociceptin receptor |
US20060178390A1 (en) * | 2004-08-02 | 2006-08-10 | Alfonzo Jordan | 1,3,8-Triazaspiro[4,5]decan-4-one derivatives useful for the treatment of ORL-1 receptor mediated disorders |
WO2006023630A2 (en) * | 2004-08-20 | 2006-03-02 | Targacept, Inc. | The use of n-aryl diazaspiracyclic compounds in the treatment of addiction |
US20080247964A1 (en) * | 2006-05-08 | 2008-10-09 | Yuelian Xu | Substituted azaspiro derivatives |
CN101622254B (zh) * | 2006-11-28 | 2013-05-29 | 詹森药业有限公司 | 3-(3-氨基-2-(r)-羟基-丙基)-1-(4-氟-苯基)-8-(8-甲基-萘-1-基甲基)-1,3,8-三氮杂-螺[4.5]癸烷-4-酮的盐 |
CN101679430B (zh) * | 2007-04-09 | 2013-12-25 | 詹森药业有限公司 | 用于治疗焦虑和抑郁症的作为orl-1受体的配体的1,3,8-三取代-1,3,8-三氮杂-螺[4.5]癸-4-酮衍生物 |
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