EP1490324A2 - Propargylamino indan derivatives and propargylamino tetralin derivatives as brain-selective mao inhibitors - Google Patents
Propargylamino indan derivatives and propargylamino tetralin derivatives as brain-selective mao inhibitorsInfo
- Publication number
- EP1490324A2 EP1490324A2 EP03716197A EP03716197A EP1490324A2 EP 1490324 A2 EP1490324 A2 EP 1490324A2 EP 03716197 A EP03716197 A EP 03716197A EP 03716197 A EP03716197 A EP 03716197A EP 1490324 A2 EP1490324 A2 EP 1490324A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- compound
- alkyl
- reacting
- aralkyl
- aryl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- RUOKEQAAGRXIBM-UHFFFAOYSA-N n-prop-2-ynyl-2,3-dihydro-1h-inden-1-amine Chemical class C1=CC=C2C(NCC#C)CCC2=C1 RUOKEQAAGRXIBM-UHFFFAOYSA-N 0.000 title abstract description 7
- 210000004556 brain Anatomy 0.000 title abstract description 5
- KAKOSJKZQFWHRT-UHFFFAOYSA-N n-prop-2-ynyl-1,2,3,4-tetrahydronaphthalen-1-amine Chemical class C1=CC=C2C(NCC#C)CCCC2=C1 KAKOSJKZQFWHRT-UHFFFAOYSA-N 0.000 title abstract description 4
- 229940082992 antihypertensives mao inhibitors Drugs 0.000 title description 4
- 239000002899 monoamine oxidase inhibitor Substances 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 402
- 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 abstract description 90
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 67
- 125000003118 aryl group Chemical group 0.000 claims abstract description 63
- 238000000034 method Methods 0.000 claims abstract description 47
- 150000003839 salts Chemical class 0.000 claims abstract description 32
- 238000004519 manufacturing process Methods 0.000 claims abstract description 24
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims abstract description 24
- 208000012902 Nervous system disease Diseases 0.000 claims abstract description 22
- 208000025966 Neurological disease Diseases 0.000 claims abstract description 21
- 230000008569 process Effects 0.000 claims abstract description 20
- 239000003814 drug Substances 0.000 claims abstract description 13
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 78
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 78
- 229910052799 carbon Inorganic materials 0.000 claims description 33
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 32
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 31
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 30
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 26
- 125000000217 alkyl group Chemical group 0.000 claims description 26
- -1 hydrogen tartarate salt Chemical class 0.000 claims description 25
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 24
- 239000000010 aprotic solvent Substances 0.000 claims description 22
- 229940002612 prodrug Drugs 0.000 claims description 19
- 239000000651 prodrug Substances 0.000 claims description 19
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 17
- 230000000926 neurological effect Effects 0.000 claims description 16
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 15
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 13
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 claims description 12
- YORCIIVHUBAYBQ-UHFFFAOYSA-N propargyl bromide Chemical compound BrCC#C YORCIIVHUBAYBQ-UHFFFAOYSA-N 0.000 claims description 12
- 229930040373 Paraformaldehyde Natural products 0.000 claims description 11
- 229920002866 paraformaldehyde Polymers 0.000 claims description 11
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 10
- 208000024827 Alzheimer disease Diseases 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 208000011580 syndromic disease Diseases 0.000 claims description 8
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 claims description 8
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 claims description 7
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 claims description 7
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical class OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 7
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 7
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 7
- 208000015802 attention deficit-hyperactivity disease Diseases 0.000 claims description 7
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 claims description 7
- 229940077388 benzenesulfonate Drugs 0.000 claims description 7
- 230000006735 deficit Effects 0.000 claims description 7
- 208000035231 inattentive type attention deficit hyperactivity disease Diseases 0.000 claims description 7
- 208000028173 post-traumatic stress disease Diseases 0.000 claims description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 7
- 229910015845 BBr3 Inorganic materials 0.000 claims description 6
- IGVPBCZDHMIOJH-UHFFFAOYSA-N Phenyl butyrate Chemical class CCCC(=O)OC1=CC=CC=C1 IGVPBCZDHMIOJH-UHFFFAOYSA-N 0.000 claims description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 6
- 159000000021 acetate salts Chemical class 0.000 claims description 6
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 claims description 6
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 claims description 6
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 6
- 208000013403 hyperactivity Diseases 0.000 claims description 6
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 6
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical class [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 claims description 6
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical class CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- TUNFSRHWOTWDNC-UHFFFAOYSA-N tetradecanoic acid Chemical class CCCCCCCCCCCCCC(O)=O TUNFSRHWOTWDNC-UHFFFAOYSA-N 0.000 claims description 6
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical class OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 5
- 208000026139 Memory disease Diseases 0.000 claims description 5
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical class OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 claims description 5
- 150000001558 benzoic acid derivatives Chemical class 0.000 claims description 5
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 claims description 5
- 229940073608 benzyl chloride Drugs 0.000 claims description 5
- 150000001860 citric acid derivatives Chemical class 0.000 claims description 5
- 201000003631 narcolepsy Diseases 0.000 claims description 5
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 4
- 208000000323 Tourette Syndrome Diseases 0.000 claims description 4
- 208000016620 Tourette disease Diseases 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
- 206010015037 epilepsy Diseases 0.000 claims description 4
- 238000001990 intravenous administration Methods 0.000 claims description 4
- 230000015654 memory Effects 0.000 claims description 4
- 150000003013 phosphoric acid derivatives Chemical class 0.000 claims description 4
- 125000003289 ascorbyl group Chemical class [H]O[C@@]([H])(C([H])([H])O*)[C@@]1([H])OC(=O)C(O*)=C1O* 0.000 claims description 3
- 229940105132 myristate Drugs 0.000 claims description 3
- 150000003890 succinate salts Chemical class 0.000 claims description 3
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- 201000001880 Sexual dysfunction Diseases 0.000 claims description 2
- 229940072107 ascorbate Drugs 0.000 claims description 2
- 235000010323 ascorbic acid Nutrition 0.000 claims description 2
- 239000011668 ascorbic acid Substances 0.000 claims description 2
- 201000010099 disease Diseases 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- 231100000872 sexual dysfunction Toxicity 0.000 claims description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 3
- 239000003937 drug carrier Substances 0.000 claims 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 1
- 102000010909 Monoamine Oxidase Human genes 0.000 abstract description 74
- 108010062431 Monoamine oxidase Proteins 0.000 abstract description 74
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 24
- 239000000047 product Substances 0.000 description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 239000003112 inhibitor Substances 0.000 description 15
- 230000000694 effects Effects 0.000 description 14
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 14
- 208000018737 Parkinson disease Diseases 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 238000003818 flash chromatography Methods 0.000 description 11
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 206010012289 Dementia Diseases 0.000 description 8
- 239000012043 crude product Substances 0.000 description 7
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical class C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 7
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 6
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- RUOKEQAAGRXIBM-GFCCVEGCSA-N rasagiline Chemical compound C1=CC=C2[C@H](NCC#C)CCC2=C1 RUOKEQAAGRXIBM-GFCCVEGCSA-N 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 125000006321 2-propynyl amino group Chemical group [H]C#CC([H])([H])N([H])* 0.000 description 5
- 102100033639 Acetylcholinesterase Human genes 0.000 description 5
- 108010022752 Acetylcholinesterase Proteins 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
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- 238000002360 preparation method Methods 0.000 description 5
- ZVFWOEJLBBKISV-UHFFFAOYSA-N 1-(prop-2-ynylamino)-2,3-dihydroinden-1-ol Chemical class C1=CC=C2C(O)(NCC#C)CCC2=C1 ZVFWOEJLBBKISV-UHFFFAOYSA-N 0.000 description 4
- XJEVHMGJSYVQBQ-UHFFFAOYSA-N 2,3-dihydro-1h-inden-1-amine Chemical class C1=CC=C2C(N)CCC2=C1 XJEVHMGJSYVQBQ-UHFFFAOYSA-N 0.000 description 4
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 229940022698 acetylcholinesterase Drugs 0.000 description 4
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
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- HDXFCPZKMFTOLH-UHFFFAOYSA-N 1-amino-2,3-dihydroinden-1-ol Chemical class C1=CC=C2C(N)(O)CCC2=C1 HDXFCPZKMFTOLH-UHFFFAOYSA-N 0.000 description 3
- MAYMVHAVYDCEHG-UHFFFAOYSA-N 3-amino-2,3-dihydro-1h-inden-4-ol Chemical compound C1=CC(O)=C2C(N)CCC2=C1 MAYMVHAVYDCEHG-UHFFFAOYSA-N 0.000 description 3
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- WZNDDVAGNXHGPO-UHFFFAOYSA-N 7-[methyl(prop-2-ynyl)amino]-1,2,3,4-tetrahydronaphthalen-2-ol Chemical compound C1CC(O)CC2=CC(N(CC#C)C)=CC=C21 WZNDDVAGNXHGPO-UHFFFAOYSA-N 0.000 description 2
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- AXIKLEVFYDZYKE-CYBMUJFWSA-N (3r)-3-[methyl(prop-2-ynyl)amino]-2,3-dihydro-1h-inden-5-ol Chemical compound C1=C(O)C=C2[C@H](N(CC#C)C)CCC2=C1 AXIKLEVFYDZYKE-CYBMUJFWSA-N 0.000 description 1
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- LIQGSWZEXYZMAP-UHFFFAOYSA-N 1-(methylamino)-2,3-dihydroinden-1-ol Chemical class C1=CC=C2C(NC)(O)CCC2=C1 LIQGSWZEXYZMAP-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C215/64—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with rings other than six-membered aromatic rings being part of the carbon skeleton
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular 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
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
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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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C219/26—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
- C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
Definitions
- the subject of this invention provides for derivatives of propargylaminoindans and propargylaminotetralins that are irreversible inhibitors of the enzyme monoamine oxidase A and/or B and also for prodrugs for the administration of these compounds .
- Such compounds may be useful in the treatment of Parkinson's disease, Alzheimer's disease, depression and other neurological disorders.
- the enzyme monoamine oxidase plays an essential role in the metabolic degradation of important amine neurotransmitters including dopamine, serotonin and noradrenaline .
- agents that inhibit MAO are of potential therapeutic benefit for a variety of neurological disease indications, including Parkinson's disease, Alzheimer's disease, depression, epilepsy, narcolepsy, amyotrophic lateral sclerosis (ALS) , etc. (Szelnyi, I.; Bentue-Ferrer et al . ; Loscher et al . ; White et al . ; U.S. Patent No. 5,744,500) .
- Other diseases and conditions which have been associated with toxic levels of monoamine oxidase-B are memory disorders (The interaction of L-deprenyl and scopolamine on spatial learning/memory in rats) , panic, post-traumatic stress disorder (PTSD) , sexual dysfunction, attention deficit and hyperactivity syndrome (ADHD) (Potential applications for monoamine oxidase B inhibitors) , attention deficit disorder (Kleywegt) , and Tourette' ⁇ syndrome (Treatment of Tourette's: Overview) .
- MAO inhibitors can also be classified as reversible inhibitors which inhibit the enzyme by a competitive mechanism or as irreversible inhibitors which are generally mechanism based (suicide inhibitors) (Dostert) .
- moclobemide is a reversible MAO-A- specific inhibitor (Fitton et al . ) developed as an anti-depre ⁇ sant .
- rasagiline U.S. Patent No. 5,744,500
- selegiline Chorisp et al .
- MAO-B-selective irreversible inhibitors are MAO-B-selective irreversible inhibitors.
- Irreversible inhibitors have the advantage of lower, less frequent dosing since their MAO inhibition is not based directly on the drugs' pharmacokinetic behavior, but rather on the de novo regeneration of the MAO enzyme.
- MAO also plays an essential role in the oxidative deamination of biogenic and food-derived amines, both in the central nervous system and in peripheral tissues.
- MAO is found in two functional isoenzyme forms, MAO-A and MAO-B, each of which shows preferential affinity for substrates and specificity toward inhibitors.
- MAO-A preferentially oxidizes serotonin, noradrenaline and adrenaline
- MAO-B preferentially metabolizes phenylethylamine .
- Dopamine is a substrate for both forms of the enzyme (Szelenyi , I.).
- N-Propargyl- (IR) -aminoindan is known to be a potent B-selective inhibitor of MAO (U.S. Patent No. 5,457,133).
- Various derivatives of this compound have been prepared and shown to have varying degrees of potency and selectivity for the inhibition of MAO-A and/or -B.
- SAR structure on the activity
- U.S. Patent No. 6,303,650 discloses derivatives of 1-aminoindan as selective MAO B inhibitors that additionally inhibit acetylcholinesterase.
- the reference teaches that its compounds can be used to treat depression, Attention Deficit Disorder (ADC) , Attention Deficit and Hyperactivity Disorder (ADHD) , Tourette's Syndrome, Alzheimer's Disease and other dementias such as senile dementia, dementia of the Parkinson's type, vascular dementia and Lewy body dementia.
- ADC Attention Deficit Disorder
- ADHD Attention Deficit and Hyperactivity Disorder
- Tourette's Syndrome Alzheimer's Disease and other dementias such as senile dementia, dementia of the Parkinson's type, vascular dementia and Lewy body dementia.
- PCT International Application No. PCT/IL96/00115 relates to pharmaceutical compositions comprising racemic, (S) , and (R)-N- propargyl-1-aminoindan.
- (R) -N-propargyl-1-aminoindan selectively inhibits MAO-B in the treatment of Parkinson's disease and other neurological disorders (PCT/IL96/00115) .
- PCT International Application No. PCT/US97 /24155 concerns aminoindan derivatives, including propargyl aminoindan, as inhibitors of MAO-A and MAO-B for the treatment of Parkinson's disease and other neurological conditions.
- the publication reveals that the disclosed compounds exhibit a greater selectivity for MAO-A and MAO-B in the brain than in the liver or intestine.
- U.S. Patent No. 6,316,504 discloses that the R(+) enantiomer of N-propargyl-1-aminoindan is a selective irreversible inhibitor of MAO-B.
- the patent indicates that (R) - N-propargyl-1-aminoindan is useful for the treatment of Parkinson's disease, a memory disorder, dementia, depression, hyperactive syndrome, an affective illness, a neurodegenerative disease, a neurotoxic injury, stroke, brain ischemia, a head trauma injury, a spinal trauma injury, neurotrauma, schizophrenia, an attention deficit disorder, multiple sclerosis, and withdrawal symptoms.
- European Patent No. 436492 discloses the R enantiomer of N- propargyl-1-aminoindan as a selective irreversible inhibitor of MAO-B in the treatment of Parkinson's disease and other neurological conditions. Numerous U.S. patents also relate to the MAO B inhibition of (R) -N-propargyl-1-aminoindan and its use for treating patients suffering from Parkinson's Disease and other neurological disorders (U.S. Patents No.
- PCT International Application No . PCT/IL.97/00205 disclpses S- (-) -N-propargyl-1-aminoindan or a pharmaceutically acceptable salt thereof for the treatment of a neurological disorder of neurotrauma or for improving memory.
- the compounds were found to be neuroprotective, but not inhibitory of MAO-A or MAO-B (PCT/IL97/00205) .
- U.S. Patent No. 5,486,541 provides N-propargyl-1-amonoindan onofluorinated in the phenyl ring as selective inhibitors. of MAO-B. These compounds are presented as useful in the treatment of Parkinson's disease, memory disorders, dementia of the Alzheimer's type, depression and the hyperactive syndrome in children.
- N-propargylamino indanol also appears in E.P. 267024 as a hydrofluorene derivative, i.e., 3-amino-4-indanol (7-OH fluorene) .
- the hydrofluorene derivatives and salts in E.P. 267024 are employed as cerebral activators in the treatment of anoxe ia and hypoxemia. In addition, such derivatives help prevent arrhythmia and heart failure caused by lack of oxygen (E.P. 267024).
- the derivatives also act as antioxidants and cholinergic nerve system activating agents (E.P. 267024). Sm ⁇ mary of the Invention
- the subject invention provides a compound having the structure:
- R 3 is OC(0)R 9 and R 2 is H, wherein R 9 is branched or unbranched C 1 to C 6 alkyl, aryl, or aralkyl, or R is OC(0)R 4 and R 2 is OC(0)R 4 , wherein R 4 is branched or unbranched C 1 to C 6 alkyl, aryl, aralkyl or NR 5 R 6 , wherein R 5 and R 6 are each independently H, C ⁇ to C B alkyl, C 6 to C 12 aryl, C 6 to C 12 aralkyl or C 6 to C 12 cycloalkyl, each optionally substituted; wherein R 3 is H or C 1 to C 6 alkyl; wherein n is 0 or 1; and wherein m is 1 or 2, or a pharmaceutically acceptable salt thereof.
- the subject invention also provides a compound having the structure:
- R x is OH; wherein R 2 is H or OC(0)R 4 when R 2 is attached to the "a" carbon or the “d” carbon, or
- R 2 is OC(0)R 4 when R x is attached to the "b" carbon or the "c” carbon; wherein R 4 is C a to C 6 branched or unbranched alkyl, aryl, aralkyl or NR 5 R 6 , wherein R 5 and R 6 are each independently H, C ⁇ to C B alkyl, C 6 to C 12 aryl, C 6 to C i2 aralkyl or C 6 to C 12 cycloalkyl, each optionally substituted; wherein n is 0 or 1, and m is 1 or 2 ; and wherein R 3 is H or Me when n is 1 and m is 1, or R 3 is H or C x to C 6 alkyl when n is 0 or m is 2, or a pharmaceutically acceptable salt thereof.
- the compound is an optically pure enantiomer; wherein R ⁇ is OH; wherein R 2 is H; wherein R 3 is H or C ⁇ to C 6 alkyl; wherein n is 0 or 1; and wherein m is 1 or 2, or a pharmaceutically acceptable salt thereof.
- the subject invention further provides a compound having the structure: wherein R-, is H, C 2 to C 6 alkyl, aryl, aralkyl or C(0)R 4 , wherein R 4 is branched or unbranched C x to C 6 alkyl, aryl, aralkyl or NR 5 R 6 , wherein R 5 and R 6 are each independently H, C 2 to C 8 alkyl, C 6 to C 12 aryl, C 6 to C 12 aralkyl or C 6 to C 12 cycloalkyl, each optionally substituted; wherein R 3 is H or C x to C 6 alkyl; wherein R 8 is H or t-butoxycarbonyl (Boc) .
- the subject invention also provides a method of treating a subject afflicted with a neurological disease comprising administering to the subject a compound having the structure:
- R ⁇ is- OH or OC(0)R 9 , and wherein R 9 is branched or unbranched C ⁇ to C 6 alkyl, aryl, or aralkyl;
- R 2 is H or OC(0)R 4 , or both R a and R 2 are OC(0)R 4 , wherein R 4 is branched or unbranched C a to C 6 alkyl, aryl, aralkyl or NR 5 R 6 , wherein R 5 and R 6 are each independently H, C x to C 8 ' alkyl, C 5 to C 12 aryl, C 6 to C 12 aralkyl or C 6 to C 12 cycloalkyl, each optionally substituted; wherein R 3 is H or C x to C 6 alkyl; wherein n is 0 or 1; and wherein m is 1 or 2, or a pharmaceutically acceptable salt thereof, or a prodrug which becomes the compound in the subject, so as to thereby treat the neurological di ⁇ ease in the subject.
- the subject invention provides a method of treating a subject afflicted with a neurological disease comprising administering to the subject a compound having the structure:
- Rj is OH or OC(0)R,; wherein R 2 is H or OC(0)R 4 ,
- R 4 is branched or unbranched C x to C 6 alkyl, aryl, aralkyl or NR 5 R 6 , wherein R 5 and R 6 are each independently H, C x to' C 8 alkyl, C 6 to C 12 aryl, C 6 to C 12 aralkyl or C 6 to C 12 cycloalkyl, each optionally substituted; wherein R 3 is H or C 2 to C 6 alkyl; wherein n is 0 or 1; and wherein m is 1 or 2, or a pharmaceutically acceptable salt thereof, or a prodrug which becomes the compound in the subject, so as to thereby treat the neurological disease in the subject.
- Th e subj ect invention additionally provides a process for preparing a compound having the structure : wherein n is 0 or 1, and ra is 1 or 2 ; wherein R 3 i ⁇ H or C ⁇ to C 6 alkyl; and wherein R s is branched or unbranched C y to C 6 alkyl, .aryl, or aralkyl; comprising the step of reacting or
- the subject invention also provides a process for preparing a compound having the structure:
- R 4 is branched or unbranched C ⁇ to C 6 alkyl, aryl, aralkyl or NR 5 R 6 , wherein R 5 and R 6 are each independently H, C ⁇ to C 8 alkyl, C 6 to C 12 aryl, C 6 to C 12 aralkyl or C 6 to C 12 cycloalkyl, each optionally substituted; which process comprises:
- step (c) reacting the product formed in step (b) with MeNH 2 ⁇ Cl, NaCNBH 3 in tetrahydrofuran (THF) /MeOH to produce a compound having the structure:
- step (d) reacting the product formed in step (c) with H 2 , Pd/C and MeOH to produce a compound having the structure: (e) reacting the product formed in step (d) with Boc 2 0, dioxane/H 2 0 and NaHC0 3 to produce a compound having the structure:
- step (f) reacting the product formed in step (e) with R 4 C0C1, Et 3 N in CH 2 C1 2 in the presence of 4-dimethylaminopyridine (DMAP) to produce a compound having the structure: boc
- step (g) reacting the product formed in step (f) with HCl/dioxane to produce a compound having the structure:
- step (h) reacting the product formed in step (g) with propargyl bromide, K 2 C0 3 in CH 3 CN and then with HCl/ether and MeOH to produce a compound having the structure:
- the subject invention also provides the use of a compound or a prodrug of a compound which become ⁇ the compound having the structure:
- R ⁇ is OH or OC(0)R 4 ; 'wherein R 2 i ⁇ H, OH or OC(0)R 4 , wherein R 4 i ⁇ branched or unbranched C 1 to C 6 alkyl, aryl, aralkyl . or NR 5 R 6 , wherein R 5 and R 6 are each independently H, Ci to C 8 alkyl, C 6 to C 12 aryl, C 6 to C 12 aralkyl or C 6 to C 12 cycloalkyl, each optionally substituted; wherein R 3 is H or C ⁇ to C 6 alkyl; wherein n i ⁇ 0 or 1 ; and wherein m i ⁇ 1. or 2, or a pharmaceutically acceptable ⁇ alt thereof, for the manufacture of a medicament for treating a subject afflicted with a neurological disea ⁇ e, wherein the compound is to be periodically administered to the subject in a therapeutically effective dose.
- the subject invention provides the use of a compound or a prodrug of a compound which becomes the compound having the structure:
- R ⁇ is OH or 0C(0)R 9 , and wherein R 9 is branched or unbranched C ⁇ to C 6 alkyl, aryl, or aralkyl;
- R 2 is H or OC(0)R 4 , or both R 2 and R 2 are OC(0)R 4 , wherein R 4 is C a to C 5 alkyl, aryl, aralkyl or NR 5 R 6 , wherein R 5 and R 6 are each independently H, Ci to C 8 alkyl, C 6 to C 12 aryl, C 6 to C 12 aralkyl or C 6 to • C 12 cycloalkyl, each optionally substituted; wherein R 3 is H or C ⁇ to C 6 alkyl; wherein n is 0 or 1; and wherein m is 1 or 2, or a pharmaceutically acceptable ⁇ alt thereof, for the manufacture of a medicament for treating neurological disease in a subject, wherein the compound is to be periodically administered to the subject in a therapeutically effective dose.
- Figure 1 presents routes for the manufacture of compounds with the following structures:
- Figure 2 displays routes for the manufacture of a compound with the following structure:
- the letter ⁇ a) - i) are used to designate the following: a) A1C1 3 , toluene; b) BnCl, K 2 C0 3 , DMF; c) R 3 -NH 2 , HCl, NaCNBH 3 , THF/MeOH; d) H 2( Pd/C, MeOH; e) Boc 2 0, dioxane/H 2 0, NaHC0 3 ; f) R 4 -COCl, Et 3 N, DMAP, CH 2 Cl 2 ; g) HCl/dioxane; h) propargyl bromide, K 2 C0 3 , CH 3 CN; and i) HCl/ether, MeOH.
- Figure 3 depicts routes for the manufacture of compounds with the structures:
- the letters g) - 1) are u ⁇ ed to designate the following: g) NaCNBH 3 , NH 4 0Ac; h) propargyl bromide, ACN, K 2 C0 3 ; i) NaCNBH 3 , paraformaldehyde; j) N-methylpropargylamine, NaCNBH 3 ; k) BBr 3 ; and 1) R 4 COCl, TFA or DMAP.
- the subject invention provides a compound having the structure: wherein R x is 0C(0)R 9 and R 2 is H, wherein R 9 is branched or unbranched Cj to C 6 alkyl, aryl, or aralkyl, or R-i is OC(0)R 4 and R 2 is 0C(0)R 4 , wherein R 4 i ⁇ branched or unbranched C x to C 6 alkyl, aryl, aralkyl or NR 5 R 6 , wherein R E and R 6 are each independently H, C : to C B alkyl, C 6 to C 12 aryl, C 6 to C 12 aralkyl or C 6 to C 12 cycloalkyl, each optionally substituted; wherein R 3 is H or C 1 to C 6 alkyl; wherein n is 0 or 1; and wherein m is 1 or 2 , or a pharmaceutically acceptable salt thereof.
- the pharmaceutically acceptable salt is the acetate salt, mesylate ⁇ alt, esylate, tartarate salt, hydrogen tartarate salt, benzoate ⁇ alt, phenylbutyrate salt, phosphate ⁇ alt, citrate salt, ascorbate ⁇ alt, mandelate ⁇ alt, adipate ⁇ alt, octanoate salt, the myristate ⁇ alt, the succinate salt, or fumarate ⁇ alt.
- the compound has the structure:
- the compound has the structure:
- the compound has the structure:
- n i ⁇ 1 the compound has the structure:
- n 0.
- the compound has the structure:
- the compound has the structure: In one embodiment, R 9 is Me and R 3 is H.
- R 9 is tBu and R 3 i ⁇ H.
- R g is nBu and R 3 i ⁇ H.
- R 9 is CHPh and R 3 is H.
- R 9 is Ph and R 3 is H. In still another embodiment, wherein R 9 is Me and R 3 is Me. .
- R 9 i ⁇ nBu and R 3 is Me.
- R 9 is Ph and R 3 is Me.
- R 9 is tBu and R 3 is Me.
- R 9 l ⁇ Ph(OMe) 2 and R 3 is Me.
- R 0 i ⁇ Ph(OMe) 2 and R 3 is H.
- the compound has the structure:
- R 3 is Me and R 9 is Me.
- R 3 i ⁇ Me and R 9 i ⁇ Ph In another embodiment, R 3 is Me and R 9 i ⁇ Ph(OMe) 2 .
- R 3 is Me and R 9 is Me.
- R 3 is H and R 9 is Ph.
- r R 3 i ⁇ H and R 9 is Ph(OMe) 2 . 5871
- the compound has the structure:
- R 4 is Ph and R 3 is Me.
- R 3 is Me.
- the compound has the structure:
- the subject invention also provides a compound having the structure: wherein R a i ⁇ OH; wherein R 2 i ⁇ H or OC(0)R 4 when R x i ⁇ attached to the "a" carbon or the "d" carbon, or
- the pharmaceutically acceptable salt is the acetate salt, mesylate salt, esylate, tartarate ⁇ alt, hydrogen tartarate salt, benzoate salt, phenylbutyrate salt, phosphate salt, citrate salt, ascorbate salt, mandelate salt, adipate salt, octanoate salt, the myristate salt, the ⁇ uccinate salt, or fumarate salt.
- the compound has the structure:
- R 3 is H.
- R 3 is Me
- R 3 is H.
- n i ⁇ 0 the subject invention provides a compound having the structure: wherein the compound is an optically pure enantiomer; wherein R 2 is OH; wherein R 2 is H; wherein R 3 i ⁇ H or C 3 to C 6 alkyl; wherein n is 0 or 1 ; and wherein m i ⁇ 1 or 2 , or a pharmaceutically acceptable salt thereof.
- the pharmaceutically acceptable salt is the acetate salt, mesylate ⁇ alt, esylate, tartarate salt, hydrogen tartarate ⁇ alt, benzoate salt, phenylbutyrate salt, phosphate salt, citrate ⁇ alt, a ⁇ corbate salt, mandelate ⁇ alt, adipate salt, octanoate salt, the myristate salt, the succinate salt, or fumarate salt.
- the compound has the structure: In another embodiment, the compound ha ⁇ the structure:
- R 3 is H.
- R 3 is Me.
- R 3 is Me
- the ⁇ ubject invention further provides a compound having the structure: wherein R 7 is H, C ⁇ to C 6 alkyl, aryl, aralkyl or C(0)R 4 , wherein R 4 i ⁇ branched or unbranched C to C 6 alkyl, aryl, aralkyl or NR £ R 6 , wherein R 5 and R f are each independently H, C : to C e alkyl, C 6 to C 12 aryl, C 6 to C 12 aralkyl or C 6 to C 12 cycloalkyl, each optionally sub ⁇ tituted; wherein R 3 is H or C 1 to C 6 alkyl; wherein R 8 i ⁇ H or t-butoxycarbonyl (Boc) .
- the compound has the structure:
- the compound ha ⁇ the ⁇ tructure: In still another embodiment, the compound has the structure;
- the compound has the structure:
- the subject invention additionally provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound having the structure:
- R x is OC(0)R 9 and R 2 i ⁇ H, wherein R 9 is branched or unbranched Ci to C 6 alkyl, aryl, or aralkyl, or R : i ⁇ OC(0)R 4 and R 2 i ⁇ OC(0)R 4 , wherein R 4 i ⁇ branched or unbranched C r to C 5 alkyl, aryl, aralkyl or NR 5 R 6 , wherein R 5 and R 6 are each independently H, C 2 to C 8 alkyl, C 6 to C 12 aryl, C 6 to C 12 aralkyl or C 6 to C 12 cycloalkyl, each optionally substituted; wherein R 3 i ⁇ H or C ⁇ to C 6 alkyl; wherein n is 0 or 1; and wherein m is 1 or 2 , or a pharmaceutically acceptable ⁇ alt thereof.
- the ⁇ ubject invention further provides a pharmaceutical compo ⁇ ition compri ⁇ ing a compound having the ⁇ tructure:
- R 2 is 0C(0)R 4 when R x i ⁇ attached to the "b" carbon or the "c" carbon; wherein R 4 is C 1 to C 6 branched or unbranched alkyl, aryl, aralkyl or NR 5 R 6 , wherein R 5 and R 6 are each independently H, C ⁇ to C 8 alkyl, C e to C 12 aryl, C 6 to C 12 aralkyl or C 6 to C 12 cycloalkyl, each optionally substituted; wherein n i ⁇ 0 or 1, and i ⁇ 1 or 2; and wherein Rj is H or Me when n i ⁇ 1 and m is 1, or R 3 is H or C 1 to C 6 alkyl when n is 0 or m i ⁇ 2, or a pharmaceutically • acceptable ⁇ alt thereof.
- the subject invention al ⁇ o provides a pharmaceutical composition comprising a compound having the ⁇ tructure:
- the compound is an optically pure enantiomer; wherein R ⁇ is OH; wherein R 2 i ⁇ H; wherein R 3 i ⁇ H or C to C 6 alkyl; wherein n i ⁇ 0 or 1; and wherein m i ⁇ 1 or 2, or a pharmaceutically acceptable ⁇ alt thereof.
- the ⁇ ubject invention al ⁇ o provides a method of treating a subject afflicted with a neurological disease comprising administering to the ⁇ ubject a compound having the structure: wherein R ⁇ is OH or OC(0)R 4 ; wherein R 2 is H, OH or 0C(0)R 4 , wherein R 4 is branched or unbranched C ⁇ to C 6 .
- R 5 and R 6 are each independently H, C x to C 8 alkyl, C 6 to C 12 aryl, C 6 to C 12 aralkyl or C 6 to C 12 cycloalkyl, each optionally substituted; wherein R 3 i ⁇ H or C ⁇ to C 6 alkyl; wherein n i ⁇ 0 or 1; and wherein m i ⁇ 1 or 2, or a pharmaceutically acceptable salt thereof, or a prodrug which become ⁇ the compound in the ⁇ ubject, ⁇ o as to thereby treat the neurological di ⁇ ea ⁇ e in the subject.
- the subject invention provides a method of treating a subject afflicted with a neurological disease comprising administering to the ⁇ ubject a compound having the structure : wherein R ⁇ is OH or OC(0)R 9 , and R 2 i ⁇ H or 0C(0)R 4 , or both R- L and R 2 are 0C(0)R 4 , wherein R 9 is branched or unbranched C 2 to C 6 alkyl, aryl, or aralkyl; wherein R 4 i ⁇ branched or unbranched C ⁇ to C 6 alkyl, aryl, aralkyl or NR 5 R 6 , wherein R 5 and R 6 are each independently H, C x to C 8 alkyl, C 6 to C l2 aryl, C 6 to C 12 aralkyl or C 6 to C 12 cycloalkyl, each optionally substituted; wherein R 3 i ⁇ H or C ⁇ to C 6 alkyl; wherein n is 0 or 1;
- the compound has the ⁇ tructure: wherein 2 i ⁇ 0C(0)R 9 and R 2 i ⁇ H, wherein R s i ⁇ branched or unbranched Cx to C 6 alkyl, ' aryl, or aralkyl, or R x is OC(0)R 4 and R 2 i ⁇ OC(0)R 4 , wherein R 4 i ⁇ branched or unbranched C ⁇ to C 6 alkyl, aryl, aralkyl or NR 5 R 6 ,
- R 5 and R 6 are each independently H, Cj to C 8 alkyl, C 6 to C 12 aryl, C 6 to C 12 aralkyl or C 6 to C 12 cycloalkyl, each optionally sub ⁇ tituted; wherein R 3 is H or Cj to C 6 alkyl; wherein n is 0 or 1; and wherein m i ⁇ 1 or 2.
- the compound ha ⁇ the structure : wherein R ⁇ is OH; wherein R 2 is H or OC(0)R 4 when R ⁇ is attached to the "a" carbon or the “d” carbon, or
- R 2 is 0C(0)R 4 when R i ⁇ attached to the "b" carbon or the "c” carbon; wherein R 4 is C a to C 6 branched or unbranched alkyl, ⁇ aryl, aralkyl or NR 5 R 6 , wherein R 5 and R 6 are each independently H, C- . to C 8 alkyl, C 6 to C 12 aryl, C 6 to C 12 aralkyl or C 6 to C 12 cycloalkyl, each optionally ⁇ ub ⁇ tituted; wherein R 3 i ⁇ H or C ⁇ to C 6 alkyl; wherein n is 0 or 1; and wherein m i ⁇ 1 or 2.
- the compound has the structure:
- the compound i ⁇ an optically pure enantiomer; wherein x i ⁇ OH; wherein R 2 i ⁇ H; wherein R 3 is H or C 1 to C 6 alkyl; wherein n is 0 or 1; and wherein m is 1 or 2.
- the ⁇ ubject i human.
- the admini ⁇ tration comprises oral, parenteral, intravenous, tran ⁇ dermal, or rectal admini ⁇ tration.
- the effective amount i ⁇ from about 0.01 mg per day to about 100.0 mg per day.
- the effective amount i ⁇ from about 0.01 mg per day to about 50.0 mg per day.
- the effective amount is from about 0.1 mg per day to about 100.0 mg per day.
- the effective amount is from about 0.1 mg per day to about 10.0 mg per day.
- the effective amount is from about 0.01 mg to about 100.0 mg .
- the effective amount is from about 0.01 mg to about 50.0 mg .
- the effective amount is from about 0.1 mg to about 100.0 mg.
- the effective amount is from about 0.1 mg to about 10.0 mg .
- the neurological disease is Parkinson's disease, Alzheimer's disease, depre ⁇ sion, epilepsy, narcolepsy, amyotrophic lateral sclerosis (ALS) , memory disorder ⁇ , panic, po ⁇ t-traumatic ⁇ tre ⁇ s disorder (PTSD), ⁇ exual dy ⁇ function, attention deficit and hyperactivity syndrome (ADHD), attention deficit di ⁇ order, or Tourette's syndrome.
- the di ⁇ ease may also be neuropathy, hyperactive syndrome, neurotrauma, stroke, Parkinson' ⁇ di ⁇ ease, Huntington' ⁇ di ⁇ ease, and other dementia such as senile dementia, dementia .of the vascular dementia or Lewy body dementia.
- the neurological disease i ⁇ depression.
- the compound has the structure:
- the subject invention further provides a proce ⁇ s for preparing a compound having the ⁇ tructure: wherein n i ⁇ 0 or 1, and m is 1 or 2 ; wherein R 3 is H or C ⁇ to C ⁇ alkyl; and wherein R 9 is branched or unbranched C x to C 6 alkyl, aryl , or aralkyl ; comprising the step of reacting or with in the presence of an acid or 4-dimethylaminopyridine (DMAP) to form the compound.
- DMAP 4-dimethylaminopyridine
- R 9 is branched or unbranched Cj , to C 6 alkyl, aryl, or aralkyl ; which process comprises:
- the leaving group in step (a) is selected from the group consi ⁇ ting of a halogen and benzene sulfonate and the aprotic solvent in step (b) is CHC1 3 .
- the subject invention further provides a process for preparing a compound having the structure:
- step (d) deprotecting the compound formed in step (c) with HCl to produce a compound having the ⁇ tructure:
- the leaving group in step (a) is selected from the group consisting of a halogen and benzene sulfonate and the aprotic solvent in step (b) is CHC1 3 .
- the subject invention additionally provides a process for preparing a compound having the structure:
- R 9 i ⁇ branched or unbranched ⁇ to C 6 alkyl, aryl, or aralkyl; which process comprises:
- step ( c ) reacting the compound formed in step (b) with a compound having the structure:
- the leaving group in ⁇ tep (a) is ⁇ elected from the group consisting of a halogen and benzene sulfonate and the aprotic ⁇ olvent in step (c) is CHC1 3 .
- the subject invention provides another process for preparing a compound having the structure:
- step (b) reacting the compound formed in step (a) with lithium aluminum hydride to produce a compound having the structure :
- step (c) reacting the compound formed in step (b) with a compound having the ⁇ tructure:
- the aprotic solvent in step (c) is CHC1 3
- the subject invention provides yet another process for preparing a compound having the structure:
- R 9 is branched or unbranched C ⁇ - to C 6 alkyl, aryl, or aralkyl ; which process comprises:
- step (b) reacting the compound formed in step (b) with a compound having the structure:
- the aprotic solvent in step (d) is CHC1 3
- the subject invention provides a process for preparing a compound having the structure:
- step (b) reacting the compound formed in step (a) with NaCNBH 3 and paraformaldehyde to produce a compound having the structure :
- step (b) reacting the compound formed in step (b) with a compound having the structure:
- the leaving group in step (a) is selected from the group consisting of a halogen and benzene sulfonate and the aprotic ⁇ olvent in step (c) is CHC1 3 .
- the ⁇ ubject invention provides another process for preparing a compound having the structure: which comprises:
- step (b) reacting the compound formed in step (a) with lithium aluminum hydride to produce a compound having the structure: (c) reacting the compound formed in ⁇ tep (b) with a compound having the structure:
- the aprotic solvent in step (c) i ⁇ CHCl i ⁇ CHCl
- the subject invention provide ⁇ yet another process for preparing a compound having the structure: which comprises:
- step (b) reacting the compound formed in step (a) with a compound having the structure:
- the aprotic ⁇ olvent in step (d) i ⁇ CHC1 3 .
- the ⁇ ubject invention further provides a process for preparing a compound having the structure:
- step (d) reacting the product formed in step (c) with H 2 , Pd/C and MeOH to produce a compound having the structure: (e) reacting the product formed in ⁇ tep (d) with Boc 2 0, dioxane/H 2 0 and NaHC0 3 to produce a compound having the ⁇ tructure :
- step (f) reacting the product formed in step (e) with R 4 COCl, Et 3 N in CH 2 C1 2 in the presence of 4-dimethylaminopyridine (DMAP) to produce a compound having the structure:
- the ⁇ ubject invention provides a process for preparing a compound having the ⁇ tructure:
- step (b) reacting the product formed in step (a) with benzyl chloride and K 2 C0 3 in the presence of dimethyl formamide (DMF) to produce a compound having the structure: .
- DMF dimethyl formamide
- step (d) reacting the product formed in ⁇ tep (c) with H 2 , Pd/C and MeOH to produce a compound having the ⁇ tructure: (e) reacting the product formed in step (d) with Boc 2 0, dioxane/H 2 0 and NaHC0 3 to produce a compound having the structure:
- step (f) reacting the product formed in step (e) with PhCOCl, Et 3 N in CH 2 C1 2 in the presence of 4-dimethylaminopyridine (DMAP) to produce a compound having the structure: boc
- step (g) reacting the product formed in step (f) with HCl/dioxane to produce a compound having the structure:
- step (h) 'reacting the product formed in step (g) with propargyl bromide, K 2 C0 3 in CH 3 CN and then with HCl/ether and MeOH to produce a compound having the ⁇ tructure:
- the ⁇ ubject invention further provides the use of a compound or a prodrug of a compound which become ⁇ the compound having the structure: wherein R a is OH or OC(0)R 4 ; wherein R 2 is H, OH or OC(0)R 4 , wherein R 4 i ⁇ branched or unbranched C 1 to C € alkyl, aryl, aralkyl or NR 5 R 6 , wherein R 5 and R 6 are each independently H, C x to C 8 alkyl, C 6 to C 12 aryl, C 6 to C ⁇ 2 aralkyl or C 6 to C 12 cycloalkyl, each optionally substituted; wherein R 3 i ⁇ H or C ⁇ to C 6 alkyl; wherein n is 0 or 1; and wherein m is 1 or 2, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a ⁇ ubject afflicted with a neurological disease, wherein the compound is to be periodically administered to the subject
- the subject invention al ⁇ o provides the use of a compound or a prodrug of a compound which become ⁇ the compound having the structure: wherein R i ⁇ OH or OC(0)R 9 , and wherein R 9 i ⁇ branched or unbranched C x to C 6 alkyl, aryl, or aralkyl; R 2 i ⁇ H or 0C(0)R 4 , or both R and R 2 are OC(0)R 4 , wherein R 4 i ⁇ branched or unbranched CT , to C 6 alkyl, aryl, aralkyl or NR 5 R 6 , wherein R 5 and R 6 are each independently H, C 1 to C 8 alkyl, C 6 to C 12 aryl, C 6 to C 12 aralkyl or C 6 to C 12 cycloalkyl, each optionally substituted; wherein R 3 i ⁇ H or C a to C 6 alkyl; wherein n is 0 or 1; and wherein m is 1 or 2, or a
- R x is OC(0)R 9 and R 2 is H, wherein R 9 is branched or unbranched C : to C £ alkyl, aryl, or aralkyl, or Ri is OC(0)R 4 and R 2 is OC(0)R 4 , wherein R 4 i ⁇ branched or unbranched C : to C 6 alkyl, aryl, aralkyl or NR 5 R 6 , wherein R 5 and R 6 are each independently H, C ⁇ to C s alkyl, C 6 to C 12 aryl, C 5 to C 12 aralkyl or C 6 to C 12 cycloalkyl, each optionally ⁇ ubstituted; wherein R, is H or Cj to C 6 alkyl; wherein n is 0 or 1; and wherein i ⁇ 1 or 2.
- Rj is OH; wherein R 2 is H or OC(0)R 4 when R is attached to the "a" carbon or the “d” carbon, or
- R 2 is OC(0)R 4 when R : is attached to the "b" carbon or the "c” carbon; wherein R 4 is Cj , to C 6 branched or unbranched alkyl, • aryl, aralkyl or NR 5 R 6 , wherein R 5 and R 6 are each independently H, Ci to C ⁇ alkyl, C 6 to C 12 aryl, C 6 to C 12 aralkyl or C 6 to C 12 cycloalkyl, each optionally substituted; wherein R 3 is H or C 1 to C 5 alkyl; wherein n is 0 or 1; and wherein m i ⁇ 1 or 2
- the compound has the structure:
- the compound i ⁇ an optically pure enantiomer; wherein R 1 i ⁇ OH; wherein R 2 is H; wherein R 3 is H or Cj to C 6 alkyl; wherein n is 0 or 1; and wherein m is 1 or 2.
- the sub ect is human.
- the medicament is formulated for oral, parenteral, intravenous, transdermal, or rectal administration.
- the therapeutically effective amount is from about 0.01 mg per day to about 50.0 mg per day.
- the therapeutically effective amount is from about 0.1 mg per day to about 100.0 mg per day.
- the therapeutically effective amount is from about 0.1 mg per day to about 10.0 mg per day .
- the neurological disease is Parkinson's disease, Alzheimer's di ⁇ ea ⁇ e, depression, epilepsy, narcolepsy, amyotrophic lateral sclerosis (ALS) , . memory disorders, panic, po ⁇ t-traumatic ⁇ tre ⁇ di ⁇ order (PTSD), ⁇ exual dysfunction, attention deficit and hyperactivity ⁇ yndrome (ADHD), attention deficit disorder, or Tourette's ⁇ yndrome.
- the neurological disease i ⁇ depres ⁇ ion.
- the ⁇ ubject invention thu ⁇ disclo ⁇ e ⁇ various derivatives and isomers of hydroxylated propargylamino indan and tetralin which have surpri ⁇ ingly varied potency and ⁇ electivity for MAO inhibition.
- the ⁇ ubject invention also provide ⁇ modification ⁇ of the hydroxy compound ⁇ which have surprisingly varied MAO inhibitory propertie ⁇ depending upon the substitution pattern, however, the hydroxy compound i ⁇ alway ⁇ a more potent inhibitor than the modified ver ⁇ ion. Thu ⁇ , the modified version may be considered a prodrug of the more active hydroxy compound into which it will be metabolized in vivo .
- the prodrug compound i ⁇ a carboxylic acid e ⁇ ter of the hydroxy compound.
- the parent is a carbamate derivative of the hydroxy compound.
- the compound ⁇ are dihydroxy derivative ⁇ of propargylamino indan or tetralin. These derivative ⁇ are expected to be antioxidants, as well a ⁇ MAO inhibitor ⁇ .
- the subject invention provide ⁇ ester prodrug ⁇ .
- the ⁇ ubject invention provide ⁇ esters or carbamates of propargylamino indanols, propargylamino indandiol ⁇ , propargylamino tetralinol ⁇ or propargylamino tetralindiol ⁇ , and may be prepared by method ⁇ of esterification or carbamoylation of hydroxy compounds.
- Ester derivatives when R 2 equals hydrogen were prepared by reacting the propargylamino indanol ⁇ with acyl chloride ⁇ in the presence of a ⁇ trong organic acid such a ⁇ trifluoroacetic acid or an acylation cataly ⁇ t ⁇ uch a ⁇ 4-dimethylaminopyridine (DMAP) , with or without an inert organic ⁇ olvent ⁇ uch a ⁇ chloroform.
- a ⁇ trong organic acid such as a ⁇ trifluoroacetic acid or an acylation cataly ⁇ t ⁇ uch a ⁇ 4-dimethylaminopyridine (DMAP)
- Propargylamino indanols may ..be prepared by reacting amino indanols with propargyl bromide in a polar organic solvent such as N,N-dimethylacetamide or acetonitrile in the presence of a base such as potassium carbonate.
- N-Methyl, N-propargylamino indanol ⁇ may be prepared by reductive alkylation of propargylamino indanol ⁇ by method ⁇ known to tho ⁇ e ⁇ killed in the art, e.g., with NaCNBH 3 and paraformaldehyde .
- N- methyl, N-propargylamino indanol ⁇ were prepared by fir ⁇ t methylating amino indanols either by NaCNBH 3 /paraformaldehyde or by ethyl formate followed by LiAlH 4 reduction, and then reacting the N-methylamino indanols thus obtained with propargyl bromide a ⁇ described above.
- N-propargyl derivatives of, inter alia , 3-amino-indan-4-ol, l-amino-indan-4-ol, 3-amino-indan-5-ol and 7-amino-5, 6, 7 , 8- tetrahydro-naphthalen-2-ol were prepared.
- the diester tetralin derivative numbered 12 ( Figure 3) was prepared by esterification of the dihydroxy tetralin numbered 11 ( Figure 3) .
- Table 1 Chemical Data P T/US03/05871
- stereochemistry pos position mesylate salts wide range, hygroscopic
- the' propargylation reaction was run in acetonitrile at elevated temperature, e.g., 60°C for 4 hours.
- the reaction mixture was then filtered, and the cake washed with acetonitrile.
- the combined layers were evaporated, to dryness, and the residue (brown oil) subjected to flash column chromatography (hexane : EtOAc, 2:1).
- the product (white solid) wa ⁇ thu ⁇ obtained in 40 - 55 % yield.
- Thu ⁇ were prepared: (R) -3-prop-2-ynylamino-5-indanol mesylate, (S) -3-prop-2-ynylamino-5-indanol mesylate, l-prop-2-ynylamino-4- indanol HCl, and 3-prop-2-ynylamino-4-indanol HCl.
- Lithium aluminium hydride (4.5 g) was added portionwise to stirred and cooled dry THF (100 ml) at 0°C.
- the reaction mixture wa ⁇ stirred at ambient temperature for 9 hr, cooled and treated with water (100 ml) .
- the pH was adjusted to 8-9, water (200 ml) wa ⁇ added, and the mixture was extracted with ether (6 X 300 ml) .
- the etheral extract wa ⁇ evaporated to dryness to give 3.2 g (94%) .
- EXAMPLE 3 GENERAL PROCEDURE FOR ESTERIFICATION OF PROP-2-YNYL AMINO INDANOLS AND TERALINOLS , EXEMPLIFIED BY PENTANOIC ACID (R)-3-PROP-2-YNYLAMINO-INDAN-5-YL ESTER HCL (Cmpd # 107)
- EXAMPLE 4 ALTERNATIVE PROCEDURE, EXEMPLIFIED BY BENZOIC ACID (R)-3-PROP-2-YNYLAMINO-INDAN-5-YL ESTER (Cmpd # 111)
- the aqueous layer wa ⁇ washed wit methylene chloride (4x100 ml) , and the combined organic phases were dried evaporated to dryness in vacuo.
- the crude product (3.78 g brown oil) wa ⁇ purified by flash column chromatography (hexane: EtOAc 4:1) to give 1.6 g (5.3 mmol, 71%) of a yellow oil.
- the free base was converted to the HCl salt (etheral HCl, 2 hours, RT) , 1.39g (4.07 mmol, 77%, 55% from the hydroxy compound) .
- the MAO enzyme source was a homogenate of rat brain in 0.3 M sucrose 1:20 w/v.
- the homogenate was pre-incubated with serial dilutions of the test compounds (Table 5) for 60 minutes at 37°C.
- 14 C-labeled substrates (2-phenylethylamine, hereinafter PEA; 5-hydroxytryptamine, hereinafter 5-HT) were then added, and the incubation continued for a further 20 minutes (PEA) , or 30- 45 minutes (5-HT) .
- PEA 2-phenylethylamine
- 5-HT 5-hydroxytryptamine
- the enzyme concentration wa ⁇ chosen so that not more than 10% of the ⁇ ub ⁇ trate was metabolized during the course of the reaction.
- the reaction was then 1 stopped by addition of citric acid.
- the activity determined using PEA as substrate is referred to a ⁇ MAO-B, and that determined using 5-HT as MAO-A.
- Rat ⁇ were treated with the te ⁇ t compounds (Table 5) at several dose levels by oral admini ⁇ tration, one dose daily for 7-21 days, and decapitated 2 hour ⁇ after the la ⁇ t dose.
- the activities of MAO-A and MAO-B were determined in the brain, liver and intestine a ⁇ described in the previous example.
- Inhibition of MAO activity wa ⁇ calculated by dividing MAO activity in the treated rats by MAO activity in the control rat ⁇ (saline treated, MAO activity in these rats was taken as 100%) .
- Tourette's An Overview, (http: //www. haverford. edu/psych/biopsych217b/tourettes/TSwebtreat . caf .html) . •
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Abstract
The subject invention provides derivatives of propargylamino indan (PAI) and propargylamino tetralin that selectively inhibit monoamine oxidase (MAO) in the brain, having the structure:, wherein R1 is OC (O) R9 and R2 is H, wherein R9 i s branched or unbranched C1 to C6 alkyl, aryl, or aralkyl, or R1 is OC (O) R4 and R2 is OC (O) R4, wherein R4 is branched or unbranched C1 to C6 alkyl, aryl, aralkyl or NR5R6, wherein R5 and R6 are each independently H, C1 to C8 alkyl, C6 to C12 aryl, C6 to C12 aralkyl or C6 to C12 cycloalkyl, each optionally substituted; wherein R3 is H or C1 to C6 alkyl; wherein n is 0 or 1; and wherein m is 1 or 2, or a pharmaceutically acceptable salt thereof. Additionally, the subject invention provides methods of treating neurological disorders using these compounds, uses of these compounds for the manufacture of medicaments for treating neurological disorders and processes for synthesis of these compounds.
Description
PROPARGYLAMINO INDAN DERIVATIVES AND PROPARGYLAMINO TETRALIN DERIVATIVES AS BRAIN-SELECTIVE MAO INHIBITORS
This application claims the benefit of U.S. Serial No. 10/085,674, filed February 27, 2002, the contents of which are hereby incorporated by reference .
Throughout this application, various references are referenced by short citations within parenthesis. Full citations for these references may be found at the end of the specification, immediately preceding the claims. These references, in their entireties, are hereby incorporated by reference to more fully describe the state of the art to which this invention pertains.
Field of the Invention
The subject of this invention provides for derivatives of propargylaminoindans and propargylaminotetralins that are irreversible inhibitors of the enzyme monoamine oxidase A and/or B and also for prodrugs for the administration of these compounds . Such compounds may be useful in the treatment of Parkinson's disease, Alzheimer's disease, depression and other neurological disorders.
Background of the Invention
The enzyme monoamine oxidase (MAO) plays an essential role in the metabolic degradation of important amine neurotransmitters including dopamine, serotonin and noradrenaline . Thus, agents that inhibit MAO are of potential therapeutic benefit for a variety of neurological disease indications, including Parkinson's disease, Alzheimer's disease, depression, epilepsy, narcolepsy, amyotrophic lateral sclerosis (ALS) , etc. (Szelnyi, I.; Bentue-Ferrer et al . ; Loscher et al . ; White et al . ; U.S. Patent No. 5,744,500) . Other diseases and conditions which have
been associated with toxic levels of monoamine oxidase-B are memory disorders (The interaction of L-deprenyl and scopolamine on spatial learning/memory in rats) , panic, post-traumatic stress disorder (PTSD) , sexual dysfunction, attention deficit and hyperactivity syndrome (ADHD) (Potential applications for monoamine oxidase B inhibitors) , attention deficit disorder (Kleywegt) , and Tourette'ε syndrome (Treatment of Tourette's: Overview) .
Many inhibitors of MAO are chiral molecules (U.S. Patent No. 5,744,500) . Although one enantiomer often shows some stereoselectivity in relative potency towards MAO-A and -B, a given enantiomeric configuration is not always more selective than its isomer in discriminating between MAO-A and -B (Hazelhoff et al . , Naunyn-Schmeideberg' s Arch. Pharmacol.).
MAO inhibitors can also be classified as reversible inhibitors which inhibit the enzyme by a competitive mechanism or as irreversible inhibitors which are generally mechanism based (suicide inhibitors) (Dostert) . For example, moclobemide is a reversible MAO-A- specific inhibitor (Fitton et al . ) developed as an anti-depreεsant . Likewise, rasagiline (U.S. Patent No. 5,744,500) and selegiline. (Chrisp et al . ) are MAO-B-selective irreversible inhibitors.
Irreversible inhibitors have the advantage of lower, less frequent dosing since their MAO inhibition is not based directly on the drugs' pharmacokinetic behavior, but rather on the de novo regeneration of the MAO enzyme.
MAO also plays an essential role in the oxidative deamination of biogenic and food-derived amines, both in the central nervous system and in peripheral tissues. MAO is found in two functional isoenzyme forms, MAO-A and MAO-B, each of which shows preferential affinity for substrates and specificity toward
inhibitors. Thus, MAO-A preferentially oxidizes serotonin, noradrenaline and adrenaline, whereas MAO-B preferentially metabolizes phenylethylamine . Dopamine is a substrate for both forms of the enzyme (Szelenyi , I.).
N-Propargyl- (IR) -aminoindan is known to be a potent B-selective inhibitor of MAO (U.S. Patent No. 5,457,133). Various derivatives of this compound have been prepared and shown to have varying degrees of potency and selectivity for the inhibition of MAO-A and/or -B. There is no currently accepted theory explaining the effect of structure on the activity (SAR) of the various substituted propargylaminoindans .
The dopamine agonistic activity and MAO inhibitory properties of 7- (methyl-prop-2-ynylamino) -tetralin-2-ol and 7- (methyl-prop-2- ynylamino) -tetralin-2 , 3-diol have been reported (Hazelhoff et
• al . , Eur . J. Pharmacol.) . The details of the synthesis of these compounds have not been published, however.
6, 7-di-0-benzoyl-2-aminotetralin has been reported as a prodrug of the dopaminergic agonist 6, 7-di-hydroxy-2-aminotetralin (Horn et al.) . However, no N-propargyl derivatives were reported and the compounds were not shown to have MAO inhibitory or neuroprotective activities.
7- (propyl-prop-2-ynylamino) -tetralin-2-ol has been reported as an intermediate in the preparation . of 7- [ (3-iodoallyl) - propylamino] -tetralin-2-ol . Only the latter has been pharmacologically characterized as D3-dopamine receptor ligand' (Chumpradit et al . ) . No other N-alkyl substituents were described.
Florvall et al . report the preparation of amino acid-based prodrugs of amiflamine analogues. Amiflamine is a reversible MAO-A inhibitor.
PCT International Application No. PCT/US97/24155 concerns carbamate aminoindan derivatives, including propargylamines, as inhibitors of MAO-A and MAO-B for the treatment of Alzheimer's disease and other neurological conditions. However, the compounds of PCT/US97/24155 are not selective for MAO over acetylcholinesterase ("AChE"). Thus, the compounds generally inhibit acetylcholinesterase along with MAO. Acetylcholinesterase inhibition is a route implicated in certain neurological disorders, but is a different route from the route of MAO inhibition.
U.S. Patent No. 6,303,650 discloses derivatives of 1-aminoindan as selective MAO B inhibitors that additionally inhibit acetylcholinesterase. The reference teaches that its compounds can be used to treat depression, Attention Deficit Disorder (ADC) , Attention Deficit and Hyperactivity Disorder (ADHD) , Tourette's Syndrome, Alzheimer's Disease and other dementias such as senile dementia, dementia of the Parkinson's type, vascular dementia and Lewy body dementia.
Many irreversible MAO inhibitors contain the propargyl amine functionality. This pharmacophore is responsible for the MAO inhibitory activity of such compounds. Some propargylamines have been shown to have neuroprotective/neurorescue properties independent of their MAO inhibition activity (U.S. Patent No. 4,844,033; Krageten et al . ) .
PCT International Application No. PCT/IL96/00115 relates to pharmaceutical compositions comprising racemic, (S) , and (R)-N- propargyl-1-aminoindan. (R) -N-propargyl-1-aminoindan selectively inhibits MAO-B in the treatment of Parkinson's disease and other neurological disorders (PCT/IL96/00115) .
Derivatives of 1-aminoindan, including propargyl aminoindan, and their salts are described in many U.S. patents (U.S. Patents No.
5,639,913, 5,877,221, 5,880,159, 5,877,218, 5,914,349, 5,994,408) and a PCT International Application (PCT/US95/00245) . These references disclose racemic, R and S enantiomers, of 1- aminoindan derivatives for the treatment of Parkinson's disease and other neurological conditions (U.S. Patents No. 5,639,913, 5,877,221, 5,880,159, 5,877,218, 5,914,349,' 5,994,408, PCT/US95/00245) .
PCT International Application No. PCT/US97 /24155 concerns aminoindan derivatives, including propargyl aminoindan, as inhibitors of MAO-A and MAO-B for the treatment of Parkinson's disease and other neurological conditions. The publication reveals that the disclosed compounds exhibit a greater selectivity for MAO-A and MAO-B in the brain than in the liver or intestine.
U.S. Patent No. 6,316,504 discloses that the R(+) enantiomer of N-propargyl-1-aminoindan is a selective irreversible inhibitor of MAO-B. The patent indicates that (R) - N-propargyl-1-aminoindan is useful for the treatment of Parkinson's disease, a memory disorder, dementia, depression, hyperactive syndrome, an affective illness, a neurodegenerative disease, a neurotoxic injury, stroke, brain ischemia, a head trauma injury, a spinal trauma injury, neurotrauma, schizophrenia, an attention deficit disorder, multiple sclerosis, and withdrawal symptoms.
European Patent No. 436492 discloses the R enantiomer of N- propargyl-1-aminoindan as a selective irreversible inhibitor of MAO-B in the treatment of Parkinson's disease and other neurological conditions. Numerous U.S. patents also relate to the MAO B inhibition of (R) -N-propargyl-1-aminoindan and its use for treating patients suffering from Parkinson's Disease and other neurological disorders (U.S. Patents No. 5,387,612, 5,453,446, 5,457,133, 5,519,061, 5,532,415, 5,576,353,
5 , 668 , 181 , 5 , 744 , 500 , 5 , 786 , 390 and 5 , 891 , 923 ) .
PCT International Application No . PCT/IL.97/00205 disclpses S- (-) -N-propargyl-1-aminoindan or a pharmaceutically acceptable salt thereof for the treatment of a neurological disorder of neurotrauma or for improving memory. The compounds were found to be neuroprotective, but not inhibitory of MAO-A or MAO-B (PCT/IL97/00205) .
U.S. Patent No. 5,486,541 provides N-propargyl-1-amonoindan onofluorinated in the phenyl ring as selective inhibitors. of MAO-B. These compounds are presented as useful in the treatment of Parkinson's disease, memory disorders, dementia of the Alzheimer's type, depression and the hyperactive syndrome in children.
Among the many derivatives of propargyla inoindan mentioned in the prior art are hydroxy-propargylaminoindans . U.S. Patent No. 3,513,244 lists some racemic N-propargylamino indanols and tetralinolε for use as antihypertenεiveε . These compounds are not exemplified chemically and are not pharmacologically characterized (U.S. ' Patent No. 3,513,244).
N-propargylamino indanol also appears in E.P. 267024 as a hydrofluorene derivative, i.e., 3-amino-4-indanol (7-OH fluorene) . The hydrofluorene derivatives and salts in E.P. 267024 are employed as cerebral activators in the treatment of anoxe ia and hypoxemia. In addition, such derivatives help prevent arrhythmia and heart failure caused by lack of oxygen (E.P. 267024). The derivatives also act as antioxidants and cholinergic nerve system activating agents (E.P. 267024).
Smπmary of the Invention
The subject invention provides a compound having the structure:
wherein R3 is OC(0)R9 and R2 is H, wherein R9 is branched or unbranched C1 to C6 alkyl, aryl, or aralkyl, or R is OC(0)R4 and R2 is OC(0)R4, wherein R4 is branched or unbranched C1 to C6 alkyl, aryl, aralkyl or NR5R6, wherein R5 and R6 are each independently H, Cα to CB alkyl, C6 to C12 aryl, C6 to C12 aralkyl or C6 to C12 cycloalkyl, each optionally substituted; wherein R3 is H or C1 to C6 alkyl; wherein n is 0 or 1; and wherein m is 1 or 2, or a pharmaceutically acceptable salt thereof.
The subject invention also provides a compound having the structure:
wherein Rx is OH; wherein R2 is H or OC(0)R4 when R2 is attached to the "a" carbon or the "d" carbon, or
R2 is OC(0)R4 when Rx is attached to the "b" carbon or the "c" carbon; wherein R4 is Ca to C6 branched or unbranched alkyl, aryl, aralkyl or NR5R6, wherein R5 and R6 are each independently H, Cα to CB alkyl, C6 to C12 aryl, C6 to Ci2 aralkyl or C6 to C12 cycloalkyl, each optionally substituted; wherein n is 0 or 1, and m is 1 or 2 ; and wherein R3 is H or Me when n is 1 and m is 1, or R3 is H or Cx to C6 alkyl when n is 0 or m is 2, or a pharmaceutically acceptable salt thereof.
In addition, the subject invention provides a compound having the structure:
wherein the compound is an optically pure enantiomer; wherein Rα is OH; wherein R2 is H; wherein R3 is H or Cτ to C6 alkyl; wherein n is 0 or 1; and wherein m is 1 or 2, or a pharmaceutically acceptable salt thereof.
The subject invention further provides a compound having the structure:
wherein R-, is H, C2 to C6 alkyl, aryl, aralkyl or C(0)R4, wherein R4 is branched or unbranched Cx to C6 alkyl, aryl, aralkyl or NR5R6, wherein R5 and R6 are each independently H, C2 to C8 alkyl, C6 to C12 aryl, C6 to C12 aralkyl or C6 to C12 cycloalkyl, each optionally substituted; wherein R3 is H or Cx to C6 alkyl; wherein R8 is H or t-butoxycarbonyl (Boc) .
The subject invention also provides a method of treating a subject afflicted with a neurological disease comprising administering to the subject a compound having the structure:
wherein Rα is- OH or OC(0)R9, and wherein R9 is branched or unbranched Cα to C6 alkyl, aryl, or aralkyl;
R2 is H or OC(0)R4, or both Ra and R2 are OC(0)R4, wherein R4 is branched or unbranched Ca to C6 alkyl, aryl, aralkyl or NR5R6, wherein R5 and R6 are each independently H, Cx to C8' alkyl, C5 to C12 aryl, C6 to C12 aralkyl or C6 to C12 cycloalkyl, each optionally substituted; wherein R3 is H or Cx to C6 alkyl; wherein n is 0 or 1; and wherein m is 1 or 2, or a pharmaceutically acceptable salt thereof, or a prodrug which becomes the compound in the subject, so as to thereby treat the neurological diεease in the subject.
Furthermore, the subject invention provides a method of treating a subject afflicted with a neurological disease comprising administering to the subject a compound having the structure:
wherein Rj is OH or OC(0)R,; wherein R2 is H or OC(0)R4,
•wherein R4 is branched or unbranched Cx to C6 alkyl, aryl, aralkyl or NR5R6, wherein R5 and R6 are each independently H, Cx to' C8 alkyl, C6 to C12 aryl, C6 to C12 aralkyl or C6 to C12 cycloalkyl, each optionally substituted; wherein R3 is H or C2 to C6 alkyl; wherein n is 0 or 1; and wherein m is 1 or 2, or a pharmaceutically acceptable salt thereof, or a prodrug which becomes the compound in the subject, so as to thereby treat the neurological disease in the subject.
Th e subj ect invention additionally provides a process for preparing a compound having the structure :
wherein n is 0 or 1, and ra is 1 or 2 ; wherein R3 iε H or Cα to C6 alkyl; and wherein Rs is branched or unbranched Cy to C6 alkyl, .aryl, or aralkyl; comprising the step of reacting
or
R, with
in the presence of -an acid or 4-dimethylaminopyridine (DMAP) to form the compound.
T U 03/05871
-13- The subject invention also provides a process for preparing a compound having the structure:
wherein R4 is branched or unbranched CΎ to C6 alkyl, aryl, aralkyl or NR5R6, wherein R5 and R6 are each independently H, Cα to C8 alkyl, C6 to C12 aryl, C6 to C12 aralkyl or C6 to C12 cycloalkyl, each optionally substituted; which process comprises:
03 05871
■14-
[a) reacting a compound having the structure:
with AlCl3 or BBr3 in the presence of toluene to produce a compound having the structure:
(b) reacting the product formed in εtep (a) with benzyl chloride and K2C03 in the presence of dimethyl formamide (DMF) to produce a compound having the structure: .
(c) reacting the product formed in step (b) with MeNH2ΗCl, NaCNBH3 in tetrahydrofuran (THF) /MeOH to produce a compound having the structure:
(d) reacting the product formed in step (c) with H2, Pd/C and MeOH to produce a compound having the structure:
(e) reacting the product formed in step (d) with Boc20, dioxane/H20 and NaHC03 to produce a compound having the structure:
(f) reacting the product formed in step (e) with R4C0C1, Et3N in CH2C12 in the presence of 4-dimethylaminopyridine (DMAP) to produce a compound having the structure:
boc
(g) reacting the product formed in step (f) with HCl/dioxane to produce a compound having the structure:
(h) reacting the product formed in step (g) with propargyl bromide, K2C03 in CH3CN and then with HCl/ether and MeOH to produce a compound having the structure:
The subject invention also provides the use of a compound or a prodrug of a compound which becomeε the compound having the structure:
wherein Rα is OH or OC(0)R4; 'wherein R2 iε H, OH or OC(0)R4, wherein R4 iε branched or unbranched C1 to C6 alkyl, aryl, aralkyl . or NR5R6, wherein R5 and R6 are each independently H, Ci to C8 alkyl, C6 to C12 aryl, C6 to C12 aralkyl or C6 to C12 cycloalkyl, each optionally substituted; wherein R3 is H or Cα to C6 alkyl; wherein n iε 0 or 1 ; and wherein m iε 1. or 2, or a pharmaceutically acceptable εalt thereof, for the manufacture of a medicament for treating a subject afflicted with a neurological diseaεe, wherein the compound is to be periodically administered to the subject in a therapeutically effective dose.
Additionally, the subject invention provides the use of a compound or a prodrug of a compound which becomes the compound having the structure:
wherein Rα is OH or 0C(0)R9, and wherein R9 is branched or unbranched Cλ to C6 alkyl, aryl, or aralkyl; R2 is H or OC(0)R4, or both R2 and R2 are OC(0)R4, wherein R4 is Ca to C5 alkyl, aryl, aralkyl or NR5R6, wherein R5 and R6 are each independently H, Ci to C8 alkyl, C6 to C12 aryl, C6 to C12 aralkyl or C6 to • C12 cycloalkyl, each optionally substituted; wherein R3 is H or Cα to C6 alkyl; wherein n is 0 or 1; and wherein m is 1 or 2, or a pharmaceutically acceptable εalt thereof, for the manufacture of a medicament for treating neurological disease in a subject, wherein the compound is to be periodically administered to the subject in a therapeutically effective dose.
Description of the Drawings
Figure 1 presents routes for the manufacture of compounds with the following structures:
and
Figure 2 displays routes for the manufacture of a compound with the following structure:
In Figure 2, the letterε a) - i) are used to designate the following: a) A1C13, toluene; b) BnCl, K2C03, DMF; c) R3-NH2, HCl, NaCNBH3, THF/MeOH; d) H2( Pd/C, MeOH; e) Boc20, dioxane/H20, NaHC03; f) R4-COCl, Et3N, DMAP, CH2Cl2; g) HCl/dioxane; h) propargyl bromide, K2C03, CH3CN; and i) HCl/ether, MeOH.
Figure 3 depicts routes for the manufacture of compounds with the structures:
and
In Figure 3, the letters g) - 1) are uεed to designate the following: g) NaCNBH3, NH40Ac; h) propargyl bromide, ACN, K2C03; i) NaCNBH3, paraformaldehyde; j) N-methylpropargylamine, NaCNBH3; k) BBr3; and 1) R4COCl, TFA or DMAP.
03 05871
-23-
Detailed Description of the Invention
The subject invention provides a compound having the structure:
wherein Rx is 0C(0)R9 and R2 is H, wherein R9 is branched or unbranched Cj to C6 alkyl, aryl, or aralkyl, or R-i is OC(0)R4 and R2 is 0C(0)R4, wherein R4 iε branched or unbranched Cx to C6 alkyl, aryl, aralkyl or NR5R6, wherein RE and R6 are each independently H, C: to CB alkyl, C6 to C12 aryl, C6 to C12 aralkyl or C6 to C12 cycloalkyl, each optionally substituted; wherein R3 is H or C1 to C6 alkyl; wherein n is 0 or 1; and wherein m is 1 or 2 , or a pharmaceutically acceptable salt thereof.
In one embodiment, the pharmaceutically acceptable salt is the acetate salt, mesylate εalt, esylate, tartarate salt, hydrogen tartarate salt, benzoate εalt, phenylbutyrate salt, phosphate εalt, citrate salt, ascorbate εalt, mandelate εalt, adipate εalt, octanoate salt, the myristate εalt, the succinate salt, or fumarate εalt.
In another embodiment, the compound has the structure:
In a further embodiment, the compound has the structure:
In yet another embodiment, the compound has the structure:
In one embodiment, n iε 1
In a further embodiment, the compound has the structure:
In an added embodiment, n is 0.
In yet another embodiment, the compound has the structure:
In still another embodiment, the compound has the structure:
In one embodiment, R9 is Me and R3 is H.
In another embodiment, R9 is tBu and R3 iε H.
In a further embodiment, Rg is nBu and R3 iε H.
In yet another embodiment, R9 is CHPh and R3 is H.
In an additional embodiment, R9 is Ph and R3 is H. In still another embodiment, wherein R9 is Me and R3 is Me. .
In a further embodiment, R9 iε nBu and R3 is Me.
In one embodiment, R9 is Ph and R3 is Me.
In an added embodiment, R9 is tBu and R3 is Me.
In another embodiment, R9 iε Ph(Me) and R3 iε Me. In still another embodiment, R9 lε Ph(OMe)2 and R3 is Me.
In a further embodiment, R0 iε Ph(OMe)2 and R3 is H.
In one embodiment, the compound has the structure:
In an additional embodiment, R3 is Me and R9 is Me.
In a further embodiment, R3 iε Me and R9 iε Ph In another embodiment, R3 is Me and R9 iε Ph(OMe)2.
In yet another embodiment, the compound haε the structure:
In an added embodiment, R3 is Me and R9 is Me.
In still another embodiment, R3 is H and R9 is Ph.
In one embodiment r R3 iε H and R9 is Ph(OMe)2.
5871
-28-
In another embodiment, the compound has the structure:
In a further embodiment, n iε 0
In yet another embodiment, R4 is Ph and R3 is Me.
In one embodiment, n iε 1
In still another embodiment, R3 is Me.
In an added embodiment, the compound has the structure:
The subject invention also provides a compound having the structure:
wherein Ra iε OH; wherein R2 iε H or OC(0)R4 when Rx iε attached to the "a" carbon or the "d" carbon, or
R2 iε OC(0)R4 when Ra iε attached to the "b" carbon or the vc" carbon; wherein R4 iε Cx to C6 branched or unbranched alkyl, aryl, aralkyl or NR5R6, wherein R5 and Re are each independently H, Ci to C8 alkyl, C6 to C12 aryl, C6 to C12 aralkyl or C6 to C12 cycloalkyl, each optionally substituted; wherein n is 0 or 1, and m iε 1 or 2; and wherein R3 is H or Me when n iε 1 and m is 1, or R3 is H or Ci to C6 alkyl when n iε 0 or m is 2, or a pharmaceutically acceptable salt thereof.
In one embodiment, the pharmaceutically acceptable salt is the acetate salt, mesylate salt, esylate, tartarate εalt, hydrogen tartarate salt, benzoate salt, phenylbutyrate salt, phosphate salt, citrate salt, ascorbate salt, mandelate salt, adipate salt, octanoate salt, the myristate salt, the εuccinate salt, or fumarate salt.
In another embodiment, the compound has the structure:
In an additional embodiment, R3 is H.
In a ' further embodiment, R3 is Me,
In yet another embodiment, the compound haε the structure:
In still another embodiment, R3 is H.
In one embodiment, R3 iε Me
In a further embodiment, n iε 0
Additionally, the subject invention provides a compound having the structure:
wherein the compound is an optically pure enantiomer; wherein R2 is OH; wherein R2 is H; wherein R3 iε H or C3 to C6 alkyl; wherein n is 0 or 1 ; and wherein m iε 1 or 2 , or a pharmaceutically acceptable salt thereof.
In one embodiment, the pharmaceutically acceptable salt is the acetate salt, mesylate εalt, esylate, tartarate salt, hydrogen tartarate εalt, benzoate salt, phenylbutyrate salt, phosphate salt, citrate εalt, aεcorbate salt, mandelate εalt, adipate salt, octanoate salt, the myristate salt, the succinate salt, or fumarate salt.
In a further embodiment, the compound has the structure:
In another embodiment, the compound haε the structure:
In an added embodiment, R3 is H.
In yet another embodiment, R3 is Me.
In a further embodiment, the compound haε the structure
In one embodiment, R3 iε H.
In another embodiment, R3 is Me
The εubject invention further provides a compound having the structure:
wherein R7 is H, Cα to C6 alkyl, aryl, aralkyl or C(0)R4, wherein R4 iε branched or unbranched C to C6 alkyl, aryl, aralkyl or NR£R6, wherein R5 and Rf are each independently H, C: to Ce alkyl, C6 to C12 aryl, C6 to C12 aralkyl or C6 to C12 cycloalkyl, each optionally subεtituted; wherein R3 is H or C1 to C6 alkyl; wherein R8 iε H or t-butoxycarbonyl (Boc) .
In one embodiment , the compound has the structure:
In another embodiment, the compound haε the εtructure:
In still another embodiment, the compound has the structure;
In an added embodiment, the compound has the structure:
In yet another embodiment, R4 iε Ph.
In one embodiment, the compound haε the structure:
In a further embodiment, R4 is Ph.
The subject invention additionally provides a pharmaceutical composition comprising a compound having the structure:
wherein Rx is OC(0)R9 and R2 iε H, wherein R9 is branched or unbranched Ci to C6 alkyl, aryl, or aralkyl, or R: iε OC(0)R4 and R2 iε OC(0)R4, wherein R4 iε branched or unbranched Cr to C5 alkyl, aryl, aralkyl or NR5R6, wherein R5 and R6 are each independently H, C2 to C8 alkyl, C6 to C12 aryl, C6 to C12 aralkyl or C6 to C12 cycloalkyl, each optionally substituted; wherein R3 iε H or Cα to C6 alkyl; wherein n is 0 or 1; and wherein m is 1 or 2 , or a pharmaceutically acceptable εalt thereof.
The εubject invention further provides a pharmaceutical compoεition compriεing a compound having the εtructure:
wherein Rj iε OH; wherein R2 iε H or 0C(0)R4 when α iε attached to the "a" carbon or the "d" carbon, or
R2 is 0C(0)R4 when Rx iε attached to the "b" carbon or the "c" carbon; wherein R4 is C1 to C6 branched or unbranched alkyl, aryl, aralkyl or NR5R6, wherein R5 and R6 are each independently H, Cα to C8 alkyl, Ce to C12 aryl, C6 to C12 aralkyl or C6 to C12 cycloalkyl, each optionally substituted; wherein n iε 0 or 1, and iε 1 or 2; and wherein Rj is H or Me when n iε 1 and m is 1, or R3 is H or C1 to C6 alkyl when n is 0 or m iε 2, or a pharmaceutically • acceptable εalt thereof.
The subject invention alεo provides a pharmaceutical composition comprising a compound having the εtructure:
wherein the compound is an optically pure enantiomer; wherein Rα is OH; wherein R2 iε H; wherein R3 iε H or C to C6 alkyl; wherein n iε 0 or 1; and wherein m iε 1 or 2, or a pharmaceutically acceptable εalt thereof.
The εubject invention alεo provides a method of treating a subject afflicted with a neurological disease comprising administering to the εubject a compound having the structure:
wherein Rλ is OH or OC(0)R4; wherein R2 is H, OH or 0C(0)R4, wherein R4 is branched or unbranched Cα to C6. alkyl, aryl, aralkyl or NR5R6, wherein R5 and R6 are each independently H, Cx to C8 alkyl, C6 to C12 aryl, C6 to C12 aralkyl or C6 to C12 cycloalkyl, each optionally substituted; wherein R3 iε H or Cα to C6 alkyl; wherein n iε 0 or 1; and wherein m iε 1 or 2, or a pharmaceutically acceptable salt thereof, or a prodrug which becomeε the compound in the εubject, εo as to thereby treat the neurological diεeaεe in the subject.
Additionally, the subject invention provides a method of treating a subject afflicted with a neurological disease comprising administering to the εubject a compound having the structure :
wherein Rα is OH or OC(0)R9, and R2 iε H or 0C(0)R4, or both R-L and R2 are 0C(0)R4, wherein R9 is branched or unbranched C2 to C6 alkyl, aryl, or aralkyl; wherein R4 iε branched or unbranched Cλ to C6 alkyl, aryl, aralkyl or NR5R6, wherein R5 and R6 are each independently H, Cx to C8 alkyl, C6 to Cl2 aryl, C6 to C12 aralkyl or C6 to C12 cycloalkyl, each optionally substituted; wherein R3 iε H or Cα to C6 alkyl; wherein n is 0 or 1; and
wherein m is 1 or 2, or a pharmaceutically acceptable εalt thereof, or a prodrug which becomeε the compound in the subject, εo as to thereby treat the neurological disease in the subject.
In one embodiment of the method, the compound has the εtructure:
wherein 2 iε 0C(0)R9 and R2 iε H, wherein Rs iε branched or unbranched Cx to C6 alkyl,' aryl, or aralkyl, or Rx is OC(0)R4 and R2 iε OC(0)R4, wherein R4 iε branched or unbranched Cα to C6 alkyl, aryl, aralkyl or NR5R6,
. wherein R5 and R6 are each independently H, Cj to C8 alkyl, C6 to C12 aryl, C6 to C12 aralkyl or C6 to C12 cycloalkyl, each optionally subεtituted; wherein R3 is H or Cj to C6 alkyl; wherein n is 0 or 1; and wherein m iε 1 or 2.
In another embodiment of the method, the compound haε the structure :
wherein Rτ is OH; wherein R2 is H or OC(0)R4 when Rλ is attached to the "a" carbon or the "d" carbon, or
R2 is 0C(0)R4 when R iε attached to the "b" carbon or the "c" carbon; wherein R4 is Ca to C6 branched or unbranched alkyl, ■ aryl, aralkyl or NR5R6, wherein R5 and R6 are each independently H, C-. to C8 alkyl, C6 to C12 aryl, C6 to C12 aralkyl or C6 to C12 cycloalkyl, each optionally εubεtituted; wherein R3 iε H or Cα to C6 alkyl; wherein n is 0 or 1; and wherein m iε 1 or 2.
In a further embodiment of the method, the compound has the structure:
wherein the compound iε an optically pure enantiomer; wherein x iε OH; wherein R2 iε H; wherein R3 is H or C1 to C6 alkyl; wherein n is 0 or 1; and wherein m is 1 or 2.
03 05871
-41-
In one embodiment, the εubject iε human.
In a further embodiment, the adminiεtration comprises oral, parenteral, intravenous, tranεdermal, or rectal adminiεtration.
In one embodiment, the effective amount iε from about 0.01 mg per day to about 100.0 mg per day.
In yet another embodiment, the effective amount iε from about 0.01 mg per day to about 50.0 mg per day.
In still another embodiment, the effective amount is from about 0.1 mg per day to about 100.0 mg per day.
In an added embodiment, the effective amount is from about 0.1 mg per day to about 10.0 mg per day.
In yet another embodiment, the effective amount is from about 0.01 mg to about 100.0 mg .
In one embodiment, the effective amount is from about 0.01 mg to about 50.0 mg .
In a further embodiment, the effective amount is from about 0.1 mg to about 100.0 mg.
In another embodiment, the effective amount is from about 0.1 mg to about 10.0 mg .
In an additional embodiment, the neurological disease is Parkinson's disease, Alzheimer's disease, depreεsion, epilepsy, narcolepsy, amyotrophic lateral sclerosis (ALS) , memory disorderε, panic, poεt-traumatic εtreεs disorder (PTSD), εexual dyεfunction, attention deficit and hyperactivity syndrome (ADHD), attention deficit diεorder, or Tourette's syndrome. The
diεease may also be neuropathy, hyperactive syndrome, neurotrauma, stroke, Parkinson' ε diεease, Huntington'ε diεease, and other dementia such as senile dementia, dementia .of the vascular dementia or Lewy body dementia.
In still another embodiment, the neurological disease iε depression.
In still another embodiment, the compound has the structure:
5871
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The subject invention further provides a proceεs for preparing a compound having the εtructure:
wherein n iε 0 or 1, and m is 1 or 2 ; wherein R3 is H or Cα to Cε alkyl; and wherein R9 is branched or unbranched Cx to C6 alkyl, aryl , or aralkyl ; comprising the step of reacting
or
with
in the presence of an acid or 4-dimethylaminopyridine (DMAP) to form the compound.
5871
-44- The εubject invention alεo provideε a process for preparing a compound having the εtructure:
wherein R9 is branched or unbranched Cj, to C6 alkyl, aryl, or aralkyl ; which process comprises:
(a) reacting a compound having the structure:
with a compound having the εtructure:
wherein X iε a leaving group, to produce a compound having the εtructure:
(b) reacting the compound formed in εtep (a) with a compound having the εtructure:
in the preεence of trifluoroacetic acid (TFA) and an aprotic solvent to produce a compound having the structure:
In one embodiment, the leaving group in step (a) is selected from the group consiεting of a halogen and benzene sulfonate and the aprotic solvent in step (b) is CHC13.
T U 03/05871
-46- The subject invention further provides a process for preparing a compound having the structure:
which comprises
(a) reacting a compound having the structure:
with a compound having the structure:
wherein X iε a leaving group, to produce a compound- having the εtructure:
(b) N-protecting the compound formed in εtep (a) with tert- butoxycarbonyl .(Boc) to -produce a compound having the εtructure:
03 05871
-47-
(c) reacting the compound formed in εtep (b) with a compound having the εtructure:
in the presence of 4-dimethylaminopyridine (DMAP) to produce a compound having the structure:
(d) deprotecting the compound formed in step (c) with HCl to produce a compound having the εtructure:
In one embodiment, the leaving group in step (a) is selected from the group consisting of a halogen and benzene sulfonate and the aprotic solvent in step (b) is CHC13.
The subject invention additionally provides a process for preparing a compound having the structure:
wherein R9 iε branched or unbranched τ to C6 alkyl, aryl, or aralkyl; which process comprises:
(a) reacting a compound having the structure:
with a compound having the structure:
wherein X is a leaving group, to produce a compound having the structure:
(b) reacting the compound formed in εtep (a) with NaCNBH3 and paraformaldehyde to produce a compound having the structure:
( c : reacting the compound formed in step (b) with a compound having the structure:
in the presence of trifluoroacetic acid (TFA) and an aprotic εolvent to form a compound having the structure:
In one embodiment, the leaving group in εtep (a) is εelected from the group consisting of a halogen and benzene sulfonate and the aprotic εolvent in step (c) is CHC13.
03 05871
-50-
The subject invention provides another process for preparing a compound having the structure:
wherein R9 iε branched or unbranched Cx to C6 alkyl, aryl, or aralkyl ; which process comprises:
[a) reacting a compound having the structure;
with ethyl formate to produce a compound having the structure:
(b) reacting the compound formed in step (a) with lithium aluminum hydride to produce a compound having the structure :
(c) reacting the compound formed in step (b) with a compound having the εtructure:
wherein X iε a leaving group, to form a compound having the εtructure:
reacting the compound formed in εtep (c) with a compound having the εtructure:
in the presence of trifluoroacetic acid (TFA) and an aprotic εolvent to form a compound having the εtructure:
In one embodiment, the aprotic solvent in step (c) is CHC13
The subject invention provides yet another process for preparing a compound having the structure:
wherein R9 is branched or unbranched C±- to C6 alkyl, aryl, or aralkyl ; which process comprises:
reacting a compound having the structure:
with NaCNBH3/paraformaldehyde to produce a compound having the εtructure:
(b) reacting the compound formed in εtep (a) with a compound having the structure:
wherein X iε a leaving group, to form a compound having the εtructure:
!c) reacting the compound formed in step (b) with a compound having the structure:
in the presence of trifluoroacetic acid (TFA) and an aprotic solvent to form a compound having the structure:
In one embodiment, the aprotic solvent in step (d) is CHC13
5871
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Additionally, the subject invention provides a process for preparing a compound having the structure:
which comprises:
(a) reacting a compound having the structure:
with a compound having the structure
wherein X is a leaving group, to produce a compound having the structure:
(b) reacting the compound formed in step (a) with NaCNBH3 and paraformaldehyde to produce a compound having the structure :
Ic) reacting the compound formed in step (b) with a compound having the structure:
in the preεence of 4-dimethylaminopyridine (DMAP) and an aprotic εolvent to form a compound having the structure:
In one embodiment, the leaving group in step (a) is selected from the group consisting of a halogen and benzene sulfonate and the aprotic εolvent in step (c) is CHC13.
The εubject invention provides another process for preparing a compound having the structure:
which comprises:
(a) reacting a compound having the structure:
,
with ethyl formate to produce a compound having the structure :
(b) reacting the compound formed in step (a) with lithium aluminum hydride to produce a compound having the structure:
(c) reacting the compound formed in εtep (b) with a compound having the structure:
wherein X is a leaving group, to form a compound having the structure:
(d) reacting the compound f ormed in εtep ( c) with a compound having the structure :
in the presence of 4-dimethylaminopyridine (DMAP) and an aprotic solvent to form a compound having the structure:
In one embodiment, the aprotic solvent in step (c) iε CHCl,
The subject invention provideε yet another process for preparing a compound having the structure:
which comprises:
(a) reacting a compound having the εtructure:
.
with NaCNBH3/para ormaldehyde to produce a compound having the εtructure:
(b) reacting the compound formed in step (a) with a compound having the structure:
wherein X is a leaving group, to form a compound having the structure:
[c) reacting the compound formed in step (b) ' with a compound having the εtructure:
in the presence of 4-dimethylaminopyridine (DMAP) and an aprotic εolvent to form a compound having the structure:
In one embodiment, the aprotic εolvent in step (d) iε CHC13.
The εubject invention further provides a process for preparing a compound having the structure:
which comprises
(a) reacting a compound having the structure:
with A1C13 or BBr3 in the presence of toluene to produce a compound having the structure:
(b) reacting the product formed in εtep (a) with benzyl chloride and K2C03 in the presence of dimethyl for amide (DMF) to produce a compound having the structure: .
(c) reacting the product formed in εtep (b) with MeNH2ΗCl, NaCNBH3 in tetrahydrofuran (THF) /MeOH to produce a compound having the structure:
(d) reacting the product formed in step (c) with H2, Pd/C and MeOH to produce a compound having the structure:
(e) reacting the product formed in εtep (d) with Boc20, dioxane/H20 and NaHC03 to produce a compound having the εtructure :
(f) reacting the product formed in step (e) with R4COCl, Et3N in CH2C12 in the presence of 4-dimethylaminopyridine (DMAP) to produce a compound having the structure:
(g) reacting the product formed in εtep (f) with HCl/dioxane to produce a compound having the structure:
(h) reacting the product formed in εtep (g) with propargyl bromide, K2C03 in CH3CN and then with HCl/ether and MeOH to produce a compound having the εtructure:
Also, the εubject invention provides a process for preparing a compound having the εtructure:
which comprises
(a) reacting a compound having the structure:
with AlClj or BBr3 in the presence of toluene to produce a compound having the structure:
03 05871
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(b) reacting the product formed in step (a) with benzyl chloride and K2C03 in the presence of dimethyl formamide (DMF) to produce a compound having the structure: .
(c) reacting the product formed in εtep (b) with MeNH2ΗCl, NaCNBH3 in tetrahydrofuran (THF) /MeOH to produce a compound having the εtructure:
(d) reacting the product formed in εtep (c) with H2, Pd/C and MeOH to produce a compound having the εtructure:
(e) reacting the product formed in step (d) with Boc20, dioxane/H20 and NaHC03 to produce a compound having the structure:
(f) reacting the product formed in step (e) with PhCOCl, Et3N in CH2C12 in the presence of 4-dimethylaminopyridine (DMAP) to produce a compound having the structure:
boc
(g) reacting the product formed in step (f) with HCl/dioxane to produce a compound having the structure:
(h) 'reacting the product formed in step (g) with propargyl bromide, K2C03 in CH3CN and then with HCl/ether and MeOH to produce a compound having the εtructure:
The εubject invention further provides the use of a compound or a prodrug of a compound which becomeε the compound having the structure:
wherein Ra is OH or OC(0)R4; wherein R2 is H, OH or OC(0)R4, wherein R4 iε branched or unbranched C1 to C€ alkyl, aryl, aralkyl or NR5R6, wherein R5 and R6 are each independently H, Cx to C8 alkyl, C6 to C12 aryl, C6 to Cα2 aralkyl or C6 to C12 cycloalkyl, each optionally substituted; wherein R3 iε H or Cα to C6 alkyl; wherein n is 0 or 1; and wherein m is 1 or 2, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a εubject afflicted with a neurological disease, wherein the compound is to be periodically administered to the subject in a therapeutically effective doεe.
The subject invention alεo provides the use of a compound or a prodrug of a compound which becomeε the compound having the structure:
wherein R iε OH or OC(0)R9, and wherein R9 iε branched or unbranched Cx to C6 alkyl, aryl, or aralkyl; R2 iε H or 0C(0)R4, or both R and R2 are OC(0)R4, wherein R4 iε branched or unbranched CT, to C6 alkyl, aryl, aralkyl or NR5R6, wherein R5 and R6 are each independently H, C1 to C8 alkyl, C6 to C12 aryl, C6 to C12 aralkyl or C6 to C12 cycloalkyl, each optionally substituted; wherein R3 iε H or Ca to C6 alkyl; wherein n is 0 or 1; and wherein m is 1 or 2, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating neurological diεease in a εubject, wherein the compound is to be periodically administered to the subject in a therapeutically effective dose. e embodiment of the use, the compound has the structure:
wherein Rx is OC(0)R9 and R2 is H, wherein R9 is branched or unbranched C: to C£ alkyl, aryl, or aralkyl, or Ri is OC(0)R4 and R2 is OC(0)R4, wherein R4 iε branched or unbranched C: to C6 alkyl, aryl, aralkyl or NR5R6, wherein R5 and R6 are each independently H, Cα to Cs alkyl, C6 to C12 aryl, C5 to C12 aralkyl or C6 to C12 cycloalkyl, each optionally εubstituted; wherein R, is H or Cj to C6 alkyl; wherein n is 0 or 1; and wherein iε 1 or 2.
In another embodiment of the use, the compound haε the structure :
wherein Rj is OH; wherein R2 is H or OC(0)R4 when R is attached to the "a" carbon or the "d" carbon, or
R2 is OC(0)R4 when R: is attached to the "b" carbon or the "c" carbon; wherein R4 is Cj, to C6 branched or unbranched alkyl, • aryl, aralkyl or NR5R6, wherein R5 and R6 are each independently H, Ci to Cε alkyl, C6 to C12 aryl, C6 to C12 aralkyl or C6 to C12 cycloalkyl, each optionally substituted; wherein R3 is H or C1 to C5 alkyl; wherein n is 0 or 1; and
wherein m iε 1 or 2
In an additional embodiment of the use, the compound .has the structure:
wherein the compound iε an optically pure enantiomer; wherein R1 iε OH; wherein R2 is H; wherein R3 is H or Cj to C6 alkyl; wherein n is 0 or 1; and wherein m is 1 or 2.
In a further embodiment of the use, the sub ect is human.
In yet another embodiment of the use, the medicament is formulated for oral, parenteral, intravenous, transdermal, or rectal administration.
In an embodiment of the use, the therapeutically effective amount is from about 0.01 mg per day to about 50.0 mg per day.
In an added embodiment of the use, the therapeutically effective amount is from about 0.1 mg per day to about 100.0 mg per day.
In -still another embodiment of the use, the therapeutically effective amount is from about 0.1 mg per day to about 10.0 mg per day .
In an embodiment of the use, the neurological disease is Parkinson's disease, Alzheimer's diεeaεe, depression, epilepsy, narcolepsy, amyotrophic lateral sclerosis (ALS) , . memory disorders, panic, poεt-traumatic εtreεε diεorder (PTSD), εexual dysfunction, attention deficit and hyperactivity εyndrome (ADHD), attention deficit disorder, or Tourette's εyndrome.
In a further embodiment of the use, the neurological disease iε depresεion. In one embodiment, the compound haε the structure:
The εubject invention thuε discloεeε various derivatives and isomers of hydroxylated propargylamino indan and tetralin which have surpriεingly varied potency and εelectivity for MAO inhibition. The εubject invention also provideε modificationε of the hydroxy compoundε which have surprisingly varied MAO inhibitory propertieε depending upon the substitution pattern, however, the hydroxy compound iε alwayε a more potent inhibitor than the modified verεion. Thuε, the modified version may be considered a prodrug of the more active hydroxy compound into which it will be metabolized in vivo .
In one embodiment of the invention, the prodrug compound iε a carboxylic acid eεter of the hydroxy compound. In another embodiment, the parent is a carbamate derivative of the hydroxy compound.
As discusεed above, carbamate propargylamino indans and
tetralinε have been reported in PCT International Application No. PCT/US97/24155 aε both MAO inhibitorε and AchE inhibitors. However, it is a further embodiment of this invention that such a prodrug compound will not be a potent inhibitor of AchE (IC5C. >500 micromolar) , and the IC50 for MAO-A inhibition of the corresponding hydroxy metabolite be at least 100 times more potent than the prodrug.
In one embodiment, the compoundε are dihydroxy derivativeε of propargylamino indan or tetralin. These derivativeε are expected to be antioxidants, as well aε MAO inhibitorε. In another embodiment, the subject invention provideε ester prodrugε .
Thuε, the εubject invention provideε esters or carbamates of propargylamino indanols, propargylamino indandiolε, propargylamino tetralinolε or propargylamino tetralindiolε , and may be prepared by methodε of esterification or carbamoylation of hydroxy compounds. Ester derivatives (Figur.e 1) when R2 equals hydrogen were prepared by reacting the propargylamino indanolε with acyl chlorideε in the presence of a εtrong organic acid such aε trifluoroacetic acid or an acylation catalyεt εuch aε 4-dimethylaminopyridine (DMAP) , with or without an inert organic εolvent εuch aε chloroform. Compounds when R3 equals hydrogen were prepared either by direct acylation as described above, or by firεt N-protecting the amine moiety, e.g., by a tert-butoxycarbonyl (Boc) group, followed by acylation as above, and finally removing the protecting group. The preparation of compounds of the εubject invention which are carbamates iε deεcribed in PCT/US97/24155.
Propargylamino indanols may ..be prepared by reacting amino indanols with propargyl bromide in a polar organic solvent such as N,N-dimethylacetamide or acetonitrile in the presence of a base such as potassium carbonate. N-Methyl, N-propargylamino
indanolε may be prepared by reductive alkylation of propargylamino indanolε by methodε known to thoεe εkilled in the art, e.g., with NaCNBH3 and paraformaldehyde . Alternatively, N- methyl, N-propargylamino indanolε were prepared by firεt methylating amino indanols either by NaCNBH3/paraformaldehyde or by ethyl formate followed by LiAlH4 reduction, and then reacting the N-methylamino indanols thus obtained with propargyl bromide aε described above.
The N-propargyl derivatives of, inter alia , 3-amino-indan-4-ol, l-amino-indan-4-ol, 3-amino-indan-5-ol and 7-amino-5, 6, 7 , 8- tetrahydro-naphthalen-2-ol were prepared.
Compounds of the subject invention with both Rx and R2 equal to OCOR4 (see Figure 2, compound numbered 9) were prepared by propargylation of 5 , 6-di-0-benzoyl-l-methylamino-l-indan (Figure 2, compound numbered 8), as described above. 5 , 6-Di-O-benzoyl- 1-methylamino-l-indan (Figure 2, compound numbered 8) waε prepared from 5 ; 6-bis-benzyloxy-l-indanone 3 aε follows:
1) reductive amination of the compound numbered 3 in Figure 2 aε described above gave 5 , 6-biε-benzyloxy-l- indanyl )methylamine (Figure 2, compound numbered 4);
2) the compound numbered 4 in Figure 2 was debenzylated by catalytic hydrogenation and protected by the Boc group to give N-Boc-l-methylamino-indan-5 , 6-diol (Figure 2, compound numbered 6) ; and
3) Compound 6 in Figure 2 waε esterified as described above and the protecting group removed as previously described to give 5 , 6-di-O-benzoyl-l-methylamino-l-indan (Figure 2, compound numbered 8) .
The diester tetralin derivative numbered 12 (Figure 3) was prepared by esterification of the dihydroxy tetralin numbered 11 (Figure 3) .
Table 1. Chemical Data
P T/US03/05871
-78-
ster = stereochemistry pos = position mesylate salts wide range, hygroscopic
U 03/05871
-79-
Table 3. αH-NMR Data (R1 = H, R3 = Me) (300 MHz,D20)
Table 3. 1H- MR Data (F^ - H, R3 = Me) (300 MHz,D20) cont.
* DM80-d6
Table 5. MAO in vitro Data
Table 5. MAO in vitro Data cont. 1
Table 5. MAO in vitro Data cont. 2
Table 5. MAO in vitro Data cont. 3
Table 5. MAO in vitro Data cont. 4
Table 5. MAO in vitro Data cont. 5
Table 5. MAO in vitro Data cont. 6
Table 5. MAO in vitro Dala cont. 7
•
Table 5. MAO in vitro Data cont. 8
Table 6. MAO in vivo Dala
Table 6. MAO in vjvo Dala cont 1.
Table 6. MAO in vivo Dala cont 2.
U 03/05871
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Experimental Details
EXAMPLE 1: GENERAL PROCEDURE FOR PROPYN-2-YLAMINO (PROPARGYLAMINO) INDANOLS (R, = H)
A mixture of amino indanol(35 mmol) , propargyl bromide (35 mmol) and potassium carbonate (35 mmol) in DMA (100 ml) was stirred at room temperature (RT) for 24 hours. The reaction mixture was filtered, diluted with water (200 ml) and extracted with toluene (4 x 100 ml) . The organic extracts were combined, dried and evaporated to dryness under reduced pressure. The residue waε then subjected to flash column chromatography (hexane : EtOAc, 1:1) .' The free base was optionally converted to an acid addition εalt.
Alternatively, the' propargylation reaction was run in acetonitrile at elevated temperature, e.g., 60°C for 4 hours. The reaction mixture was then filtered, and the cake washed with acetonitrile. The combined layers were evaporated, to dryness, and the residue (brown oil) subjected to flash column chromatography (hexane : EtOAc, 2:1). The product (white solid) waε thuε obtained in 40 - 55 % yield.
Thuε were prepared: (R) -3-prop-2-ynylamino-5-indanol mesylate, (S) -3-prop-2-ynylamino-5-indanol mesylate, l-prop-2-ynylamino-4- indanol HCl, and 3-prop-2-ynylamino-4-indanol HCl.
EXAMPLE 2: GENERAL PROCEDURES FOR N-METHYL-PROP-2-YNYLAMINO INDANOLS (R,=Me) , EXEMPLIFIED BY 3- (METHYL-PROP-2-YNYL AMINO) -5- INDANOL
Experiment 2A
A mixture of (S) -3-prop-2-ynylamino-5-indanol (5.0 g, 26.7 mmol), paraformaldehyde (3.6 g, 30 mmol) and NaCNBH3 (1.96 g, 31.2 mmol) in abs MeOH (90 ml) was refluxed under argon for 4 hours. The crude product obtained after evaporation of the solvent was purified by flash chromatography (hexane: EtOAc, 70:30) and was converted to its HCl salt (etheral HCl: 4.2g(17.6 mmol, 66%)). H NMR (DMSO-d6) : 11.7 (br d,NH) , 9.62 (br s, OH), 6.8-7.3(3H), 4.98(m,lH), 3.98 (ABq, 2H) , 3.0 (m, IH) . 2.90(m,lH), 2.77(s,Me), 2.48(mlH), 2.40 (m, lH)ppm. αH NMR(D20) :7.29 (d,lH) , 6.95-7.02 (2H) ,5.09(m,lH) ,4.0(AB q, 2H) , 3.0 ( , IH) ,2.90 ( , IH) , 2.77 (s,Me) ,2.48 (m, IH) , 2.40 (m, lH)ppm.
Thus were prepared (R) 3- (methyl-prop-2-ynylamino) -5-indanol and 1- (methyl-prop-2-ynylamino) -4-indanol .
Example 2B: 3- (methyl-prop-2-ynylamino) -4-indanol
Experiment 2B1
3-amino-4-indanol (3.70 g, 24.8 mmol) in ethylformate (200 ml) was refluxed for 18 hr . The solvent was then removed under reduced pressure, and the residue was purifed by flash chromatography to give 4.10 g (93%) of N- (7-hydroxy-indan-1-yl) - formamide as a yellow solid.
Experiment 2B2
Lithium aluminium hydride (4.5 g) was added portionwise to stirred and cooled dry THF (100 ml) at 0°C. A solution of N-(7- hydroxy-indan-1-yl) -formamide (4.1 g) in dry THF (70 ml) waε
added while maintaining the temperature at 5-10°C The reaction mixture waε stirred at ambient temperature for 9 hr, cooled and treated with water (100 ml) . The pH was adjusted to 8-9, water (200 ml) waε added, and the mixture was extracted with ether (6 X 300 ml) . The etheral extract waε evaporated to dryness to give 3.2 g (94%) .
Experiment 2B3
3-Methylamino-4-indanol was reacted- with propargyl bromide in acetonitrile as described in Example 1.
Example 2C
7- (methyl-prop-2-ynylamino) -2-tetralinol and 6- (methyl-prop-2- ynyla ino) -2 , 3-tetralindiol were prepared according to Chumpradit et al . and Horn et al .
EXAMPLE 3: GENERAL PROCEDURE FOR ESTERIFICATION OF PROP-2-YNYL AMINO INDANOLS AND TERALINOLS , EXEMPLIFIED BY PENTANOIC ACID (R)-3-PROP-2-YNYLAMINO-INDAN-5-YL ESTER HCL (Cmpd # 107)
To a solution of (R) 3-prop-2-ynylamino-5-indanol (2.5 g, 13.4 mmol) in CHCl3(30ml) and TFA (5 ml), was added valeryl chloride (2.03 g, 2.0 ml, 16.7 mmol) . The solution was heated at 60° for 8 hours and cooled to RT. Water (250 ml) was added, and the pH adjusted to 7 by means of concentrated aqueous ammonia. Extracted with methylene chloride (4x100 ml) , dried and evaporated to dryness under reduced pressure. The residue (brown oil, 3.65 g) was purified by flash chromatography (Si02, CH2Cl2:MeOH 99:1). The free base thus obtained (3.25 g) waε diεεolved in dry ether (80 ml), and 20% etheral HCl was added. The resulting suspension waε stirred for 2 hours at RT, the solid product was collected by filtration and washed with ether (20 ml) and dried at 60° to give 3.45 g (11.2 mmol, 85%) of the ester HCl .
EXAMPLE 4: ALTERNATIVE PROCEDURE, EXEMPLIFIED BY BENZOIC ACID (R)-3-PROP-2-YNYLAMINO-INDAN-5-YL ESTER (Cmpd # 111)
(R) 3-prop-2-ynylamino-5-indanol (3.0 g, 16 mmol) was dissolved in dry THF (75 ml), and triethylamine' (3.15 ml, 22.6 mmol) followed by Boc20(4.5 g, 20.6 mmol) was added. The solution was stirred at RT for 24 hours and evaporated to dryness. The residue waε taken up in water (200 ml) and extracted with CH2Cl2(4xl00 ml). The organic layers were combined, dried and evaporated to dryness. The crude product was purified by flash column chromatography (hexane: EtOAc 3:1) to give 3.75 g (81.5%) of a white solid.
*H NMR (DMSO-d6) (a 1:1 mixture of 2 rotamers): 9.17 (ε, OH), 7.0 (d,lH), 6.62 (dd, IH) , 6.5(br ε, IH) , 5.51 & 5.22 (brε, IH) , 4.05, 3.72, 3.60, 3.38(m,2H), 3.06(br ε, IH) , 2.83 (m,lH), 2.64 (m,lH) ,2.30 (br ε, IH, 2.10(br ε, IH) , 1.4 & 1.27 (2s, 9H)ppm.
(R) N-Boc 3-prop-2-ynylamino-5-indanol (2.65 g, 9.23 mmol) waε dissolved in dry methylene chloride (20 ml) , and triethylamine (2.65 ml, 18.5, mmol), DMAP (0.11 g, 0.9 mmol) and benzoyl chloride (1.7 ml, 18.5 mmol) was added. The solution was stirred at RT for 3 hours, water (100 ml) -was added and acidified to pH 4 (aq HCl) . The organic layer was separated and washed with 10% HCl. The aqueous layer was washed with methylene chloride (100 ml) , and the combined organic phases were dried and evaporated to dryness in vacuo. The crude product (5.2 g brown oil) was purified .by flash column chromatography (hexane: EtOAc 3:1) to give 4.1 g (90%) of a white solid.
(R) N-Boc-3-prop-2-ynylamino-5-benzoyloxy indan (2.55 g, 6.5 mmol) was dissolved in dioxan --(25 ml), and HCl/dioxan (25 ml) was added. The mixture was stirred at RT for 4 hours and the solvent was evaporated to dryness in vacuo. Ether (50 ml) was added, the suspension was then εtirred at RT for 2 hours. The
εolid was collected by filtration, washed with ether and dried (1.5 g) . The crude product was crystallized from iPrOH (90 ml) to give 1.3 g (3.96 mmol, 61%), mp 210-2°C.
EXAMPLE 5: PREPARATION OF BENZOIC ACID (S) -3- (METHYL-PROP-2- YNYL-AMINO)-INDAN-5-YL ESTER HCL Cmpd # 127
(S) 3- (methyl-prop-2-ynylamino) -5-indanol (1.5 g, 7.46 mmol) was dissolved in dry methylene chloride (15 ml), and triethylamine (2.15 ml, 15.5 mmol), DMAP (0.08 g, 0.66 mmol) and benzoyl chloride (2.1 ml, 18.1 mmol) was added. The solution waε stirred at RT for 2 hours, water (100 ml) was added and acidified to pH 4 (aq HCl) . The organic layer was separated, washed with 10% HCl. The aqueous layer waε washed wit methylene chloride (4x100 ml) , and the combined organic phases were dried evaporated to dryness in vacuo. The crude product (3.78 g brown oil) waε purified by flash column chromatography (hexane: EtOAc 4:1) to give 1.6 g (5.3 mmol, 71%) of a yellow oil. The free base was converted to the HCl salt (etheral HCl, 2 hours, RT) , 1.39g (4.07 mmol, 77%, 55% from the hydroxy compound) .
By the same proce'dure was prepared 7-0-benzoyl-2- (methyl-prop-2- ynyla ino) -tetralin Hcl, αHNMR (D20): 7.20, 6.98, 6.95 (3H, ArOCO), 8.05, 7.71, 7.53 (5H, PhCOO), 4.15 (m, 2H, CH2CCH) , 3.80 (m, IH, C7-H) , 3.15 (t, IH, CH2CCH) , 3.14, 3.01 (m, 2H, C8-H) , 2.8-3.0 ( , 2H, C5-H) , 2.31, 1.87 (m, 2H, C6-H) , 3.0 (S, 3H, Me) pp .
The same procedure was also used to prepare 6, 7-di-0-benzoyl-2- (methyl-prop-2-ynylamino) -tetralin HCl, 1HNMR (DM80-d6) : 7.91 (dd, 4H) , 7.65 (t,2H), 7.46 (t,4H), 7.28 (s, 2H) , 4.24 (br s, 2H) , 3.87 (br s, IH) , 3.74 (m, IH) , 3.35-2.90 ( , 4H) , 2.87 (s, 3H) , 2.39 (m, IH) , 1.90 (m, IH) ppm.
EXAMPLE 6: PREPARATION OF 5.6-DI-O-BENZOYL-l- (METHYL-PROP-2- YNYL-AMINO) -INDAN HCL Cmpd # 137) :
Experiment 6A: (5, 6-Bis-benzyloxy-l-indan-l-yl) -methylamine HCl (Figure 2, Compound 4) ■
A mixture of 5, 6-dibenzyloxy-l-indanone (10.0 g, 29 mmol), 8M ethanolic methylamine (30 ml, 240 mmol), methylamine HCl (7.15 g, 106 mmol), and NaCNBH3 (2.95 g, 47 mmol) in dry THF (750 ml) and methanol (250 ml) was refluxed under nitrogen for 4 hours. The reaction mixture waε cooled to 5°C, acidified with concentrated HCl to pH 1.5, and evaporated to dryness. The solid residue was treated with a mixture of methylene chloride (600 ml) and water (400 ml) . The aqueous layer was separated, extracted with methylene chloride (4x100 ml) , and the combined organic layers were evaporated to dryness. The crude product thus obtained was slurried in EtOAc (80 ml) for 30 min at RT, filtered and purified by flash column chromatography (CH2C12 : MeOH, 80:20), to give 6.3 g (54.8 %) , mp: 180-182°C.
Experiment 6B: 1- Methylamino -1-indan- 5,6-diol HCl (Figure 2, Compound 5)
A solution of (5 , 6-biε-ben'zyloxy-l-indan-l-yl) -methylamine HCl (3.15 g, 7.96 mmol) in MeOH (250 ml) was hydrogenated (44 psi) over 10% Pd/C (1.05 g) at RT for 3 hours. The mixture was filtered (Filteraid) , and the filtrate evaporated to dryness. The residue waε treated with charcoal in boiling MeOH, filtered and evaporated to dryness, to give 1.6 g of a light grey solid, mp : 153-5°C lHNMR (DM80-d6) : 9.3-8.8 (3H, br , OH, NH2) , 7.02 (s, IH, Ar) , •6.08 (s, IH, Ar) , 4.7 (dd, IH, C3-H) , 2.92 (m, IH, Cx-H) , 2.66 ( , IH, Cj-H) , 2.44 (s, 3H, Me), 2.33 (m, IH, C2-H) , 2.11 (m, IH, C2-H') ppm.
Experiment 6C: N-Boc-1- methylamino -1-indan- 5,6-diol (Figure 2 , Compound 6)
To a solution of l-methylamino-l-indan-5, 6-diol HCl (0.5 g, 2.32 mmol) in water (30 ml) was added dioxane (30 ml), NaHC03 (0.6 g) and Boc20 (0.6 g) . The reaction mixture waε stirred at RT for 4 hours under nitrogen, evaporated to dryness, and the solid residue taken up in a mixture of water (100 ml) and methylene chloride (100 ml) . The aqueous layer waε εeparated and extracted with methylene chloride (5x50 ml) . The latter waε filtered, washed with water, dried and evaporated to dryneεε to give a viscous oil which waε purified by flaεh column chromatography (CH2C12 : MeOH, 95:5) to give 0.35 g (54 %) of a viscouε oil which soon solidified.
Experiment 6D: N-Boc- ( 5, 6-di-O-benzoyl-l-indan-l-yl) -methylamine (Figure 2, Compound 7)
To a solution of N-Boc-l-methylamino-l-indan-5 , 6-diol (0.34 g, 1.22 mmol) in methylene chloride (15 ml) was added triethylamine (0.49 g, 4.88 mmol), DMAP (0.03 g, 0.244 mmol) and benzoyl chloride (0.69 g, 4.88 mmol), and the εolution was stirred at RT for 4.5 hours. Water (100 ml) was added, acidified to pH 4 with dilute HCl. The organic layer was separated and washed with 10% HCl. The aqueous layer was extracted with methylene chloride (2x75 ml.), and the latter was washed with 10% HCl. The combined organic layers were dried, evaporated to dryness, and the residue purified by flash column chromatography (hexane : EtOAc, 50:50) to give 0.50 g (40%) of a yellow oil.
5871
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Experiment 6Es (5, 6-di-O-Benzoyl-l-indan-l-yl) -methylamine HCl (Figure 2 , Compound 8)
To a εolution of N-Boc- (5 , 6-di-O-benzoyl-l-indan-l-yl) - methylamine (0.29 g, 0.59 mmol) in dioxane (5 ml) was added 20% HCl, in dioxane (5 ml) , and the mixture stirred at RT for 4 hours under nitrogen. The solvent was removed and ether (40 ml) was added to the reεidue, and the suspension stirred at RT for 1 hour. The εolvent waε removed' to give 0.11 g (89 %) of a white solid, mp : 192-3°C. lE NMR (CDC13) : 8.1-7.2 (12H, Ar) , 4.79 (br s, IH, C3-H) , 3.40 (m, IH, Ci-H) , 3.01 ( , lH.Ci-H) , 2.60 (s, 3H, Me), 2.50 ( , IH, C2-H) , 1.83 (m, IH, Ca-H') ppm.
Experiment 6F: 5 , 6-di-O-Benzoyl-l- (methyl-prop-2-ynyl-amino) - indan HCl (Figure 2, Compound 9 (Cmpd # 137))
To a εolution of (5 , 6-di-O-benzoyl-l-indan-l-yl) -methylamine HCl (-0.2 g, 0.48 mmol) in acetonitrile (100 ml) was added K2C03 (130 mg, 0.96 mmol), followed after 15 min by a εolution of propargyl bromide (56 mg, 0.48 mmol) in acetonitrile (10 ml). The reaction mixture waε εtirred under nitrogen at RT for 20 hours, filtered and evaporated to dryness. The crude product waε purified by flash column chromatography (hexane : EtOAc, 50:50) to give 0.15 g (0.35 mmol, 75 %) of a viscous light tan oil.
The free base . was disεolved in MeOH (30 ml), and saturated etheral HCl (4 ml) waε added. The solution was stirred at RT' for 30 min and evaporated to dryness. The oily residue was triturated three times in ether, to give 120 mg (0.26 mmol, 74%) • of a light tan solid. NMR (CDC13) : 8.1 - 7.2 (m, 12H, Ar) , 5.1 (br d, IH, Cl-H) , 3.91 (br s, 2H, CH2CCH) , 3.6 - 2.5 ( , 8H, indan CH2's, Me, CH,CCH) .
EXAMPLE 7 : INHIBITION OF MAO ACTIVITY IN VITRO EXPERIMENTAL PROTOCOL
The MAO enzyme source was a homogenate of rat brain in 0.3 M sucrose 1:20 w/v. The homogenate was pre-incubated with serial dilutions of the test compounds (Table 5) for 60 minutes at 37°C. 14C-labeled substrates (2-phenylethylamine, hereinafter PEA; 5-hydroxytryptamine, hereinafter 5-HT) were then added, and the incubation continued for a further 20 minutes (PEA) , or 30- 45 minutes (5-HT) . In the case of PEA, the enzyme concentration waε chosen so that not more than 10% of the εubεtrate was metabolized during the course of the reaction. The reaction was then1 stopped by addition of citric acid. Radioactivity indicates the production of 5-HT and PEA metabolites formed aε a result of MAO activity. Activity of MAO in the sample waε expressed aε a percentage of control activity in the absence of test compounds after subtraction of appropriate blank values. The activity determined using PEA as substrate is referred to aε MAO-B, and that determined using 5-HT as MAO-A.
1
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EXAMPLE 8 : INHIBITION OF MAO ACTIVITY IN VIVO : CHRONIC TREATMENT EXPERIMENTAL PROTOCOL
Ratε were treated with the teεt compounds (Table 5) at several dose levels by oral adminiεtration, one dose daily for 7-21 days, and decapitated 2 hourε after the laεt dose. The activities of MAO-A and MAO-B were determined in the brain, liver and intestine aε described in the previous example. Inhibition of MAO activity waε calculated by dividing MAO activity in the treated rats by MAO activity in the control ratέ (saline treated, MAO activity in these rats was taken as 100%) .
A mixture of toluene: ethyl acetate (1:1) waε added to the reaction and mixed for 10 minutes, followed by 5 minutes of centrifugation at 1760 g. The upper phase was taken for radioactive determination by liquid scintillation εpectrometry .
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Claims
What is claimed is;
1. A compound having the structure:
wherein Rα is OC(0)R9 and R2 is H, wherein R9 is branched or unbranched C to C6 alkyl, aryl, or aralkyl, or Rj. iε 0C(0)R4 and R2 iε OC(0)R4, wherein R4 iε branched or unbranched Cα to C6 alkyl, aryl, aralkyl or NR5R6, wherein R5 and R6 are each independently H, Cx to C8 alkyl, C6 to C12 aryl, C6 to C12 aralkyl or C6 to C12 cycloalkyl, each optionally substituted; wherein R3 iε H or Cx to C6 alkyl; wherein n iε 0 or 1; and wherein m iε 1 or 2, or a pharmaceutically acceptable salt thereof.
The compound of claim 1, wherein the pharmaceutically acceptable salt iε the acetate salt,, mesylate salt, esylate, tartarate salt, hydrogen tartarate salt, benzoate salt, phenylbutyrate salt, phosphate εalt, citrate salt, ascorbate εalt, mandelate salt, adipate salt, octanoate salt, the myristate salt, the succinate salt, or fumarate salt.
The compound of claim 1 having the structure:
The compound of claim 1 having the structure:
The compound of claim 1 having the structure:
The compound of claim 5, wherein n is 1.
7. The compound of claim 6 having the structure:
8. The compound of claim.5, wherein n is 0
9. The compound of claim 8 having the structure:
10. The compound of claim 8 having the structure:
RQ V ^s^
he compound of claim 8, wherein R9 iε Me and R3 is H.
The compound of claim 8, wherein R9 is tBu and R3 i.s H.
The compound of claim 8, wherein R9 is nBu and R3 is H.
The compound of claim 8, wherein R9 is CH2Ph and R3 is H.
The compound of claim 8, wherein R9 is Ph and R3 is H.
The compound of claim 8, wherein R9 is Me and R3 is Me..
The compound of claim 8, wherein R9 is nBu and R3 is Me.
The compound of claim 8, wherein R9 iε Ph and R3 is Me.
The compound of claim 8, wherein R9 is tBu and R3 is Me.
The compound of claim 8, wherein R9 is Ph(Me) and R3 is Me.
The compound of claim 8, wherein R9 is Ph(0Me)2 and R3 is Me.
The compound of claim 8, wherein R9 is Ph(0Me)2 and R3 is H.
he compound of claim 1 having the structure:
The compound of claim 23, wherein R3 is Me and R9 is Me.
The compound of claim 23, wherein R3 is Me and R9 iε Ph.
The compound of claim 23, wherein R3 iε Me and R9 iε Ph (OMe) 2.
The compound of claim 1 having the structure:
The compound of claim 27, wherein R3 is Me and R9 is Me.
The compound of claim 27, ••wherein R3 is H and R9 is Ph.
The compound, of claim 27, wherein R3 is H and R9 is Ph(OMe)2.
31. The compound of claim 1 having the structure:
32. The compound of claim 31, wherein n i-s 0
33. The compound of claim 32, wherein R4 is Ph and R3 is Me,
34. The compound of claim 31, wherein n iε 1
35. The compound of claim 34, wherein R3 is Me.
36. The compound of claim 31 having the structure;
5871
-116- A compound having the εtructure:
wherein R2 is OH; wherein R2 is H or OC(0)R4 when R3 is attached to the "a" carbon or the "d" carbon, or
R2 is 0C(0)R4 when Rx iε attached to the "b" carbon or the "c" carbon; wherein R4 is Cx to C6 branched or unbranched alkyl, aryl , aralkyl or NR5R6 , wherein R5 and R6 are each independently H, C1 to C8 alkyl, C6 to C12 aryl, C6 to C12 aralkyl or C6 to C12 cycloalkyl, each optionally substituted; wherein n is 0 or 1, and m iε 1 or 2; and wherein R3 is H or Me when n is 1 and m is 1, or R3 is H or Cl to C6 alkyl when n is 0 or m iε 2, or a pharmaceutically acceptable εalt thereof.
The compound of claim 37, wherein the pharmaceutically acceptable salt is the acetate salt, mesylate εalt, esylate, tartarate salt, hydrogen tartarate salt, benzoate salt, phenylbutyrate salt, phosphate salt, citrate salt, ascorbate salt, mandelate salt, adipate salt, octanoate salt, the myristate εalt, the εuccinate salt, or fu arate salt .
39. The compound of claim 37 having the structure:
40. The compound of claim 39, wherein R3 is H. .
41. The compound of claim 39, wherein R3 is Me.
42. The compound of claim 37 having the εtructure:
OH
N
F
43. The compound of claim 42, wherein R3 iε H.
44. The compound of claim 42, wherein R3 iε Me,
A compound having the structure:
wherein the compound is an optically pure enantiomer; wherein Rx is OH; wherein R is H; wherein R3 is H or Cj to C6 alkyl; wherein n is 0 or 1; .and wherein m is 1 or 2, • or a pharmaceutically acceptable salt thereof.
The compound of claim 45, wherein the pharmaceutically acceptable salt is the acetate salt, mesylate salt, esylate, tartarate εalt, hydrogen tartarate salt, benzoate salt, phenylbutyrate salt, phosphate salt, citrate salt, ascorbate salt, mandelate salt, adipate salt, octanoate salt, the myristate εalt, the εuccinate εalt, or fumarate salt.
The" compound of claim 45 having the structure:
48. The compound of claim 47 having the εtructure:
49. The compound of claim 48, wherein R3 is H.
50. The compound of claim 48, wherein R3 is Me,
51. The compound of claim 47 having the structure:
52. The compound of claim 51, wherein R3 iε H.
53. The compound of claim 51, wherein R3 iε Me,
P T/US03/05871
-120- A compound having the structure:
wherein R7 iε H, C2 to C6 alkyl, aryl, aralkyl or C(0)R4, wherein R4 iε branched or unbranched Cj to C6 alkyl, aryl, aralkyl or NR5R6, wherein R5 and R6 are each independently H, C: to Cs alkyl, C6 to C12 aryl, C6 to C1 aralkyl or C6 to C12 cycloalkyl, each optionally εubεtituted; wherein R3 iε H or CΎ to C6 alkyl; wherein R8 is H or t-butoxycarbonyl (Boc) .
The compound of claim 54 having the structure:
The compound of claim 54 having the structure:
57. The compound of claim 54 having the structure:
58. The compound of claim 54 having the structure:
59. The compound of claim 58, wherein R4 is Ph,
60. The compound of claim 54 having the structure:
61. The compound of claim 60, wherein R4 is Ph.
5871
-122- A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
A pharmaceutical composition comprising the compound of claim 37 or a pharmaceutically acceptable εalt thereof, and a pharmaceutically acceptable carrier.
A pharmaceutical composition comprising the compound of claim 45 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
A method of treating a εubject afflicted with a neurological disease comprising administering to the subject a compound having the εtructure:
wherein R1 iε OH or OC(0)R4; wherein R2 is H, OH or OC (0) R4, wherein R4 iε branched or unbranched C1 to C6 alkyl, aryl, aralkyl or NR5R6, wherein R5 and R6 are each independently H, Cx to C8 alkyl, C6 to C12 aryl, C6 to C12 aralkyl or C6 to C12 cycloalkyl, each optionally substituted; wherein R3 is H or C1 to C6 alkyl; wherein n is 0 or 1; and wherein m is 1 or 2, or a pharmaceutically acceptable salt thereof, or a prodrug which becomes the compound in the sub ect, so as to thereby treat the neurological diseaεe in the subject.
A method of treating a subject afflicted with a neurological disease comprising administering to the subject a compound having the structure :
wherein x iε OH or OC(0)R9, and wherein R9 is branched or unbranched Cα to C6 alkyl, aryl, or aralkyl;
R2 iε H or OC(0)R4, or both Rr and R2 are OC(0)R4, wherein R4 is branched or unbranched Cx to C€ alkyl, aryl, aralkyl or NR5R6, wherein R5 and R6 are each independently H, Cx to C8 alkyl, C6 to C12 aryl, C6 to C12 aralkyl or C€ to C12 cycloalkyl, each optionally εubstituted; wherein R3 iε H or Cj. to C6 alkyl; wherein n iε 0 or 1; and wherein m iε 1 or 2, or a pharmaceutically acceptable salt thereof, or a prodrug which becomes the compound in the subject, so as to thereby treat the neurological diseaεe in the subject.
The method of claim 66, wherein the compound has the εtructure:
P T/US03/05871
-124- wherein R2 is OC(0)R9 and R2 is H, wherein R9 is branched or unbranched Cα to C6 alkyl, aryl, or aralkyl, or R1 is OC(0)R4 and R2 is OC(0)R4, wherein R4 is branched or unbranched Cx to C6 alkyl, aryl, aralkyl or NR5R6, wherein R5 and R6 are each independently H, C2 to CB alkyl, C6 to C12 aryl, C6 to C1 aralkyl or C5 to C12 cycloalkyl, each optionally substituted; wherein R3 iε H or Cα to C6 alkyl; wherein n iε 0 or 1; and wherein m iε 1 or 2.
The method of claim 66, wherein the compound has the structure:
wherein Rj is OH; wherein R2 is H or OC(0)R4 when Rx is attached to the "a" carbon or the "d" carbon, or
R2 is OC(0)R4 when R3 iε attached to the "b" carbon or the "c" carbon; wherein R4 is C2 to C6 branched or unbranched alkyl, aryl, aralkyl or NR5R6, wherein R5 and R6 are each independently H, Cx to C8 alkyl, C6 to C12 aryl, C6 to C12 aralkyl or C6 to C12 cycloalkyl, each optionally substituted; wherein R3 is H or Cx to C6 alkyl; wherein n is 0 or 1; and wherein m is 1 or 2.
T U 03/05871
-125-
69. The method of claim 66, wherein the compound has the structure:
wherein the compound is an optically pure enantiomer; wherein Rα is OH; wherein R2 is H; wherein R3 is H or Cx to C6 alkyl; wherein n is 0 or 1; and wherein m is 1 or 2.
70. The method of claim 66, wherein the subject is human.
71. The method of claim 66, wherein the administration comprises oral, parenteral, intravenous, transdermal, or rectal administration.
72. The method of claim 66, wherein the effective amount is from about 0.01 mg per day to about 50.0 mg per day.
73. The method of claim 66, wherein the effective amount is from about 0.1 mg per day to about 100.0 mg per day.
T U 03/05871
-126-
74. The method of claim 73, wherein the effective amount is from about 0.1 mg per day to about 10.0 mg per day.
75. The method of claim 66, wherein the neurological diεeaεe is Parkinεon'ε . diεease, Alzheimer's disease, depreεεion, epilepεy, narcolepsy, amyotrophic lateral sclerosis (ALS) , memory disorders, panic, post-traumatic streεε diεorder
(PTSD) , sexual dysfunction, attention deficit and hyperactivity syndrome (ADHD) , attention deficit disorder, or Tourette's syndrome.
76. The method of claim 75, wherein the neurological diseaεe iε Qepreεεion.
77. The method of claim 75, wherein the compound has" the structure:
P T/US03/05871
-127-
78 A process for preparing a compound having the structure:
wherein n is 0 or 1, and m is 1 or 2; wherein' R3 iε H or Cx to C6 alkyl; and wherein R9 iε branched or unbranched C3 to C6 alkyl, aryl, or aralkyl; compriεing the εtep of reacting
or
with
in the presence of an acid or 4-dimethylaminopyridine (DMAP) to form the compound.
P T/US03/05871
-128-
79. The proceεs of claim 78 for preparing a compound having the εtructure:
wherein R9 iε branched or unbranched Ci to C6 alkyl, aryl, or aralkyl; which proceεε compriεeε:
(a) reacting a compound having the εtructure:
,
with a compound having the structure:
wherein X is a leaving group, to produce a compound having the structure:
(b) reacting the compound formed in step (a) with a compound havingι the structure:
in the presence of trifluoroacetic acid (TFA) and an aprotic solvent to produce a compound having the structure:
80. The process of claim 79, wherein the leaving group in step (a) is εelected from the group consiεting of a halogen and benzene εulfonate and the aprotic solvent in step (b) is CHC13.
T U 03/05871
-130-
81. The process of claim 78 for preparing a compound having the structure:
which comprises
[a) reacting a compound haying the structure:
with a compound having the εtructure:
wherein X is a leaving group, to produce a compound having the structure:
(b) N-protecting the compound formed in εtep (a) with tert- butoxycarbonyl (Boc) to produce a compound having the structure:
P T/US03/05871
-131-
(c) reacting the compound formed in step (b) with a compound having the structure:
in the presence of 4-dimethylaminopyridine (DMAP) to produce a compound having the εtructure:
(d) deprotecting the compound formed in εtep (c) with HCl to produce a compound having the εtructure :
82. The process of claim 81, wherein the leaving group in step (a) is εelected from the group conεiεting of a halogen and benzene sulfonate and the aprotic εolvent in step (b) is CHCl,.
The process of claim 78 for preparing a compound having the structure:
wherein R9 is branched or unbranched Cx to C6 alkyl, aryl , or aralkyl; which process comprises:
reacting a compound having the structure:
,
with a compound having the structure:
wherein X is a leaving group, to produce a compound having the εtructure:
(b) reacting the compound formed in εtep (a) with NaCNBH3 and paraformaldehyde to produce a compound having the εtructure:
(c) reacting the compound formed in step (b) with a compound having the structure:
in the presence of trifluoroacetic acid (TFA) and an aprotic solvent to form a compound having the structure:
84. The procesε of claim 83, wherein the leaving group in εtep (a) is selected from the group conεiεting of a halogen and benzene sulfonate and the aprotic solvent in step (c) iε CHC13.
55. The process of claim 78 for preparing a compound having the structure:
wherein R9 is branched or unbranched Cα to C6 alkyl, aryl, aralkyl' or NR5R6; which process compriεeε:
(a) reacting a compound having the structure:
with ethyl formate to produce a compound ■ having the structure:
(b) reacting the compound formed in εtep (a), with lithium aluminum hydride to produce a compound having the structure:
5871
-135-
!c) reacting the compound formed in εtep (b) with a compound having the εtructure:
wherein X iε a leaving group, to form a compound having the structure:
(d) reacting the compound formed in step (c) with a compound having the εtructure:
l
in the presence of trifluoroacetic acid (TFA) and an aprotic solvent to form a compound having the εtructure:
56. The process of claim 85, wherein the aprotic solvent in step (c) is CHC13.
87. The process of claim 78 for preparing a compound having the structure:
wherein R9 is branched or unbranched Cx to C6 alkyl, aryl, or aralkyl; which procesε compriεes:
(a) reacting a compound having the structure:
with NaCNBH3/paraformaldehyde to produce a compound having the structure:
(b) reacting the compound formed in step (a) with a compound having the structure:
wherein X is a leaving group, to form a compound having 'the structure:
(c) reacting the compound formed in εtep (b) with a compound having the εtructure:
in the presence of trifluoroacetic acid (TFA) and an aprotic solvent to form a compound having the structure:
88. The process of claim 87, wherein the aprotic solvent in step (d) is CHC13.
03 05871
-138- 9. The process of claim 78 for preparing a compound having the structure:
which compriseε;
(a) reacting a compound having the εtructure:
with a compound having the structure:
wherein X is a leaving group, to produce a compound having the structure:
T U 03/05871
-139-
(b) ■ reacting the compound formed in step (a) with NaCNBH3 and paraformaldehyde to produce a compound having the structure:
(c) reacting the compound formed in step (b) with a compound having the structure:
in the presence of 4-dimethylaminopyridine (DMAP) and an aprotic solvent to form a compound having the structure:
90. The method of claim 89, wherein the leaving group in step (a) iε selected from the group consisting of a halogen and benzene sulfonate and the aprotic solvent in step (c) is CHC13.
91. The process of claim 78 for preparing a compound having the structure:
which comprises:
(a) reacting a compound having the structure:
with ethyl formate to produce a compound having the structure:
(b) reacting the compound formed in step (a) with lithium aluminum hydride to produce a compound having the εtructure :
-Wife) reacting the compound formed in εtep (b) with a compound having the εtructure:
wherein X is a leaving group, to form a compound having the structure:
(d) reacting the compound formed in step (c) with a compound having the structure:
in the presence of 4-dimethylaminopyridine (DMAP) and an aprotic solvent to form a compound having the structure:
92. The process of claim 91, wherein the aprotic solvent in step (c) is CHC13.
93. The proceεε of claim 78 for preparing a compound having the εtructure:
which compriεes:
(a) reacting a compound having the structure:
with NaCNBH3/paraformaldehyde to produce a compound having the structure:
(b) reacting the compound formed in εtep (a) with a compound having the structure:
wherein X is a leaving group, to form a compound having the structure:
(c) reacting the compound formed in step (b) with a compound having, the structure:
in the presence of 4-dimethylaminopyridine ' (DMAP) and an aprotic solvent to form a compound having the structure:
94. The procesε of claim 93, wherein the aprotic solvent in step (d) is CHC13.
95. A procesε for preparing a compound having the structure:
wherein R4 is branched or unbranched C3 to C6 alkyl, aryl, aralkyl or NR5R6, wherein R5 and R6 are each independently H, Cλ to C8 alkyl, C6 to C12 aryl, C6 to C12 aralkyl or C6 to C12 cycloalkyl, each optionally subεtituted; which proceεε comprises:
(a) reacting a compound having the structure:
with A1C13 or BBr3 in the presence of toluene to produce a compound having the structure:
(b) reacting the product formed in εtep (a) with benzyl chloride and K2C03 in the presence of dimethyl formamide (DMF) to produce a compound having the structure:
(c) reacting the product formed in εtep (b) with MeNH2"HCl, NaCNBH3 in tetrahydrofuran (THF) /MeOH to produce a compound having the εtructure:
(d) reacting the product formed in εtep (c) with H2, Pd/C and MeOH to produce a compound having the structure:
(e) reacting the product formed in εtep (d) with Boc20, dioxane/H20 and NaHC03 to produce a compound having the εtructure:
(f) reacting the product formed in εtep (e) with R^COCl, Et3N in CH2C12 in the presence of 4-dimethylaminopyridine (DMAP) to produce a compound having the εtructure:
(g) reacting the product formed in step (f) with HCl/dioxane to produce a compound having the εtructure:
(h) reacting the product formed in step (g) with propargyl bromide, K2C03 in CH3CN and then with HCl/ether and MeOH to produce a compound having the structure:
96. The process of claim 95 for preparing a compound having the structure:
which comprises:
(a) reacting a compound having the εtructure:
with AlCl3 or BBr3 in the presence of toluene to produce a compound having the structure:
(b) reacting the product formed in εtep (a) with benzyl chloride and K2C03 in the presence of dimethyl formamide (DMF) to produce a compound having the structure:
(c) reacting the product formed in εtep (b) with MeNH2"HCl, NaCNBH3 in tetrahydrofuran (THF) /MeOH to produce a compound having the εtructure:
(d) reacting the product formed in εtep (c) with H2, Pd/C and MeOH to produce a compound having the structure:
(e) reacting the product formed in step (d) with Boc20, dioxane/H20 and NaHC03 to produce a compound having the structure :
reacting the product formed in step (e) with PhCOCl, Et3N in CH2C12 in the presence of 4-dimethylaminopyridine (DMAP) to produce a compound having the εtructure:
(g) reacting the product formed in εtep (f) with HCl/dioxane to produce a -compound having the εtructure:
(h) reacting the product formed in step (g) with propargyl bromide, K2C03 in CH3CN and then with HCl/ether and MeOH to produce a compound having the εtructure:
97. Uεe of a compound or a prodrug of a compound which becomeε the compound having the structure:
wherein Rα is OH or OC(0)R4; wherein R2 is H, OH or OC(0)R4, wherein R4 is branched or unbranched Cα to C6 alkyl, aryl, aralkyl or NR5R5, wherein R5 and R6 are each independently H, Cα to C8 alkyl, Cs to C12 aryl, C6 to C12 aralkyl or C6 to C12 cycloalkyl, each optionally substituted; wherein R3 is H or Cx to C6 alkyl; wherein n is 0 or 1; and wherein m is 1 or 2, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a subject afflicted with a neurological diseaεe, wherein the compound is to be periodically administered to the subject in a therapeutically effective dose.
98. Uεe of a compound or a prodrug of a compound which becomeε the compound having the εtructure:
wherein R1 is OH or OC(0)R9, and wherein R9 is branched or unbranched C1 to C6 alkyl, aryl, or aralkyl; R2 is H or OC(0)R4, or both Rj. and R2 are OC(0)R4, wherein R4 iε branched or unbranched C: to C6 alkyl, aryl, aralkyl or NR5R6, wherein R5 and R6 are each independently H, Cx to C8 alkyl, Cs to C12 aryl, C6 to C12 aralkyl or C6 to C12 cycloalkyl, each optionally εubεtituted; wherein R3 iε H or Cx to C6 alkyl; wherein n iε 0 or 1; and wherein m iε 1 or 2, or a pharmaceutically acceptable εalt thereof, for the manufacture of a medicament for treating neurological diεease in a εubject, wherein the compound is to be periodically adminiεtered to the εubject in a therapeutically effective doεe.
99. The uεe of claim 98, wherein the compound haε the εtructure:
wherein Rx is OC(0)Rg and R2 is H, wherein R9 is branched or unbranched Cx to C6 alkyl, aryl, or aralkyl, or Rx is OC(0)R4 and R2 is 0C(0)R4, wherein R4 is branched or unbranched Cx to C6 alkyl, aryl, aralkyl or NR5R6, wherein R5 and R6 are each independently H, C2 to C8 alkyl, C6 to C12 aryl, C6 to C12 aralkyl or C5 to C12 cycloalkyl, each optionally subεtituted; wherein R3 is H or Cα to C6 alkyl; wherein n iε 0 or 1; and wherein iε 1 or 2.
The use of claim 98, wherein the compound has the εtructure:
wherein R3 iε OH; wherein R2 iε H or OC(0)R4 when Rα is attached to the "a" carbon or the "d" carbon, or
R2 is 0C(0)R4 when Rλ iε attached to the "b" carbon or the "c" carbon; wherein R4 iε 0χ to C6 branched or unbranched alkyl, aryl, aralkyl or NR5R6, wherein R5 and R6 are each independently H, Cλ to CB alkyl, C6 to C12 aryl, C6 to C12 aralkyl or C6 to C12 cycloalkyl, each optionally εubεtituted; wherein R3 iε H or Cx to C6 alkyl; wherein n is 0 or 1; and wherein m is 1 or 2.
101. The use of claim 98, wherein the compound has the structure:
wherein the compound is an optically pure enantiomer; wherein R1 is OH; wherein R2 iε H; wherein R3 iε H or Cx to C6 alkyl; wherein n is 0 or 1; and wherein m is 1 or 2.
102. The use of claim 98, wherein the εubject is human.
103. The use of claim 98, wherein the medicament is formulated for oral, parenteral, intravenous, transdermal, or rectal administration.
104. The uεe of claim 98, wherein the therapeutically effective amount iε from about 0.01 mg per day to about 50.0 mg per day.
105. The uεe of claim 98, wherein the therapeutically effective amount iε from about 0.1 mg per day to about 100.0 mg per day.
106.. The use of claim 105, wherein the therapeutically effective amount is from about 0.1 mg per day to about 10.0 mg per day.
107. The uεe of claim 98, wherein the neurological diεease iε Parkinson' ε disease, Alzheimer's disease, depression, epilepsy, narcolepsy, amyotrophic lateral sclerosis . (ALS) , memory disorderε, panic, post-traumatic stress disorder
(PTSD) , εexual dyεfunction, attention deficit and hyperactivity syndrome (ADHD) , attention deficit disorder, or Tourette's syndrome.
108. The use of claim 107, wherein the neurological diεease iε depression.
109. The use of claim 108, wherein the compound has the structure:
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US8567402A | 2002-02-27 | 2002-02-27 | |
| US85674 | 2002-02-27 | ||
| PCT/US2003/005871 WO2003072055A2 (en) | 2002-02-27 | 2003-02-27 | Propargylamino indan derivatives and propargylamino tetralin derivatives as brain-selective mao inhibitors |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EP1490324A2 true EP1490324A2 (en) | 2004-12-29 |
| EP1490324A4 EP1490324A4 (en) | 2007-10-10 |
Family
ID=27765338
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP03716197A Withdrawn EP1490324A4 (en) | 2002-02-27 | 2003-02-27 | Propargylamino indan derivatives and propargylamino tetralin derivatives as brain-selective mao inhibitors |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP1490324A4 (en) |
| JP (1) | JP2005523289A (en) |
| AU (1) | AU2003219913A1 (en) |
| CA (1) | CA2477218A1 (en) |
| WO (1) | WO2003072055A2 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SI1567152T1 (en) | 2002-11-15 | 2013-10-30 | Teva Pharmaceutical Industries Ltd. | Use of rasagiline with riluzole to treat amyotrophic lateral sclerosis |
| CA2901244A1 (en) | 2005-02-23 | 2006-08-31 | Teva Pharmaceutical Industries, Ltd. | Rasagiline formulations of improved content uniformity |
| EP1848417A1 (en) | 2005-02-24 | 2007-10-31 | Teva Pharmaceutical Industries Ltd | Formulations of ladostigil tartrate |
| CN101300006B (en) | 2005-06-02 | 2012-07-25 | 叶林发现公司 | MAO-B inhibitors useful for treating obesity |
| AU2006265639A1 (en) | 2005-07-01 | 2007-01-11 | Jenrin Discovery | MAO-B inhibitors useful for treating obesity |
| EP1954667B1 (en) * | 2005-11-17 | 2017-02-08 | Teva Pharmaceutical Industries Ltd | Methods for isolating propargylated aminoindans |
| US7572834B1 (en) | 2005-12-06 | 2009-08-11 | Teva Pharmaceutical Industries, Ltd. | Rasagiline formulations and processes for their preparation |
| TW200744576A (en) | 2006-02-24 | 2007-12-16 | Teva Pharma | Propargylated aminoindans, processes for preparation, and uses thereof |
| CA2646250A1 (en) | 2006-04-03 | 2007-10-18 | Teva Pharmaceutical Industries Ltd. | Use of rasagiline for the treatment of restless legs syndrome |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1187017A (en) * | 1966-07-16 | 1970-04-08 | Aspro Nicholas Ltd | Substituted 1-Amino Indanes and Tetrahydronaphthalens |
| SE9103745D0 (en) * | 1991-12-18 | 1991-12-18 | Wikstroem Haakan | ARYL-TRIFLATES AND RELATED COMPOUNDS |
| WO1994022495A1 (en) * | 1993-03-31 | 1994-10-13 | The Trustees Of The University Of Pennsylvania | Dopamine d-3 and serotonin (5-ht1a) receptor ligands and imaging agents |
| DE69535315T2 (en) * | 1994-01-10 | 2007-06-28 | Teva Pharmaceutical Industries Ltd. | 1-AMINOINDANDERIVATE AND COMPOSITIONS HEREVON |
| AU5772396A (en) * | 1995-05-19 | 1996-11-29 | Chiroscience Limited | 3,4-disubstituted-phenylsulphonamides and their therapeutic use |
| WO1997030999A1 (en) * | 1996-02-21 | 1997-08-28 | Darwin Discovery Limited | Quinolones and their therapeutic use |
| DE69738275T2 (en) * | 1996-12-18 | 2008-08-28 | Teva Pharmaceutical Industries Ltd. | Aminoindanderivate |
-
2003
- 2003-02-27 JP JP2003570802A patent/JP2005523289A/en active Pending
- 2003-02-27 CA CA002477218A patent/CA2477218A1/en not_active Abandoned
- 2003-02-27 EP EP03716197A patent/EP1490324A4/en not_active Withdrawn
- 2003-02-27 AU AU2003219913A patent/AU2003219913A1/en not_active Abandoned
- 2003-02-27 WO PCT/US2003/005871 patent/WO2003072055A2/en not_active Ceased
Also Published As
| Publication number | Publication date |
|---|---|
| WO2003072055A3 (en) | 2003-12-31 |
| CA2477218A1 (en) | 2003-09-04 |
| JP2005523289A (en) | 2005-08-04 |
| AU2003219913A8 (en) | 2003-09-09 |
| AU2003219913A1 (en) | 2003-09-09 |
| WO2003072055A2 (en) | 2003-09-04 |
| EP1490324A4 (en) | 2007-10-10 |
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