AU2996397A - Enhancement of sleep with a growth hormone secretagogue - Google Patents
Enhancement of sleep with a growth hormone secretagogueInfo
- Publication number
- AU2996397A AU2996397A AU29963/97A AU2996397A AU2996397A AU 2996397 A AU2996397 A AU 2996397A AU 29963/97 A AU29963/97 A AU 29963/97A AU 2996397 A AU2996397 A AU 2996397A AU 2996397 A AU2996397 A AU 2996397A
- Authority
- AU
- Australia
- Prior art keywords
- aryl
- alkyl
- amino
- carbonyl
- dihydro
- 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.)
- Granted
Links
- 230000007958 sleep Effects 0.000 title claims description 101
- 239000003324 growth hormone secretagogue Substances 0.000 title claims description 67
- 102100033367 Appetite-regulating hormone Human genes 0.000 title claims description 58
- 101710111255 Appetite-regulating hormone Proteins 0.000 title claims description 54
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 64
- 150000001875 compounds Chemical class 0.000 claims description 53
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 53
- 108010051696 Growth Hormone Proteins 0.000 claims description 50
- 102000018997 Growth Hormone Human genes 0.000 claims description 50
- 239000000122 growth hormone Substances 0.000 claims description 49
- 125000003118 aryl group Chemical group 0.000 claims description 48
- -1 methylenedioxy Chemical group 0.000 claims description 45
- 238000000034 method Methods 0.000 claims description 38
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 29
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 25
- 125000000217 alkyl group Chemical group 0.000 claims description 24
- 150000003839 salts Chemical class 0.000 claims description 24
- 239000001257 hydrogen Substances 0.000 claims description 21
- 229910052739 hydrogen Inorganic materials 0.000 claims description 21
- 101710142969 Somatoliberin Proteins 0.000 claims description 20
- 239000000095 Growth Hormone-Releasing Hormone Substances 0.000 claims description 19
- 230000002708 enhancing effect Effects 0.000 claims description 18
- 229910052736 halogen Inorganic materials 0.000 claims description 17
- 150000002367 halogens Chemical class 0.000 claims description 17
- 229910052757 nitrogen Chemical group 0.000 claims description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
- 229910052717 sulfur Inorganic materials 0.000 claims description 13
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 12
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- 239000011593 sulfur Substances 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 241000124008 Mammalia Species 0.000 claims description 9
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 9
- 125000001424 substituent group Chemical group 0.000 claims description 9
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 9
- VIROVYVQCGLCII-UHFFFAOYSA-N amobarbital Chemical compound CC(C)CCC1(CC)C(=O)NC(=O)NC1=O VIROVYVQCGLCII-UHFFFAOYSA-N 0.000 claims description 8
- ZRIHAIZYIMGOAB-UHFFFAOYSA-N butabarbital Chemical compound CCC(C)C1(CC)C(=O)NC(=O)NC1=O ZRIHAIZYIMGOAB-UHFFFAOYSA-N 0.000 claims description 8
- 125000005842 heteroatom Chemical group 0.000 claims description 8
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 claims description 8
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 7
- YJPIGAIKUZMOQA-UHFFFAOYSA-N Melatonin Natural products COC1=CC=C2N(C(C)=O)C=C(CCN)C2=C1 YJPIGAIKUZMOQA-UHFFFAOYSA-N 0.000 claims description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 7
- 125000005843 halogen group Chemical group 0.000 claims description 7
- DRLFMBDRBRZALE-UHFFFAOYSA-N melatonin Chemical compound COC1=CC=C2NC=C(CCNC(C)=O)C2=C1 DRLFMBDRBRZALE-UHFFFAOYSA-N 0.000 claims description 7
- 229960003987 melatonin Drugs 0.000 claims description 7
- 239000001301 oxygen Substances 0.000 claims description 7
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical group N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 claims description 6
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 claims description 6
- 125000004429 atom Chemical group 0.000 claims description 6
- 230000012010 growth Effects 0.000 claims description 6
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 6
- HRNLPPBUBKMZMT-SSSXJSFTSA-N (2s)-6-amino-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2r)-2-[[(2r)-2-aminopropanoyl]amino]-3-naphthalen-2-ylpropanoyl]amino]propanoyl]amino]-3-(1h-indol-3-yl)propanoyl]amino]-3-phenylpropanoyl]amino]hexanamide Chemical compound C([C@H](NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](C)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(=O)[C@H](N)C)C(=O)N[C@@H](CCCCN)C(N)=O)C1=CC=CC=C1 HRNLPPBUBKMZMT-SSSXJSFTSA-N 0.000 claims description 5
- 102000004218 Insulin-Like Growth Factor I Human genes 0.000 claims description 5
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 claims description 5
- 108010085742 growth hormone-releasing peptide-2 Proteins 0.000 claims description 5
- 229960000208 pralmorelin Drugs 0.000 claims description 5
- AHOUBRCZNHFOSL-YOEHRIQHSA-N (+)-Casbol Chemical compound C1=CC(F)=CC=C1[C@H]1[C@H](COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-YOEHRIQHSA-N 0.000 claims description 4
- NWQWNCILOXTTHF-HLCSKTDOSA-N (2s)-6-amino-2-[[(2r)-2-[[(2s)-2-[[(2s)-2-[[(2r)-2-[[(2s)-2-[[(2s)-2-aminopropanoyl]amino]-3-(1h-imidazol-5-yl)propanoyl]amino]-3-naphthalen-2-ylpropanoyl]amino]propanoyl]amino]-3-(1h-indol-3-yl)propanoyl]amino]-3-phenylpropanoyl]amino]hexanamide Chemical compound C([C@H](NC(=O)[C@@H](N)C)C(=O)N[C@H](CC=1C=C2C=CC=CC2=CC=1)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCCN)C(N)=O)C1=CNC=N1 NWQWNCILOXTTHF-HLCSKTDOSA-N 0.000 claims description 4
- DIWRORZWFLOCLC-HNNXBMFYSA-N (3s)-7-chloro-5-(2-chlorophenyl)-3-hydroxy-1,3-dihydro-1,4-benzodiazepin-2-one Chemical compound N([C@H](C(NC1=CC=C(Cl)C=C11)=O)O)=C1C1=CC=CC=C1Cl DIWRORZWFLOCLC-HNNXBMFYSA-N 0.000 claims description 4
- FJIKWRGCXUCUIG-HNNXBMFYSA-N (3s)-7-chloro-5-(2-chlorophenyl)-3-hydroxy-1-methyl-3h-1,4-benzodiazepin-2-one Chemical compound O=C([C@H](O)N=1)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1Cl FJIKWRGCXUCUIG-HNNXBMFYSA-N 0.000 claims description 4
- ICPHJSKVAZMKIV-QGZVFWFLSA-N (5r)-7,8-dimethoxy-3-methyl-5-phenyl-1,2,4,5-tetrahydro-3-benzazepine Chemical compound C1([C@H]2CN(C)CCC=3C=C(C(=CC=32)OC)OC)=CC=CC=C1 ICPHJSKVAZMKIV-QGZVFWFLSA-N 0.000 claims description 4
- RTHCYVBBDHJXIQ-MRXNPFEDSA-N (R)-fluoxetine Chemical compound O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=C(C(F)(F)F)C=C1 RTHCYVBBDHJXIQ-MRXNPFEDSA-N 0.000 claims description 4
- ZEHYJZXQEQOSON-AATRIKPKSA-N (e)-1-chloro-3-ethylpent-1-en-4-yn-3-ol Chemical compound CCC(O)(C#C)\C=C\Cl ZEHYJZXQEQOSON-AATRIKPKSA-N 0.000 claims description 4
- QECAKYKTTYQVKX-RMKNXTFCSA-N (e)-3-(2,5-dihydropyrrol-1-yl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one Chemical compound COC1=C(OC)C(OC)=CC(C(=O)\C=C\N2CC=CC2)=C1 QECAKYKTTYQVKX-RMKNXTFCSA-N 0.000 claims description 4
- DWPQODZAOSWNHB-UHFFFAOYSA-N 1-(3-chlorophenyl)-3-(3-methyl-5-oxo-4H-imidazol-2-yl)urea Chemical compound CN1CC(=O)N=C1NC(=O)NC1=CC=CC(Cl)=C1 DWPQODZAOSWNHB-UHFFFAOYSA-N 0.000 claims description 4
- KYWMWUUMCDZISK-UHFFFAOYSA-N 2,2,5,5-tetrakis(trifluoromethyl)-1h-imidazol-4-amine Chemical compound NC1=NC(C(F)(F)F)(C(F)(F)F)NC1(C(F)(F)F)C(F)(F)F KYWMWUUMCDZISK-UHFFFAOYSA-N 0.000 claims description 4
- FXZJKVODWNYPKK-UHFFFAOYSA-N 3-[3-[4-(3-chlorophenyl)piperazin-1-yl]propyl]-1h-quinazoline-2,4-dione Chemical compound ClC1=CC=CC(N2CCN(CCCN3C(C4=CC=CC=C4NC3=O)=O)CC2)=C1 FXZJKVODWNYPKK-UHFFFAOYSA-N 0.000 claims description 4
- PCTRYMLLRKWXGF-UHFFFAOYSA-N 4-(butylamino)-1-ethyl-6-methyl-5-pyrazolo[3,4-b]pyridinecarboxylic acid ethyl ester Chemical compound CCCCNC1=C(C(=O)OCC)C(C)=NC2=C1C=NN2CC PCTRYMLLRKWXGF-UHFFFAOYSA-N 0.000 claims description 4
- XWVOEFLBOSSYGM-UHFFFAOYSA-N 4-morpholinyl-(3,4,5-trimethoxyphenyl)methanone Chemical compound COC1=C(OC)C(OC)=CC(C(=O)N2CCOCC2)=C1 XWVOEFLBOSSYGM-UHFFFAOYSA-N 0.000 claims description 4
- FDQGNLOWMMVRQL-UHFFFAOYSA-N Allobarbital Chemical compound C=CCC1(CC=C)C(=O)NC(=O)NC1=O FDQGNLOWMMVRQL-UHFFFAOYSA-N 0.000 claims description 4
- UMSGKTJDUHERQW-UHFFFAOYSA-N Brotizolam Chemical compound C1=2C=C(Br)SC=2N2C(C)=NN=C2CN=C1C1=CC=CC=C1Cl UMSGKTJDUHERQW-UHFFFAOYSA-N 0.000 claims description 4
- GDLIGKIOYRNHDA-UHFFFAOYSA-N Clomipramine Chemical compound C1CC2=CC=C(Cl)C=C2N(CCCN(C)C)C2=CC=CC=C21 GDLIGKIOYRNHDA-UHFFFAOYSA-N 0.000 claims description 4
- HCYAFALTSJYZDH-UHFFFAOYSA-N Desimpramine Chemical compound C1CC2=CC=CC=C2N(CCCNC)C2=CC=CC=C21 HCYAFALTSJYZDH-UHFFFAOYSA-N 0.000 claims description 4
- JMBQKKAJIKAWKF-UHFFFAOYSA-N Glutethimide Chemical compound C=1C=CC=CC=1C1(CC)CCC(=O)NC1=O JMBQKKAJIKAWKF-UHFFFAOYSA-N 0.000 claims description 4
- WYCLKVQLVUQKNZ-UHFFFAOYSA-N Halazepam Chemical compound N=1CC(=O)N(CC(F)(F)F)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 WYCLKVQLVUQKNZ-UHFFFAOYSA-N 0.000 claims description 4
- PWWVAXIEGOYWEE-UHFFFAOYSA-N Isophenergan Chemical compound C1=CC=C2N(CC(C)N(C)C)C3=CC=CC=C3SC2=C1 PWWVAXIEGOYWEE-UHFFFAOYSA-N 0.000 claims description 4
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 4
- NPPQSCRMBWNHMW-UHFFFAOYSA-N Meprobamate Chemical compound NC(=O)OCC(C)(CCC)COC(N)=O NPPQSCRMBWNHMW-UHFFFAOYSA-N 0.000 claims description 4
- JEYCTXHKTXCGPB-UHFFFAOYSA-N Methaqualone Chemical compound CC1=CC=CC=C1N1C(=O)C2=CC=CC=C2N=C1C JEYCTXHKTXCGPB-UHFFFAOYSA-N 0.000 claims description 4
- PHVGLTMQBUFIQQ-UHFFFAOYSA-N Nortryptiline Chemical compound C1CC2=CC=CC=C2C(=CCCNC)C2=CC=CC=C21 PHVGLTMQBUFIQQ-UHFFFAOYSA-N 0.000 claims description 4
- AHOUBRCZNHFOSL-UHFFFAOYSA-N Paroxetine hydrochloride Natural products C1=CC(F)=CC=C1C1C(COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-UHFFFAOYSA-N 0.000 claims description 4
- PWRPUAKXMQAFCJ-UHFFFAOYSA-N Perlapine Chemical compound C1CN(C)CCN1C1=NC2=CC=CC=C2CC2=CC=CC=C12 PWRPUAKXMQAFCJ-UHFFFAOYSA-N 0.000 claims description 4
- RMUCZJUITONUFY-UHFFFAOYSA-N Phenelzine Chemical compound NNCCC1=CC=CC=C1 RMUCZJUITONUFY-UHFFFAOYSA-N 0.000 claims description 4
- MWQCHHACWWAQLJ-UHFFFAOYSA-N Prazepam Chemical compound O=C1CN=C(C=2C=CC=CC=2)C2=CC(Cl)=CC=C2N1CC1CC1 MWQCHHACWWAQLJ-UHFFFAOYSA-N 0.000 claims description 4
- IKMPWMZBZSAONZ-UHFFFAOYSA-N Quazepam Chemical compound FC1=CC=CC=C1C1=NCC(=S)N(CC(F)(F)F)C2=CC=C(Cl)C=C12 IKMPWMZBZSAONZ-UHFFFAOYSA-N 0.000 claims description 4
- PPTYJKAXVCCBDU-UHFFFAOYSA-N Rohypnol Chemical compound N=1CC(=O)N(C)C2=CC=C([N+]([O-])=O)C=C2C=1C1=CC=CC=C1F PPTYJKAXVCCBDU-UHFFFAOYSA-N 0.000 claims description 4
- SEQDDYPDSLOBDC-UHFFFAOYSA-N Temazepam Chemical compound N=1C(O)C(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 SEQDDYPDSLOBDC-UHFFFAOYSA-N 0.000 claims description 4
- KLBQZWRITKRQQV-UHFFFAOYSA-N Thioridazine Chemical compound C12=CC(SC)=CC=C2SC2=CC=CC=C2N1CCC1CCCCN1C KLBQZWRITKRQQV-UHFFFAOYSA-N 0.000 claims description 4
- YYQRGCZGSFRBAM-UHFFFAOYSA-N Triclofos Chemical compound OP(O)(=O)OCC(Cl)(Cl)Cl YYQRGCZGSFRBAM-UHFFFAOYSA-N 0.000 claims description 4
- GDSCFOSHSOWNDL-UHFFFAOYSA-N Zolasepam Chemical compound N=1CC(=O)N(C)C(N(N=C2C)C)=C2C=1C1=CC=CC=C1F GDSCFOSHSOWNDL-UHFFFAOYSA-N 0.000 claims description 4
- 229960003148 adinazolam Drugs 0.000 claims description 4
- GJSLOMWRLALDCT-UHFFFAOYSA-N adinazolam Chemical compound C12=CC(Cl)=CC=C2N2C(CN(C)C)=NN=C2CN=C1C1=CC=CC=C1 GJSLOMWRLALDCT-UHFFFAOYSA-N 0.000 claims description 4
- 108010083553 alanyl-histidyl-(2-naphthyl)alanyl-tryptophyl-phenylalanyl-lysinamide Proteins 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 229960000880 allobarbital Drugs 0.000 claims description 4
- 229950003674 alonimid Drugs 0.000 claims description 4
- 229960004538 alprazolam Drugs 0.000 claims description 4
- 229960000836 amitriptyline Drugs 0.000 claims description 4
- KRMDCWKBEZIMAB-UHFFFAOYSA-N amitriptyline Chemical compound C1CC2=CC=CC=C2C(=CCCN(C)C)C2=CC=CC=C21 KRMDCWKBEZIMAB-UHFFFAOYSA-N 0.000 claims description 4
- 229960001301 amobarbital Drugs 0.000 claims description 4
- 229960002519 amoxapine Drugs 0.000 claims description 4
- QWGDMFLQWFTERH-UHFFFAOYSA-N amoxapine Chemical compound C12=CC(Cl)=CC=C2OC2=CC=CC=C2N=C1N1CCNCC1 QWGDMFLQWFTERH-UHFFFAOYSA-N 0.000 claims description 4
- AIZFEOPQVZBNGH-UHFFFAOYSA-N bentazepam Chemical compound C1=2C=3CCCCC=3SC=2NC(=O)CN=C1C1=CC=CC=C1 AIZFEOPQVZBNGH-UHFFFAOYSA-N 0.000 claims description 4
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- GNRXCIONJWKSEA-UHFFFAOYSA-N benzoctamine Chemical compound C12=CC=CC=C2C2(CNC)C3=CC=CC=C3C1CC2 GNRXCIONJWKSEA-UHFFFAOYSA-N 0.000 claims description 4
- IEPBPSSCIZTJIF-UHFFFAOYSA-N bis(2,2,2-trichloroethyl) carbonate Chemical compound ClC(Cl)(Cl)COC(=O)OCC(Cl)(Cl)Cl IEPBPSSCIZTJIF-UHFFFAOYSA-N 0.000 claims description 4
- 229960003051 brotizolam Drugs 0.000 claims description 4
- 229960001058 bupropion Drugs 0.000 claims description 4
- SNPPWIUOZRMYNY-UHFFFAOYSA-N bupropion Chemical compound CC(C)(C)NC(C)C(=O)C1=CC=CC(Cl)=C1 SNPPWIUOZRMYNY-UHFFFAOYSA-N 0.000 claims description 4
- 229940015694 butabarbital Drugs 0.000 claims description 4
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- 229960002546 butalbital Drugs 0.000 claims description 4
- HLSLSXBFTXUKCY-UHFFFAOYSA-N capuride Chemical compound CCC(C)C(CC)C(=O)NC(N)=O HLSLSXBFTXUKCY-UHFFFAOYSA-N 0.000 claims description 4
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- ITMSAWKLJVGBIT-UHFFFAOYSA-N carbocloral Chemical compound CCOC(=O)NC(O)C(Cl)(Cl)Cl ITMSAWKLJVGBIT-UHFFFAOYSA-N 0.000 claims description 4
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- UKFDTMNJMKWWNK-UHFFFAOYSA-N chembl2104165 Chemical compound C12=CC(Cl)=CC=C2N\C(=N\CC2CC2)C[N+]([O-])=C1C1=CC=CC=C1 UKFDTMNJMKWWNK-UHFFFAOYSA-N 0.000 claims description 4
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- 229940118803 chloral betaine Drugs 0.000 claims description 4
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- 125000001153 fluoro group Chemical group F* 0.000 claims description 4
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- SAADBVWGJQAEFS-UHFFFAOYSA-N flurazepam Chemical compound N=1CC(=O)N(CCN(CC)CC)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1F SAADBVWGJQAEFS-UHFFFAOYSA-N 0.000 claims description 4
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- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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Description
TITLE OF THE INVENTION
ENHANCEMENT OF SLEEP WITH A GROWTH HORMONE
SECRETAGOGUE
BACKGROUND OF THE INVENTION
Although sleep is necessary for survival, its precise homeostatic contribution is unknown. Sleep is not a uniform state, but rather involves several stages characterized by changes in the individual's EEG. A non rapid eye movement (NREM) type (75 to 80% of total sleep time) ranges in depth through stages 1 to 4 (deepest level). Stage 1 sleep is drowsiness, in which the EEG displays a lower voltage, more mixed frequencies and deterioration of alpha rhythm relative to the EEG when the individual is awake. In stage 2, background activity similar to that of stage 1 is experienced, with bursts of slightly higher frequency "sleep spindles" and sporadic higher amplitude slow wave complexes. The third and fourth stages of sleep display increasing high amplitude slow wave activity. The separate sleep stage in which the individual undergoes rapid eye movement (REM) occupies the remainder of the sleep time and occurs 5 to 6 times during a normal nights sleep. REM sleep is characterized by a lower voltage, higher frequency EEG and other characteristics similar to those which occur when the individual is awake, whereas the other four sleep stages are categorized as NREM sleep. Individuals vary widely in their requirements for sleep, which is influenced by a number of factors including their current emotional state. The natural aging process is associated with changes in a variety of circadian and diurnal rhythms. Age-related changes in the timing and structure of sleep are surprisingly common problems for older people, and are often associated with significant morbidity. With advancing age, the total amount of sleep tends to shorten. Stage 4 can decrease or disappear and sleep may become more fragmented and
interrupted. Evaluation of sleep patterns in elderly people shows that the timing of sleep is also phase advanced, especially in women. This tendency to go to sleep and wake up earlier is very frustrating to older people who feel that they are out of step with the rest of the world. In addition, the quality of sleep in the elderly is diminished with a marked reduction in slow wave sleep, a reduction in the deep stages of sleep (especially stage 4), fragmentation of REM sleep and more frequent awakenings. Similarly, non-elderly people may exhibit disturbances in the normal sleep process. These changes in the structure of sleep have been correlated to more frequent napping, decreased daytime alertness and declining intellectual function and cognitive ability. Deprivation of REM sleep has been suggested to interfere with the memory consolidation involved in learning skills through repetitive activity, and slow wave sleep has been implicated as being important in consolidation of events into long term memory. Likewise, decreases in the length of REM stages of sleep may be associated with a decrease in cognitive function and learning, especially diminished retention of memory.
Sleep disorders generally involve disturbances of sleep that affect a subject's ability to fall and/or stay asleep, and involve sleeping too little, too much or resulting in abnormal behavior associated with sleep.
Numerous compounds are employed in the art to facilitate normal sleep and to treat sleep disorders and sleep disturbances, including e.g., sedatives, hypnotics, anxiolytics, antipsychotics, antianxiety agents, minor tranquilizers, melatonin agonists and antagonists, melatonergic agents, benzodiazepines, barbituates, 5HT-2 antagonists, and the like. Similarly, physical methods have been employed to treat patients with sleep disorders such as the use of light therapy or the application of modulated electrical signals to selected nerves or nerve bundles. Nevertheless, the known threapeutic regimens suffer from numerous problems, including residual effects in daytime function, impairment of memory, potential for addiction, rebound insomnia, "REM rebound" which may be associated with increased dream intensity and the
occurrence of nightmares, and the like. Accordingly, a more physiological way to enhance sleep would be highly desirable.
Growth hormone, which is secreted from the pituitary, stimulates growth of all tissues of the body that are capable of growing. In addition, growth hormone is known to have the following basic effects on the metabolic processes of the body: (1) Increased rate of protein synthesis in all cells of the body; (2) Decreased rate of carbohydrate utilization in cells of the body; (3) Increased mobilization of free fatty acids and use of fatty acids for energy. A deficiency in growth hormone secretion can result in various medical disorders, depending on the age of onset. In children, the syndrome is characterized by short stature with normal body proportions and reduced growth rate (dwarfism). A deficiency in growth hormone secretion in adult life may be characterized by excessive adiposity, reduced muscle mass, impaired exercise capacity, reduced body water, decreased bone mineral density, and psychological disorders.
The temporal association of growth hormone secretion and sleep is well established. In particular, growth hormone release and slow wave sleep both predominate in the first part of sleep. Maximal growth hormone secretion is observed during stages 3 and 4 (slow wave) sleep. Additional studies, however, suggest that although slow wave sleep and growth hormone secretion occur simultaneously (and may influence each other), there may be another stimulus or series of neural events which trigger both processes. A study of the interaction between sleep and growth hormone indicates that subjects with growth hormone disturbances have abnormal REM and delta sleep and that normalization of growth hormone levels corrects the sleep stages (Astrom, Acta. Neurol. Scand...92, 281- 286 (1995); Astrom, et al., Neuroendocrinologv. 51, 82-84 (1990)). In particular, young adults with lack of growth hormone compared to normal subjects revealed increased total sleep time, decreased delta sleep time, normal total REM sleep time, and increased stage 1 and stage 2 sleep time. Young adults with high growth hormone concentration (acromegalic) compared to normal subjects revealed decresed REM sleep
time, decresed delta sleep time, and increased stage 2 and stage 1 sleep time. Administration of systemic growth hormone, however, is reported to not affect human sleep (Kern, et al., J. Clin. Endo. Metab.. 76, 1428- 1432 (1993)). Gamma-hydroxybutyrate has been reported to be useful for increasing slow-wave sleep in patients exhibiting low levels of slow wave sleep (see e.g. PCT Patent Pub. No. WO 96/40105). Effects of oral administration of a growth hormone secretagogue to healthy young men (Copinschi, et al., J. Clin. Endo. Metab.. £1(8), 2776-2782) and to healthy elderly subjects have been reported (Chapman, et al., J. Clin. Endo. Metab.. 31(12) 4249-4257 (1996).
Various ways are known to release growth hormone. For example, chemicals such as arginine, L-3,4-dihydroxyphenylalanine (L-DOPA), glucagon, vasopressin, and insulin induced hypoglycemia, as well as activities such as sleep and exercise, indirectly cause growth hormone to be released from the pituitary by acting in some fashion on the hypothalamus perhaps either to decrease somatostatin secretion or to increase the secretion of the known growth hormone secretagogue growth hormone releasing factor (GRF) or an unknown endogenous growth hormone-releasing hormone or all of these. In cases where increased levels of growth hormone were desired, the problem was generally solved by providing exogenous growth hormone or by administering GRF, IGF-I or a peptidal compound which stimulated growth hormone production and/or release. In either case the peptidyl nature of the compound necessitated that it be administered by injection. Initially the source of growth hormone was the extraction of the pituitary glands of cadavers. This resulted in a very expensive product and carried with it the risk that a disease associated with the source of the pituitary gland could be transmitted to the recipient of the growth hormone. Recombinant growth hormone has become available which, while no longer carrying any risk of disease transmission, is still a very expensive product which must be given by injection or by a nasal spray. In addition, administration of exogenous growth hormone may result in side-effects, including edema, and does not
correlate with the pulsitile release seen in the endogenous release of growth hormone.
Certain compounds have been developed which stimulate the release of endogenous growth hormone. Peptides which are known to stimulate the release of endogenous growth hormone include growth hormone releasing hormone, the growth hormone releasing peptides GHRP-6 and GHRP-1 (described in U.S. Patent No. 4,411,890, PCT Patent Pub. No. WO 89/07110, and PCT Patent Pub. No. WO 89/07111) and GHRP-2 (described in PCT Patent Pub. No. WO 93/04081), as well as hexarelin (J. Endocrinol Invest..15(Suppl 4), 45 (1992)).
Growth hormone releasing peptide-6 (GHRP-6) is believed to act via a unique pituitary and hypothalamic receptor and stimulates the release of growth hormone, cortisol and prolactin. In a study in young men, repeated intravenous boluses of GHRP-6 increased stage 2 sleep without affecting slow wave or REM sleep (Frieboes, et al.,
Neuroendocrinology. 61:584-589 (1995)). Growth hormone-releasing hormone is reported to mediate feeding-specific feedback to the suprachiasmatic circadian clock (Vaccarino, et al., Peptides. Jϋ(4), 595- 598 (1995). Although the effects of systemic administration of growth hormone-releasing hormone on sleep are not consistent, episodic administration of growth hormone-releasing hormone is reported to promote slow wave sleep and enhance REM sleep, relative to placebo or continuous infusion of growth hormone-releasing hormone (Marshall, et al., J. Clin. Endocrinol. Metab.. 81(31 1009-1013 (1996)). Nevertheless, a disadvantage of these peptidal growth hormone secretagogues is that they have very low oral bioavailability. Although oral administration of GHRP-2 is under clinical investigation, all of the other peptidal growth hormone secretagogues must be administered parenterally.
Other compounds possessing growth hormone secretagogue activity are disclosed in the following: U.S. Patent No. 3,239,345; U.S. Patent No. 4,036,979; U.S. Patent No. 4,411,890; U.S. Patent No. 5,206,235; U.S. Patent No. 5,283,241; U.S. Patent No. 5,284,841; U.S. Patent No. 5,310,737; U.S. Patent No. 5,317,017; U.S. Patent No. 5,374,721; U.S. Patent No. 5,430,144; U.S. Patent No. 5,434,261; U.S.
Patent No. 5,438,136; U.S. Patent No. 5,494,919; U.S. Patent No. 5,494,920; U.S. Patent No. 5,492,916; U.S. Patent No. 5,536,716; EPO Patent Pub. No. 0,144,230; EPO Patent Pub. No. 0,513,974; PCT Patent Pub. No. WO 94/07486; PCT Patent Pub. No. WO 94/08583; PCT Patent Pub. No. WO 94/11012; PCT Patent Pub. No. WO 94/13696; PCT Patent Pub. No. WO 94/19367; PCT Patent Pub. No. WO 95/03289; PCT Patent Pub. No. WO 95/03290; PCT Patent Pub. No. WO 95/09633; PCT Patent Pub. No. WO 95/11029; PCT Patent Pub. No. WO 95/12598; PCT Patent Pub. No. WO 95/13069; PCT Patent Pub. No. WO 95/14666; PCT Patent Pub. No. WO 95/16675; PCT Patent Pub. No. WO 95/16692; PCT Patent Pub. No. WO 95/17422; PCT Patent Pub. No. WO 95/17423; PCT Patent Pub. No. WO 95/34311; PCT Patent Pub. No. WO 96/02530; PCT Patent Pub. No. WO 96/05195; PCT Patent Pub. No. WO 96/15148; PCT Patent Pub. No. WO 96/22782; PCT Patent Pub. No. WO 96/22997; PCT Patent Pub. No. WO 96/24580; PCT Patent Pub. No. WO 96/24587; PCT Patent Pub. No. WO 96/35713; PCT Patent Pub. No. WO 96/38471 ; PCT Patent Pub. No. WO 97/00894; PCT Patent Pub. No. WO 97/06803; PCT Patent Pub. No. WO 97/07117; Science. 260. 1640-1643 (June 11, 1993); Ann- Rep. Med. Chem.. 2&, 177-186 (1993); Bioorg. Med. Chem. Ltrs.. 4(22), 2709-2714 (1994); and Proc. Natl. Acad. Sci. USA 22, 7001-7005 (July 1995). Additional compounds with growth hormone secretagogue activity are described herein.
SUMMARY OF THE INVENTION The present invention is directed to the use of a compound which has the ability to stimulate or amplify the release of natural or endogenous growth hormone or growth hormone-releasing hormone for enhancing or improving sleep quality, in particular by increasing sleep efficiency and augmenting sleep maintenance, as well as for preventing and treating sleep disorders and sleep disturbances, in a warm-blooded animal. The known threapeutic regimens regarding sleep suffer from numerous problems, including residual effects in daytime function, impairment of memory, potential for addiction, rebound insomnia, "REM rebound" which may be associated with increased dream intensity and the
occurrence of nightmares, and the like. An advantage of the present method is that it provides a physiological-like pulsatile profile of growth hormone release from the pituitary gland and further provides for the release of growth hormone-releasing hormone. Accordingly, the present invention provides a method for enhancing or improving sleep quality and increasing sleep efficiency and sleep maintenance in a warm-blooded animal comprising the administration of a growth hormone secretagogue. The present invention further provides a pharmaceutical composition for enhancing or improving sleep quality and increasing sleep efficiency and sleep maintenance.
DESCRIPTION OF THE INVENTION
The present invention is directed to the use of a compound which has the ability to stimulate or amplify the release of natural or endogenous growth hormone for enhancing or improving sleep quality as well as preventing and treating sleep disorders and sleep disturbances in a warm-blooded animal. In particular, the present invention provides a method for enhancing or improving sleep quality by increasing sleep efficiency and augmenting sleep maintenance. In addition, the present invention provides a method for preventing and treating sleep disorders and sleep disturbances in a warm-blooded animal which comprising the administration of a growth hormone secretagogue. The present invention further provides a pharmaceutical composition for enhancing or improving sleep quality and increasing sleep efficiency and sleep maintenance
The following outcomes in a subject which are provided by the present invention may be correlated to enhancement in sleep quality: an increase in the value which is calculated from the time that a subject sleeps divided by the time that a subject is attempting to sleep; a decrease in sleep latency (the time it takes to fall asleep); a decrease in difficulties in falling asleap; a decrease in the number of awakenings during sleep; a decrease in nocturnal arousals; a decrease in the time spent awake following the initial onset of sleep; an increase in the total amount of sleep; an increase the amount and percentage of REM sleep; an increase
in the duration and occurrence of REM sleep; a reduction in the fragmentation of REM sleep; an increase in the amount and percentage of slow-wave (i.e. stage 3 or 4) sleep; an increase in the amount and percentage of stage 2 sleep; an enhancement of EEG-delta activity during sleep; a decrease in the number of awakenings; a decrease in nocturnal arousals, especially early morning awakenings; an increase in daytime alertness; an increased satisfaction with the intensity of sleep; and increased sleep maintenance. Secondary outcomes which may be provided by the present invention include enhanced cognitive function and increased memory retention.
The present invention is further useful for the prevention and treatment of sleep disorders and sleep disturbances including sleep problems associated with insomnia, hypersomnia, sleep apnea, narcolepsy, nocturnal myoclonus, REM sleep interruptions, jet-lag, shift workers' sleep disturbances, dysomnias, night terror, insomnias associated with depression or with emotional/mood disorders, as well as sleep walking and enuresis, as well as sleep disorders which accompany aging. Sleep disorders and sleep disturbances are generally characterized by difficulty in initiating or maintaining sleep or in obtaining restful or enough sleep. Similarly, the present invention is useful for treating conditions associated with circadian rhythmicity as well as mental and physical disorders associated with travel across time zones and with rotating shift-work schedules. In addition, certain drags may also cause reductions in REM sleep as a side effect and the present invention may be used to correct those types of sleeping disorders as well. The present invention would also be of benefit in the treatment of syndromes such as fϊbromyalgia which are manifested by non-restorative sleep and muscle pain or sleep apnea which is associated with respiratory disturbances during sleep. In this case, the release of growth hormone associated with the growth hormone secretagogue may also improve respiratory function as a result of increased muscle strength and tone associated with growth hormone release. It will be clear to one skilled in the art that the present invention is not limited to just sleep disorders and sleep disturbances, but
is applicable to a wide variety of conditions which result from a diminished quality of sleep.
In the present invention, it is preferred that the subject mammal is a human. Although the present invention is applicable both old and young people, it would find greater application in elderly people. Further, although the invention may be employed to enhance the sleep of healthy people, it may be especially beneficial for enhancing the sleep quality of people suffering from sleep disorders or sleep disturbances. By the term "growth hormone secretagogue" is meant any exogenously administered compound or agent that directly or indirectly stimulates or increases the endogenous release of growth hormone, growth hormone-releasing hormone or somatostatin in an animal, in particular, a human.
The growth hormone secretagogue may be peptidal or non-peptidal in nature, however, the use of a non-peptidal growth hormone secretagogue is preferred. In addition, for convenience the use of an orally active growth hormone secretagogue is preferred. In addition, it is preferred that the growth hormone secretagogue induce or amplify a pulsatile release of endogenous growth hormone. It is also preferred that the growth hormone secretagogue be able to cause the release of growth hormone at night or during the sleep cycle, especially in the first half of the night or of the sleep cycle, and even more especially in the first few hours following sleep onset, or alternatively in the period immediately preceding sleep onset. The growth hormone secretagogue may be used alone or in combination with other growth hormone secretagogues or with other agents which are known to be beneficial in the enhancement of sleep efficiency. The growth hormone secretagogue and the other agent may be coadministered, either in concomitant therapy or in a fixed combination. For example, the growth hormone secretagogue may be administered in conjunction with other compounds which are known in the art to be useful for enhancing sleep quality and preventing and treating sleep disorders and sleep disturbances, including e.g., sedatives, hypnotics, anxiolytics, antipsychotics, antianxiety agents, minor
tranquilizers, melatonin agonists and antagonists, melatonergic agents, benzodiazepines, barbituates, 5HT-2 antagonists, and the like, such as: adinazolam, allobarbital, alonimid, alprazolam, amitriptyline, amobarbital, amoxapine, bentazepam, benzoctamine, brotizolam, bupropion, busprione, butabarbital, butalbital, capuride, carbocloral, chloral betaine, chloral hydrate, chlordiazepoxide, clomipramine, cloperidone, clorazepate, clorethate, clozapine, cyprazepam, desipramine, dexclamol, diazepam, dichloralphenazone, divalproex, diphenhydramine, doxepin, estazolam, ethchlorvynol, etomidate, fenobam, flunitrazepam, flurazepam, fluvoxamine, fluoxetine, fosazepam, glutethimide, halazepam, hydroxyzine, imipramine, lithium, lorazepam, lormetazepam, maprotiline, mecloqualone, melatonin, mephobarbital, meprobamate, methaqualone, midaflur, midazolam, nefazodone, nisobamate, nitrazepam, nortriptyline, oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine, perphenazine, phenelzine, phenobarbital, prazepam, promethazine, propofol, protriptyline, quazepam, reclazepam, roletamide, secobarbital, sertraline, suproclone, temazepam, thioridazine, tracazolate, tranylcypromaine, trazodone, triazolam, trepipam, tricetamide, triclofos, trifluoperazine, trimetozine, trimipramine, uldazepam, venlafaxine, zaleplon, zolazepam, zolpidem, and salts thereof, and combinations thereof, and the like, or the growth hormone secretagogue may be administered in conjunction with the use of physical methods such as with light therapy or electrical stimulation.
Representative growth hormone secretagogues are disclosed in: U.S. Patent No. 3,239,345; U.S. Patent No. 4,036,979; U.S. Patent No. 4,411,890; U.S. Patent No. 5,206,235; U.S. Patent No. 5,283,241; U.S. Patent No. 5,284,841; U.S. Patent No. 5,310,737; l/.S. Patent No. 5,317,017; U.S. Patent No. 5,374,721; U.S. Patent No. 5,430,144; U.S. Patent No. 5,434,261; U.S. Patent No. 5,438,136; U.S. Patent No. 5,494,919; U.S. Patent No. 5,494,920; U.S. Patent No. 5,492,916; U.S. Patent No. 5,536,716; EPO Patent Pub. No. 0,144,230; EPO Patent Pub. No. 0,513,974; PCT Patent Pub. No. WO 89/07110; PCT Patent Pub. No. WO 89/07111; PCT Patent Pub. No. WO 93/04081; PCT Patent Pub. No. WO 94/07486; PCT Patent Pub. No. WO 94/08583; PCT Patent Pub. No.
O 94/11012; PCT Patent Pub. No. WO 94/13696; PCT Patent Pub. No. O 94/19367; PCT Patent Pub. No. WO 95/03289; PCT Patent Pub. No. O 95/03290; PCT Patent Pub. No. WO 95/09633; PCT Patent Pub. No. WO 95/11029; PCT Patent Pub. No. WO 95/12598; PCT Patent Pub. No. WO 95/13069; PCT Patent Pub. No. WO 95/14666; PCT Patent Pub. No. WO 95/16675; PCT Patent Pub. No. WO 95/16692; PCT Patent Pub. No. WO 95/17422; PCT Patent Pub. No. WO 95/17423; PCT Patent Pub. No. WO 95/34311; PCT Patent Pub. No. WO 96/02530; PCT Patent Pub. No. WO 96/05195; PCT Patent Pub. No. WO 96/15148; PCT Patent Pub. No. WO 96/22782; PCT Patent Pub. No. WO 96/22997; PCT Patent Pub. No. WO 96/24580; PCT Patent Pub. No. WO 96/24587; PCT Patent Pub. No. WO 96/35713; PCT Patent Pub. No. WO 96/38471; PCT Patent Pub. No. WO 97/00894; PCT Patent Pub. No. WO 97/06803; PCT Patent Pub. No. WO 97/07117; J. Endocrinol Invest.. 15(Suppl 4), 45 (1992)); Science. 260. 1640-1643 (June 11, 1993): Ann. Rep. Med. Chem.. 28. 177-186 (1993); Bioorg. Med. Chem. Ltrs.. 4(22), 2709-2714 (1994); and Proc. Natl. Acad. Sci. USA 92. 7001-7005 (July 1995).
A representative first class of growth hormone secretagogues is set forth in U.S. Patent No. 5,206,235 as follows:
wherein the various substituents are as defined in U.S. Patent 5,206,235.
The most preferred compounds within this first class are identified as having the following structures:
or
A representative second class of growth hormone secretagogues is set forth in U.S. Patent No. 5,283,241 and PCT Patent Publication No. 94/05634 as having the following structural formula:
wherein the various substituents are as defined in U.S. Patent 5,283,241 and PCT Patent Publication No. 94/05634.
A representative third class of growth hormone secretagogues is disclosed in PCT Patent Pub. No. WO 94/13696 as compounds of the following structural Formulas I and II:
Formula Formula wherein:
Rl is selected from the group consisting of: -Cl-ClO alkyl, -aryl, -aryl-(Cl-C6 alkyl),
-C3-C7 cycloalkyl-(Cl-C6alkyl), -Cl-C5alkyl-K-Cl-C5 alkyl, -aryl(Cθ- C5alkyl)-K-(Cl-C5 alkyl), -C3-C7 cycloalkyl(Co-C5 alkyl)-K-(Cl-C5 alkyl), wherein K is O, S(0)m, N(R2>C(0), C(0)N(R2), OC(O), C(0)0, or -CR2=CR2-, or -C≡C-, and wherein the aryl groups are as defined below and the R2 and alkyl groups may be futher substituted by 1 to 9 halogen, S(0)mR2a. 1 to 3 OR2a. or C(0)OR2a. and the aryl groups may be further substituted by phenyl, phenoxy, halophenyl, 1-3 C1-C6 alkyl, 1 to 3 halogen, 1 to 2 -OR2, methylenedioxy, -S(0)mR2, 1 to 2 -CF3, -OCF3, nitro,
-N(R2)(R2). -N(R2)C(0)R2, -C(0)OR2, -C(0)N(R2)(R2), -Sθ2N(R2)(R2), -N(R2)S(0)2 aryl, and -N(R2)Sθ2R2; R2 is selected from the group consisting of: hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, and where two C1-C6 alkyl groups are present on one atom, they may be optionally joined to form a C3-C8 cyclic ring optionally including oxygen, sulfur or NR2a',
R2a is hydrogen, or C1-C6 alkyl;
R3a and R3b are independently selected from the group consisting of: hydrogen, halogen, -C1-C6 alkyl, -OR2, cyano, -OCF3, methylenedioxy, nitro, -S(0)mR. -CF3 or -C(0)OR2 and when R3a and R3b are in an ortho arrangement, they may be joined to form a C5 to C8 aliphatic or aromatic ring optionally including 1 or 2 heteroatoms selected from oxygen, sulfur or nitrogen;
R4 and R5 are independently selected from the group consisting of: hydrogen, -C1-C6 alkyl, substituted C1-C6 alkyl wherein the substituents are selected from 1 to 5 halo, 1 to 3 hydroxy, 1 to 3 Cl-Cio alkanoyloxy, 1 to 3 C1-C6 alkoxy, phenyl, phenoxy, 2-furyl, Cl- C6 alkoxycarbonyl, -S(0)m(Cl-C6 alkyl); or R4 and R5 can be taken together to form -(CH2)rLa (CH2)s- where La is -C(R2)2-, -O-, -S(0)m-, or -N(R2)-, where r and s are independently 1 to 3 and R2 is as defined above;
R6 is hydrogen or C1-C6 alkyl;
A is:
R-.
— (CH2)X-C— (CH2)y—
^7a or
R?
— Z-(CH2)X-C — (CH2)y—
R7a wherein x and y are independently 0-3; Z is N-R2 or O; Rγ and Rγa are independently selected from the group consisting of: hydrogen, -Cl-C6 alkyl, -OR2. trifluoromethyl, phenyl, substituted C1-C6 alkyl where the substituents are selected from imidazolyl, phenyl, indolyl, p-hydroxyphenyl, -OR2, 1 to 3 fluoro, -S(0)mR2, -C(0)OR2, -C3-C7 cycloalkyl, -N(R2)(R2), -C(0)N(R2)(R2); or R7 and R7a can independently be joined to one or both of R4 and R5 groups to form alkylene bridges between the terminal nitrogen and the alkyl portion of the R7 or R7a groups, wherein the bridge contains 1 to 5 carbons atoms;
B, D, E, and F are independently selected from the group consisting of: -C(R8)(RlθK -0-, C=0, -S(0)m-, or -NR9-, such that one or two of B, D, E, or F may be optionally absent to provide a 5, 6, or 7 membered ring; and provided that B, D, E and F can be -C(R8)(Rl0)- or C=0 only when one of the remaining B, D, E and F groups is simultaneously -0-, -S(0)m-, or -NR9-, or B and D, or D and E taken together may be -N=CRlθ- or -CRio=N-, or B and D, or D and E taken together may be -CR8=CRio-, provided one of the other of B and E or F is simultaneously -O-, -S(0)nr. or -NR9-;
R8 and Rio are independently selected from the group consisting of: hydrogen, -R2, -OR2, (-CH2)q-aryl, -(CH2)q-C(0)OR2, -(CH2)q- C(0)0(CH2)q-aryl, or -(CH2)q-(lH-tetrazol-5-yl), where the aryl may be optionally substituted by 1 to 3 halo, 1 to 2 C1-C8 alkyl, 1 to 3 -OR2 or 1 to 2 -C(0)OR2;
R9 is selected from the group consisting of: -R2, -(CH2)q-aryl, -C(0)R2, -C(0)(CH2)q-aryl, -SO2R2. -Sθ2(CH2)q-aryl, -C(0)N(R2)(R2), -C(0)N(R2)(CH2)q-aryl, -C(0)OR2, l-H-tetrazol-5-yl, -SO3H, -Sθ2NHC≡N, -Sθ2N(R2)aryl,
-S02N(R2)(R2), and wherein the (CH2)q may be optionally substituted by 1 to 2 C1-C4 alkyl, and the R2 and aryl may be optionally further substituted by 1 to 3 -OR2a, -0(CH2)q aryl, 1 to 2 -C(0)OR2a, 1 to 2 -C(0)0(CH2)q aryl, 1 to 2 -C(0)N(R2a)(R2a). 1 to 2 -C(0)N(R2a)(CH2)q aryl, 1 to 5 halogen, 1 to 3 C1-C4 alkyl, 1,2,4-triazolyl, l-H-tetrazol-5-yl, -C(0)NHSθ2R2a, -S(0)mR2a, -C(0)NHS02(CH2)q-aryl, -Sθ2NHC≡N, -Sθ2NHC(0)R2a, -S02NHC(0)(CH2)qaryl, -N(R2)C(0)N(R2a)(R2a), -N(R2a)C(0)N(R2a)(CH2)q-aryl, -N(R2a)(R2a), -N(R2a)C(0)R2a, -N(R2a)C(0)(CH2)q aryl, -OC(0)N(R2a)(R2a), -OC(0)N(R2a)(CH2)q aryl, -Sθ2(CH2)qCONH-(CH2)wNHC(0)Rl 1, wherein w is 2-6 and Rl 1 may be biotin, aryl, or aryl substituted by 1 or 2 OR2, 1-2 halogen, azido or nitro;
m is 0, 1 or 2; n is 1, or 2; q may optionally be 0, 1, 2, 3, or 4; and
G, H, I and J are carbon, nitrogen, sulfur or oxygen atoms, such that at least one is a heteroatom and one of G, H, I or J may be optionally missing to afford a 5 or 6 membered heterocyclic aromatic ring; and pharmaceutically acceptable salts and individual diastereomers thereof.
O
- 17 -
Within this third class, the most preferred growth hormone secretagogues employed in the instant invention are realized in structural Formula V:
V wherein Rl is selected from the group consisting of:
R3a is H, or fluoro;
D is is selected from the group consisting of: -O-, -S-, -S(0)m-. N(R2), NSθ2(R2), NSθ2(CH2)taryl, NC(0)(R2),
NSθ2(CH2)qOH, NSθ2(CH2)qCOOR2, NS02(CH2)qC(0)-N(R2)(R2), N-S02(CH2)qC(0)-N(R2)(CH2)w0H,
HN NH
Y O
N-S02(CH2)qC(0)-N(R2)(CH2)w '
N-NH
N-SO2(CH2)q-^
N=N ' and the aryl is phenyl or pyridyl and the phenyl may be substituted by 1-2 halogen;
R2 is H, or C1-C4 alkyl; m is 1, 2; t is O, 1, or 2; q is 1, 2, or 3; w is 2, 3, 4, 5, or 6; and the pharmaceutically acceptable salts and individual diastereomers thereof.
Representative most preferred growth hormone secretagoues within this third class which may be employed in the present invention include the following:
1 ) N-[ 1 (R)-[( 1 ,2-Dihydro- 1 -methanesulfonylspiro[3H-indole-3,4'- piperidin]-r-yl)carbonyl]-2-(lH-indol-3-yl)ethyl]-2-amino-2-methyl- propanamide;
2) N-[l (R)-[( 1 ,2-Dihydro- 1 -methanecarbonylspiro[3H-indole-3,4'- piperidin]-r-yl)carbonyl]-2-(lH-indol-3-yl)ethyl]-2-amino-2-methyl- propanamide;
3) N-[l(R)-[(l,2-Dihydro-l-benzenesulfonylspiro[3H-indole-3,4,- piperidin]-r-yl)carbonyl]-2-(lH-indol-3-yl)ethyl]-2-amino-2-methyl- propanamide;
4) N-[ 1 (R)-[(3,4-Dihydro-spiro[2H- 1 -benzopyran-2,4'-piperidin]- 1 '-yl) carbonyl]-2-(lH-indol-3-yl)ethyl]-2-amino-2-methylpropanamide;
5) N-[l(R)-[(2-Acetyl-l,2,3,4-tetrahydrospiro[isoquinolin-4,4'- piperidin]-r-yl)carbonyl]-2-(indol-3-yl)ethyl]-2-amino-2-methyl- propanamide;
6) N-[l(R)-[(l,2-Dihydro-l-methanesulfonylspiro[3H-indole-3,4'- piperidin]- 1 '-yl)carbonyl j-2-(phenylmethyloxy)ethylJ-2-amino-2- methy lpropanamide ;
7) N-[l(R)-[(l,2-Dihydro-l-methanesulfonylspiro[3H-indole-3,4'- piperidin]- 1 '-yl)carbonyl]-2-(phenylmethyloxy)ethyl]-2-amino-2- methylpropanamide methanesulfonate;
8) N-[l (R)-[( 1 ,2-Dihydro- l-methanesulfonylspiro[3H-indole-3,4*- piperidin]- 1 '-yl)carbonyl]-2-(2',6'-difluorophenylmethyloxy)ethyl]-2- amino-2-methylpropanamide;
9) N- [ 1 (R)-[( 1 ,2-Dihydro- 1 -methanesulfony l-5-fluorospiro[3H-indole- 3,4'-piperidin]-r-yl)carbonyl]-2-(phenylmethyloxy)ethyl]-2-amino-2- methy lpropanamide;
10) N-[l(S)-[(l,2-Dihydro-l-methanesulfonylspiro[3H-indole-3,4'- piperidin]- 1 -yl) carbonyl]-2-(phenylmethylthio)ethyl]-2-amino-2- methy lpropanamide ;
11) N-[ 1 (R)-[( 1 ,2-Dihydro- 1 -methanesulfonylspiro[3H-indole-3,4'- piperidin]- 1 '-yl)carbonyl]-3-phenylpropyl]-2-amino-2-methyl- propanamide;
12) N-[ 1 (R)-[( 1 ,2-Dihydro- 1 -methanesulfonylspiro[3H-indole-3,4'- piperidin]- 1 '-yl)carbonyl]-3-cyclohexylpropyl]-2-amino-2-methyl- propanamide;
13) N-[ 1 (R)-[( 1 ,2-Dihydro- l-methanesulfonylspiro[3H-indole-3,4'- piperidin]- 1 '-yl)carbonyl]-4-phenylbutyl]-2-amino-2-methyl- propanamide;
14) N-[l(R)-[(l,2-Dihydro-l-methanesulfonylspiro[3H-indole-3,4'- piperidin]-r-yl)carbonyl]-2-(5-fluoro-lH-indol-3-yl)ethyl]-2-amino-2- methylpropanamide;
15) N-[l(R)-[(l,2-Dihydro-l-methanesulfonyl-5-fluorospiro[3H-indole- 3,4'-piperidin]-r-yl)carbonyl]-2-(5-fluoro-lH-indol-3-yl)ethyl]-2-amino- 2-methy lpropanamide;
16) N-[ 1 (R)-[( 1 ,2-Dihydro- 1 -(2-ethoxycarbonyl)methylsulfonylspiro- [3H-indole-3,4'-piperidin]-l'-yl)carbonyl]-2-(lH-indol-3-yl)ethyl]-2- amino-2-methylpropanamide ;
17) N-[ 1 (R)-[( 1 ,2-Dihydro- 1 , l-dioxospiro[3H-benzothiophene-3,4'- piperidin]- 1 '-yl)carbonyl]-2-(phenylmethyloxy)ethyl]-2-amino-2- methylpropanamide;
and pharmaceutically acceptable salts thereof.
Expecially preferred growth hormone secretagogues within this third class which may be employed in the present invention include:
N-[ 1 (R)-[(l ,2-dihydro- 1 -methanesulfonylspiro[3H-indole-3,4'-piperidin]- l'-yl)carbonyl]-2-(phenylmethyloxy)ethyl]-2-amino-2- methylpropanamide;
N-[l(R)-[(l,2-dihydro-l-methanesulfonylspiro[3H-indole-3,4'-piperidin]- r-yl)carbonyl]-2-(phenylmethyloxy)ethyl]-2-amino-2- methylpropanamide methanesulfonate;
and pharmaceutically acceptable salts thereof.
The most preferred compounds within this third class which may be employed in the present invention are identified as having the following structure:
and pharmaceutically acceptable salts thereof, in particular, the methanesulfonate salt.
A representative fourth class of growth hormone secretagogues is disclosed in U.S. Patent No. 5,492,916 as being compounds of the structural formula I:
Formula I
wherein the various substituents are as defined in U.S. Patent 5,492,916.
In the above structural formulas and throughout the instant specification, the following terms have the indicated meanings:
The alkyl groups specified above are intended to include those alkyl groups of the designated length in either a straight or branched configuration which may optionally contain double or triple bonds. Exemplary of such alkyl groups are methyl, ethyl, propyl, ethinyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, hexyl, isohexyl, allyl, propenyl, butenyl, butadienyl and the like. The alkoxy groups specified above are intended to include those alkoxy groups of the designated length in either a straight or branched configuration which may optionally contain double or triple bonds. Exemplary of such alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy allyloxy, propinyloxy, isobutenyloxy, 2-hexenyloxy, and the like. The term "halogen" is intended to include the halogen atom fluorine, chlorine, bromine and iodine. The term "aryl" is intended to include phenyl and naphthyl and aromatic residues of 5- and 6- membered rings with 1 to 3 heteroatoms or fused 5 or 6 membered bicyclic rings with 1 to 3 heteroatoms of nitrogen, sulfur or oxygen. Examples of such heterocyclic aromatic rings are pyridine, thiophene, benzothiophene, tetrazole, indole, N-methylindole, dihydroindole, indazole, N-formylindole, benzimidazole, thiazole, furan, pyrimidine, and thiadiazole.
Certain of the above defined terms may occur more than once in the above formula and upon such occurrence each term shall be defined independently of the other. Similarly, the use of a particular variable within a noted structural formula is intended to be independent of the use of such variable within a different structural formula.
For use in medicine, the salts of the compounds of this invention refer to non-toxic "pharmaceutically acceptable salts." Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts. Salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts include the following: Acetate, Benzenesulfonate, Benzoate, Bicarbonate, Bisulfate, Bitartrate, Borate, Bromide, Calcium, Camsylate, Carbonate, Chloride, Clavulanate, Citrate, Dihydrochloride, Edetate, Edisylate, Estolate, Esylate, Fumarate, Gluceptate, Gluconate, Glutamate, Glycollylarsanilate, Hexylresorcinate, Hydrabamine, Hydrobromide, Hydrochloride, Hydroxynaphthoate, Iodide, Isothionate, Lactate, Lactobionate, Laurate, Malate, Maleate, Mandelate, Mesylate, Methylbromide, Methylnitrate, Methylsulfate,
Mucate, Napsylate, Nitrate, N-methylglucamine ammonium salt, Oleate, Oxalate, Pamoate (Embonate), Palmitate, Pantothenate, Phosphate/diphosphate, Polygalacturonate, Salicylate, Stearate, Subacetate, Succinate, Sulfate, Sulfonate, Tannate, Tartrate, Teoclate, Tosylate, Triethiodide and Valerate. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts.
The compounds employed in the present invention, may have chiral centers and occur as racemates, racemic mixtures and as individual diastereomers, or enantiomers with all isomeric forms being included in the present invention. Therefore, where a compound is chiral,
-
24
the separate enantiomers, substantially free of the other, are included within the scope of the invention; further included are all mixtures of the two enantiomers.
Full descriptions of the preparation of the growth hormone secretagoue employed in the present invention may be found e.g., in: U.S. Patent No. 3,239,345; U.S. Patent No. 4,036,979; U.S. Patent No. 4,411,890; U.S. Patent No. 5,206,235; U.S. Patent No. 5,283,241; U.S. Patent No. 5,284,841; U.S. Patent No. 5,310,737; U.S. Patent No. 5,317,017; U.S. Patent No. 5,374,721; U.S. Patent No. 5,430,144; U.S. Patent No. 5,434,261; U.S. Patent No. 5,438,136; U.S. Patent No. 5,494,919; U.S. Patent No. 5,494,920; U.S. Patent No. 5,492,916; U.S. Patent No. 5,536,716; EPO Patent Pub. No. 0,144,230; EPO Patent Pub.
No. 0,513,974 PCT Patent Pub. No. WO 89/07110; PCT Patent Pub. No. WO 89/07111 PCT Patent Pub. No. WO 93/04081; PCT Patent Pub. No. WO 94/07486 PCT Patent Pub. No. WO 94/08583; PCT Patent Pub. No. WO 94/11012 PCT Patent Pub. No. WO 94/13696; PCT Patent Pub. No. WO 94/19367 PCT Patent Pub. No. WO 95/03289; PCT Patent Pub. No. WO 95/03290 PCT Patent Pub. No. WO 95/09633; PCT Patent Pub. No. WO 95/11029 PCT Patent Pub. No. WO 95/12598; PCT Patent Pub. No. WO 95/13069 PCT Patent Pub. No. WO 95/14666; PCT Patent Pub. No. WO 95/16675 PCT Patent Pub. No. WO 95/16692; PCT Patent Pub. No. WO 95/17422 PCT Patent Pub. No. WO 95/17423; PCT Patent Pub. No. WO 95/34311 PCT Patent Pub. No. WO 96/02530; PCT Patent Pub. No. WO 96/05195 PCT Patent Pub. No. WO 96/15148; PCT Patent Pub. No. WO 96/22782 PCT Patent Pub. No. WO 96/22997; PCT Patent Pub. No. WO 96/24580 PCT Patent Pub. No. WO 96/24587; PCT Patent Pub. No. WO 96/35713 PCT Patent Pub. No. WO 96/38471; PCT Patent Pub. No. WO 97/00894 PCT Patent Pub. No. WO 97/06803; PCT Patent Pub. No. WO 97/07117 J. Endocrinol Invest.. H(Suppl 4), 45 (1992)); Science.
260. 1640-1643 (June 11, 1993): Ann. Rep. Med. Chem.. 28. 177-186 (1993); Bioorg. Med. Chem. Ltrs.. 4(22), 2709-2714 (1994); and Proc. Natl. Acad. Sci. USA £2, 7001-7005 (July 1995), as well as herein.
Methods to obtain the growth hormone releasing peptides GHRP-6 and GHRP-1 are described in U.S. Patent Nos. 4,411,890 and
PCT Patent Publications WO 89/07110, WO 89/07111, methods to obtain the growth hormone releasing peptide GHRP-2 are described in PCT Patent Publication WO 93/04081, and methods to obtain hexarelin are described in J. Endocrinol Invest.. ϋ(Suppl 4), 45 (1992). The identification of a compound as a growth hormone secretagogue and thus able to directly or indirectly stimulate or increase the endogenous release of growth hormone in an animal may be readily determined without undue experimentation by methodology well known in the art, such as the assay described by Smith, et al., Science, 260, 1640-1643 (1993) (see text of Figure 2 therein). In a typical experiment pituitary glands are aseptically removed from 150-200 g Wistar male rats and cultures of pituitary cells are prepared according to Cheng et al. Endocrinol. , 124, 2791-2798 (1989). The cells are treated with the subject compound and assayed for growth hormone secreting activity and intracellular cAMP levels as described by Chang et al. In particular, the intrinsic growth horomone secretagogue activity of a compounds which may be used in the present invention may be determined by this assay.
The term "therapeutically effective amount" shall mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by a researcher or clinician.
Accordingly, the present invention includes within its scope the use of a growth hormone secretagogue, alone or in combination with other agents, for the prevention or treatment of sleep disorders and sleep disturbances in a warm-blooded animal. For the purposes of this disclosure, a warm-blooded animal is a member of the animal kingdom which includes but is not limited to mammals and birds. The preferred mammal for purposes of this invention is human.
Included within the scope of the present invention is the method of using a growth hormone secretagogue for enhancing and improving the quality of sleep. The growth hormone secretagogue is useful in enhancing or improving sleep quality as well as preventing and treating sleep disorders and sleep disturbances in a warm-blooded animal. In addition, the use of the growth hormone secretagogue increases sleep
efficiency and augments sleep maintenance. The growth hormone secretagogue may further be used in a a method for preventing and treating sleep disorders and sleep disturbances in a warm-blooded animal. The present invention further provides a pharmaceutical composition for enhancing or improving sleep quality and increasing sleep efficiency and sleep maintenance.
The present method of using a growth hormone secretagogue further provides the following: an increase in the value which is calculated from the time that a subject sleeps divided by the time that a subject is attempting to sleep; a decrease in sleep latency (the time it takes to fall asleep); a decrease in difficulties in falling asleap; a decrease in the number of awakenings during sleep; a decrease in nocturnal arousals; a decrease in the time spent awake following the initial onset of sleep; an increase in the total amount of sleep; an increase the amount and percentage of REM sleep; an increase in the duration and occurrence of REM sleep; a reduction in the fragmentation of REM sleep; an increase in the amount and percentage of slow- wave (i.e. stage 3 or 4) sleep; an increase in the amount and percentage of stage 2 sleep; an enhancement of EEG-delta activity during sleep; a decrease in the number of awakenings; a decrease in nocturnal arousals, especially early morning awakenings; an increase in daytime alertness; an increased satisfaction with the intensity of sleep; and increased sleep maintenance. Secondary outcomes which may be provided by the present invention include enhanced cognitive function and increased memory retention. The present invention is further useful for the prevention and treatment of sleep disorders and sleep disturbances including: sleep problems associated with insomnia, hypersomnia, sleep apnea, narcolepsy, nocturnal myoclonus, REM sleep interruptions, jet-lag, shift workers' sleep disturbances, dysomnias, night terror, insomnias associated with depression or with emotional/mood disorders, as well as sleep walking and enuresis, as well as sleep disorders which accompany aging, conditions associated with circadian rhythmicity, mental and physical disorders associated with travel across time zones and with rotating shift¬ work schedules, or syndromes such as fibromyalgia which are manifested
by non-restorative sleep and muscle pain or sleep apnea which is associated with respiratory disturbances during sleep.
This particular application of growth hormone secretagogues provides unexpected benefit relative to the administration of exogenous growth hormone. In particular, the growth hormone secretagogue enhances the normal pulsatile releases of endogenous growth hormone or growth hormone-releasing hormone and thus is more likely to reproduce the natural pattern of endogenous growth hormone release, especially with regard to increasing the level of endogenous growth hormone prior to or in during the initial onset of sleep. Growth hormone secregagogues which are orally active also have the benefit being able to be administered orally, rather than just intravenously, intraperitoneally or subcutaneously. Although the specific mechanism underlying the present invention is not currently understood, it may be possible that the growth hormone secretagogue not only stimulates the production of growth hormone which provides benefical outcomes in sleep, but it also acts to increase the levels of growth hormone-releasing hormone and/or somatostatin which then directly enhance the quality of sleep.
In addition, the present invention includes within its scope a pharmaceutical composition for enhancing and improving the quality of sleep comprising, as an active ingredient, at least one growth hormone secretagogues in association with a pharmaceutical carrier or diluent. Optionally, the active ingredient of the pharmaceutical compositions can comprise an anabolic agent in addition to at least one growth hormone secretagogue or another composition which exhibits a different activity, e.g., an antibiotic growth promoting agent or in combination with a corticosteroid to minimize the catabolic side effects or with other pharmaceutically active materials wherein the combination enhances efficacy and minimizes side effects. Growth promoting and anabolic agents include, but are not limited to, TRH, diethylstilbesterol, estrogens, β-agonists, theophylline, anabolic steroids, dehydroepiandrosterone, enkephalins, E series prostaglandins, retinoic acid, compounds disclosed in U.S. Patent No. 3,239,345, e.g., zeranol, and compounds disclosed in U.S. Patent No. 4,036,979, e.g., sulbenox. or peptides disclosed in U.S.
Patent No. 4,411,890. Similarly, the growth hormone secretagogue may be administered with somatomedin-C for the treatment of disorders characterized by non-restorative sleep, such as fibromyalgia (U.S. Patent No. 5,378,686). The present invention further includes the use of a growth hormone secretagogue in the manufacture of a medicament for enhancing and improving the quality of sleep and for the treatement of sleep disorders and sleep disturbances.
In addition, the present invention contemplates the use of a growth hormone secretagogue for enhancing and improving the quality of sleep in combination with another growth hormone secretagogues such as those referenced herein, including the growth hormone releasing peptides GHRP-6 and GHRP-1 (described in U.S. Patent No. 4,411,890 and PCT publications WO 89/07110, WO 89/07111) and GHRP-2 (described in WO 93/04081 ) and B-HT920, as well as hexarelin or growth hormone releasing hormone (GHRH, also designated GRF) and its analogs, or growth hormone and its analogs, or somatomedins including IGF-1 and IGF-2, or with α-adrenergic agonists such as clonidine or serotonin 5HTD agonists such as sumatriptan, or agents which inhibit somatostatin or its release such as physostigmine and pyridostigmine. For example, a growth hormone secretagogue may be used in combination with IGF-1 for enhancing and improving the quality of sleep.
It will be known to those skilled in the art that there are numerous compounds now being used in an effort to enhance and improve the quality of sleep. Combinations of these therapeutic agents some of which have also been mentioned herein with a growth hormone secretagogue will bring additional, complementary, and often synergistic properties to enhance the desirable properties of these various therapeutic agents. In these combinations, the growth hormone secretagogue and the therapeutic agents may be independently present in dose ranges from one one-hundredth to one times the dose levels which are effective when these compounds and secretagogues are used singly.
The growth hormone secretagogue may be administered in combination with sedatives, hypnotics, anxiolytics, antipsychotics,
antianxiety agents, minor tranquilizers, melatonin agonists and antagonists, melatonergic agents, benzodiazepines, barbituates, 5HT-2 antagonists, and the like, or the growth hormone secretagogue may be administered in conjunction with the use of physical methods such as with light therapy or electrical stimulation. For example, to enhance and improve the quality of sleep a growth hormone secretagogue may be given in combination with such compounds as: adinazolam, allobarbital, alonimid, alprazolam, amitriptyline, amobarbital, amoxapine, bentazepam, benzoctamine, brotizolam, bupropion, busprione, butabarbital, butalbital, capuride, carbocloral, chloral betaine, chloral hydrate, chlordiazepoxide, clomipramine, cloperidone, clorazepate, clorethate, clozapine, cyprazepam, desipramine, dexclamol, diazepam, dichloralphenazone, divalproex, diphenhydramine, doxepin, estazolam, ethchlorvynol, etomidate, fenobam, flunitrazepam, flurazepam, fluvoxamine, fluoxetine, fosazepam, glutethimide, halazepam, hydroxyzine, imipramine, lithium, lorazepam, lormetazepam, maprotiline, mecloqualone, melatonin, mephobarbital, meprobamate, methaqualone, midaflur, midazolam, nefazodone, nisobamate, nitrazepam, nortriptyline, oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine, peφhenazine, phenelzine, phenobarbital, prazepam, promethazine, propofol, protriptyline, quazepam, reclazepam, roletamide, secobarbital, sertraline, suproclone, temazepam, thioridazine, tracazolate, tranylcypromaine, trazodone, triazolam, trepipam, tricetamide, triclofos, trifluoperazine, trimetozine, trimipramine, uldazepam, venlafaxine, zaleplon, zolazepam, zolpidem, and salts thereof, and combinations thereof, and the like, as well as admixtures and combinations thereof.
Typically, the individual daily dosages for these combinations may range from about one-fifth of the minimally recommended clinical dosages to the maximum recommended levels for the entities when they are given singly.
To illustrate these combinations, a growth hormone secretagogue effective clinically effective clinically at a given daily dose range may be effectively combined, at levels which are equal or less than
the daily dose range, with the following compounds at the indicated per day dose range: adinazolam, allobarbital, alonimid, alprazolam, amitriptyline, amobarbital, amoxapine, bentazepam, benzoctamine, brotizolam, bupropion, busprione, butabarbital, butalbital, capuride, carbocloral, chloral betaine, chloral hydrate, chlordiazepoxide, clomipramine, cloperidone, clorazepate, clorethate, clozapine, cyprazepam, desipramine, dexclamol, diazepam, dichloralphenazone, divalproex, diphenhydramine, doxepin, estazolam, ethchlorvynol, etomidate, fenobam, flunitrazepam, flurazepam, fluvoxamine, fluoxetine, fosazepam, glutethimide, halazepam, hydroxyzine, imipramine, lithium, lorazepam, lormetazepam, maprotiline, mecloqualone, melatonin, mephobarbital, meprobamate, methaqualone, midaflur, midazolam, nefazodone, nisobamate, nitrazepam, nortriptyline, oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine, perphenazine, phenelzine, phenobarbital, prazepam, promethazine, propofol, protriptyline, quazepam, reclazepam, roletamide, secobarbital, sertraline, suproclone, temazepam, thioridazine, tracazolate, tranylcypromaine, trazodone, triazolam, trepipam, tricetamide, triclofos, trifluoperazine, trimetozine, trimipramine, uldazepam, venlafaxine, zaleplon, zolazepam, zolpidem, and salts thereof, and combinations thereof, and the like, as well as admixtures and combinations thereof. It will be readily apparent to one skilled in the art that the growth hormone secretagogue may be employed with other agents to control sleep disorders and sleep disturbances in depressed patients and/or provide benefit in the prevention or treatment of sleep disorders and sleep disturbances.
Naturally, these dose ranges may be adjusted on a unit basis as necessary to permit divided daily dosage and, as noted above, the dose will vary depending on the nature and severity of the disease, weight of patient, special diets and other factors. Anabolic effects especially in the treatment of geriatric male patients are obtained with compounds of this invention in combination with anabolic steroids such as dehydroepiandrosterone, oxymetholone, methyltesterone, fluoxymesterone, Testosterone and stanozolol.
These combinations may be formulated into pharmaceutical compositions as known in the art and as discussed below. A growth hormone secretagogue may be administered alone or in combination by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous or subcutaneous injection, or implant), nasal, vaginal, rectal, sublingual, or topical routes of administration and can be formulated in dosage forms appropriate for each route of administration.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is admixed with at least one inert pharmaceutically acceptable carrier such as sucrose, lactose, or starch. Such dosage forms can also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate. Illustrative of the adjuvants which may be incorporated in tablets, capsules and the like are the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; an excipient such as microcrystalline cellulose; a disintegrating agent such as corn starch, pregelatinized starch, alginic acid and the like; a lubricant such as magnesium stearate; a sweetening agent such as sucrose, lactose or saccharin; a flavoring agent such as peppermint, oil of wintergreen or cherry. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. When the dosage unitform is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as fatty oil. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. Tablets and pills can additionally be prepared with enteric coatings and tablets may be coated with shellac, sugar or both.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, the elixirs containing inert diluents commonly used in the art, such as water. Besides such inert diluents, compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and
propyl parabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
Preparations according to this invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Sterile compositions for injection may be formulated according to conventional pharmaceutical practice by dissolving or suspending the active substance in a vehicle such as water for injection, a naturally occurring vegetable oil like sesame oil, coconut oil, peanut oil, cottonseed oil, etc., or a synthetic fatty vehicle like ethyl oleate or the like. Buffers, preservatives, antioxidants and the like may be incoφorated as required. Examples of non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate. Such dosage forms may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. They may be sterilized by, for example, filtration through a bacteria-retaining filter, by incoφorating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be manufactured in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use. Compositions for rectal or vaginal administration are preferably suppositories which may contain, in addition to the active substance, excipients such as cocoa butter or a suppository wax. Compositions for nasal or sublingual administration are also prepared with standard excipients well known in the art.
The dosage of active ingredient in the compositions of this invention may be varied, however, it is necessary that the amount of the active ingredient be such that a suitable dosage form is obtained. The active ingredient may be administered to patients (animals and human) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. The selected dosage depends upon the desired therapeutic effect, on the route of administration, and on the duration of the treatment. The dose will vary from patient to patient depending upon the nature and severity of disease, the patient's weight, special diets
then being followed by a patient, concurrent medication, and other factors which those skilled in the art will recognize. Generally, dosage levels of between 0.0001 to 10 mg/kg. of body weight daily are administered to patients and animals, e.g., mammals, to obtain effective release of growth hormone. The dosage range will generally be about 0.5 mg to 1.0 g. per patient per day which may be administered in single or multiple doses. Perferably, the dosage range will be about 0.5 mg to 500 mg per patient per day; more preferably about 0.5 mg to 200 mg per patient per day; and even more preferably about 5 mg to 50 mg per patient per day. Pharmaceutical compositions of the present invention may be provided in a solid dosage formulation preferably comprising about 0.5 mg to 500 mg active ingredient, more preferably comprising about 1 mg to 250 mg active ingredient. The pharmaceutical composition is preferably provided in a solid dosage formulation comprising about 1 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg or 250 mg active ingredient.
The following examples are provided for the puφose of further illustration only and are not intended to be limitations on the disclosed invention.
EXAMPLE 1
3-Amino-3-memyl-N-[2,3,4,5-tetrahydro-2-oxo-l-[[2'-(lH-tetrazol-5- yl ) r 1.1 '-biphen yll-4-ynmethyll - 1 H- 1 -benzazepin-3 OR)-y 11-butanamide.
Step A: 3-Amino-2.3.4.5-tetrahvdro- 1 H- 1 -benzazepin-2-one A solution of 9.22 g (45.6 mmol) of 3-azido-2,3,4,5- tetrahydro-lH-l-benzazepin-2-one (prepared by the method of Watthey, et al., J. Med. Chem..2&, 1511-1516 (1985)) in 30 mL methanol was hydrogenated at 40 psi in the presence of 1.0 g of 5% Pt/C for 4.5 hours. Celite was added and the mixture filtered through a pad of Celite. The filtrate was concentrated and allowed to stand for 16 hours at room temperature which resulted in formation of crystals. The material was isolated by filtration and dried under vacuum to afford 4.18 g (23.7
mmol, 52%) of the product. The mother liquors were diluted to 100 mL with methanol, treated with 2 g of charcoal, filtered through Celite and the filtrate concentrated under vacuum to approximatley 15 mL. A second crop formed yielding 2.02 g of product (11.5 mmol, 25%). Another recycling of the mother liquors afforded a third crop of 0.88 g (5.0, 11%). A total of 7.08 g (40.2 mmol, 88%) of the product was thus obtained. *H NMR (200 MHz, CDC13): 1.6 (br s, 2H), 1.80 (m, IH), 2.55 (m, 2H), 2.88 (m, IH), 3.42 (dd; 7Hz, 11Hz; IH), 6.98 (d, 8Hz, IH), 7.2 (m, 3H), 8.3 (br s, IH). FAB-MS: calculated for C10H12N2O 176; found 177 (M+H, 100%).
Step B: 3(RV Amino-2.3.4.5-tetrahydro- 1 H- 1 -benzazepin-2-one 2.37 g (13.5 mmol) of 3-amino-2,3,4,5-tetrahydro-lH-l- benzazepin-2-one (Step A) and 2.02 g (13.5 mmol) of L-tartaric acid were suspended in 40 mL of ethanol. The mixture was gently heated and complete dissolution achieved by dropwise addition of 5 mL of distilled water. The solution was cooled to room temperature and aged overnight. The solid that formed was removed by filtration, washed with ethanol/diethyl ether (1:1) and dried under vacuum to afford 1.75 g of crude L-tartrate salt. The mother liquors were evaporated to dryness under vacuum, redissolved in 40 mL of water and the pH adjusted to 10- 11 by the addition of solid potassium carbonate. The mixture was extracted with chloroform (6x20 mL) and the combined extracts washed with water (lx) and brine (lx), dried over potassium carbonate, filtered and solvents removed under vacuum to afford 1.29 g (7.33 mmol) of partially enriched 3(R) amine. The original 1.75 g batch of L-tartrate salt was recrystallized twice from aqueous ethanol to afford 1.03 g (3.17 mmol, 24%) of purified L-tartrate salt with [a]D=_212° (c=l, H2θ). The purified L-tartrate salt was dissolved in 20 mL of water and the pH adjusted to 10-11 by the addition of solid potassium carbonate. The mixture was extracted with chloroform (5x10 mL); combined extracts were washed with water and brine then dried over potassium carbonate, filtered and solvents removed under vacuum to afford 522 mg (2.96 mmol, 22% overall) of the 3(S) amine, [aJD=-446° (c=l,CH30H). The
remaining 1.29 g (7.33 mmol) of partially enriched 3(R) amine was treated with 1.10 g (7.33 mmol) of D-tartaric acid as described above and the resulting salt recrystallized twice from aqueous ethanol to afford 1.20 g of purified D-tartrate salt, [a]D=-214° (c=l,H2θ). The purified D- tartrate salt was dissolved in 20 mL of water and the free base isolated as described above to give 629 mg (3.57 mmol, 26% overall) of the 3(R) amine, [a]D=+455° (c=l,CH3θH).
Step C: 2.2-DimethyIbutanedioic acid. 4-methyl ester 2,2-dimethylsuccinic acid (20 g, 137 mmol) dissolved in 200 mL absolute methanol at 0°C was treated dropwise with 2 mL concentrated sulfuric acid. After the addition was complete, the mixture was allowed to warm to room temperature and stirred for 16 hours. The mixture was concentrated in vacuo to 50 mL and slowly treated with 200 mL of saturated aqueous sodium bicarbonate. The mixture was washed with hexane (3x) and the aqueous layer removed and cooled in an ice bath. The mixture was acidified to pH 2 by slow addition of 6N HCl then extracted with ether (8x). The combined extracts were washed with brine, dried over magnesium sulfate, filtered and solvents removed in vacuo. The residue was dried at room temperature under vacuum to afford 14.7 g (91.8 mmol, 67%) of a viscous oil that slowly solidified upon standing. lH NMR analysis indicates the product is a mixture of the tide compound and 15% of the isomeric 2,2-dimethylbutanedioic acid, 1 -methyl ester. NMR (200 MHz, CDCI3) of title compound: 1.29 (s, 6H), 2.60 (s, 2H), 3.66 (s, 3H). NMR (200 MHz, CDCI3) of isomer: 1.28 (s, 6H), 2.63 (s, 2H), 3.68 (s, 3H).
Step D: 3-[Benzyloxycarbonylamino]-3-methylbutanoic acid, methyl ester To 14.7 g (91.8 mmol) of 2,2-dimethylbutanedioic acid-4- methyl ester (Step C), containing 15% of the isomeric 1-methyl ester compound, in 150 mL benzene was added 13 mL of triethylamine (9.4 g, 93 mmol, 1.01 eq) followed by 21.8 mL diphenylphosphoryl azide (27.8 g, 101 mmol, 1.1 eq). The mixture was heated under nitrogen at reflux
for 45 minutes then 19 mL (19.9 g, 184 mmol, 2 eq) of benzyl alcohol was added and refluxing continued for 16 hours. The mixture was cooled, filtered and the filtrate concentrated to a minimum volume under vacuum. The residue was redissolved in 250 mL ethyl acetate, washed with water (lx), saturated aqueous sodium bicarbonate (2x) and brine (lx). The organic layer was removed, dried over magnesium sulfate, filtered and the filtrate concentrated to a minimum volume in vacuo. The crude product was purified by medium pressure liquid chromatography on silica, eluting with hexane/ethyl acetate (4:1), to afford 18.27 g (68.9 mmol, 75%) of the title compound as a pale yellow liquid in addition to a small amount of pure 3-[benzyloxycarbonylamino]-2,2-imethylpropanoic acid, methyl ester. lH NMR (200MHz, CDC13) of title compound: 1.40 (s, 6H), 2.69 (s, 2H), 3.63 (s, 3H), 5.05 (s, 2H), 5.22 (br s, IH), 7.32 (s, 5H). lH NMR (200 MHz, CDCI3) of 3-[benzyloxycarbonylamino]-2,2- dimethylpropanoic acid, methyl ester (200 MHz, CDCI3): 1.19 (s, 6H), 3.30 (d, 7Hz, 2H; resonance collapses to singlet in CD3OD), 3.67 (s, 3H), 5.09 (s, 2H), 5.22 (br s,lH; resonance not observed in CD3OD), 7.3 (br s, 5H).
Step E: 3-Benzyloxycarbonylamino-3-methylbutanoic acid A solution of 18.27 g (68.9 mmol) of methyl 3- benzyloxycarbonylamino-3-methylbutanoate (Step D) in 20 mL of methanol at room temperature was treated dropwise with 51 mL of 2N_ NaOH (102 mmol, 1.5 eq). The mixture was stirred at room temperature for 16 hours then transferred to a separatory funnel and washed with hexane (3x). The aqueous layer was removed, cooled to 0°C and slowly acidified to pH 2 (paper) by dropwise addition of 6N HCl. This mixture was extracted with ether (6x); combined extracts were washed with IN HCl and brine, then dried over magnesium sulfate, filtered and solvent removed under vacuum to afford 17.26 g (68.7 mmol, 99%) of the product. lH NMR (200 MHz, CDCI3): 1.42 (s, 6H), 2.77 (s, 2H), 5.06 (s, 2H), 5.2 (br s, IH), 7.3 (s, 5H).
Step F: 3-Benzyloxycarbonylannno-3-methyl-N-[2,3,4,5-tetrahyo!ro-
2-oxo- 1 H- 1 -benzazepin-3(R)-yll-butanamide To a solution of 252 mg (1.43 mmol) of 3(R)-amino-2,3,4,5- tetrahydro-lH-[l]benzazepin-2-one (Step B) in 4 mL of methylene chloride at room temperature was added 400 mg (1.60 mmol, 1.1 eq) of 3-benzyloxycarbonylamino-3-methylbutanoic acid (Step E) followed by 760 mg (1.7 mmol, 1.2 eq) benzotriazol-l-yloxytris(dimethylamino)- phosphonium hexafluoro-phosphate and 0.50 mL of diisopropyl¬ ethylamine (380 mg, 2.9 mmol, 2 eq). After 3 hours at room temperature, the mixture was diluted into 30 mL of ethyl acetate and washed with 5% aqueous citric acid, saturated aqueous sodium bicarbonate (2x) and brine. The organic layer was removed, dried over magnesium sulfate, filtered and solvents removed under vacuum. The residue was purified by medium pressure liquid chromatography on silica, eluting with ethyl acetate to afford 586 mg ( 1.43 mmol, 100%) of the product. 1 H NMR (200 MHz, CDC13): 1.38 (s, 3H), 1.39 (s, 3H), 1.82 (m, IH), 2.52 (s, 2H), 2.5-3.0 (m, 3H), 4.51 (m, IH), 5.07 (br s, 2H), 5.57 (br s, IH), 6.68 (d, 7Hz, IH), 6.97 (d, 8Hz, IH), 7.1-7.4 (m, 8H), 7.61 (br s, IH). FAB- MS: calculated for C23H27N3O4409; found 410 (M+H, 100%); [a]D=+137° (c=l, CHCI3).
Step G: 5-Phenyltetrazole
Zinc chloride (3.3 g, 24.3 mmol, 0.5 eq) was added to 15 mL of N,N-dimethylformamide in small portions while maintaining the temperature below 60°C. The suspension of zinc chloride was cooled to room temperature and treated with 5.0 g of benzonitrile (48.5 mmol, 1.0 eq) followed by 3.2 g of sodium azide (48.5 mmol, 1.0 eq). The heterogeneous mixture was heated at 115°C with agitation for 18 hours. The mixture was cooled to room temperature, water (30 mL) was added and the mixture acidified by the addition of 5.1 mL of concentrated hydrochloric acid. The mixture was cooled to 0°C and aged for one hour, then filtered and the filter cake washed with 15 mL of cold 0.1N HCl then dried at 60°C under vacuum to afford 6.38 g (43.7 mmol, 90%) of the product.
Step H: 5-Phenyl-2-trityltetrazole
To a suspension of 5.0 g (34.2 mmol) of 5-phenyltetrazole in 55 mL of acetone was added 5.0 mL of triethylamine (3.6 g, 35.6 mmol,
1.04 eq). After 15 minutes, a solution of 10.0 g of triphenyl-methyl chloride (35.9 mmol, 1.05 eq) in 20 mL of tetrahydrofuran was added and the mixture stirred at room temperature for one hour. Water (75 mL) was slowly added and the mixture stirred for one hour at room temperature. The product was collected by filtration, washed with 75 mL of water and dried at 60°C under vacuum to give 13.3 g (34.2 mmol, 100%) of the product.
Step I: N-Triphenylmethyl-5-f2-(4'-methylbiphen-4-vDl tetrazole
A solution of zinc chloride (6.3 g, 46.2 mmol, 0.6 eq) in 35 mL of tetrahydrofuran was dried over molecular sieves. 5-Phenyl-2- trityltetrazole (30.0 g, 77.3 mmol, 1.0 eq) was dissolved in 300 mL of dry tetrahydrofuran and the solution gently stirred while being degassed three times by alternating vacuum and nitrogen purges. The stirred solution was cooled to -15°C and treated slowly with 50.5 mL of 1.6 M n- butyllithium in hexane (80.0 mmol, 1.05 eq) so as to maintain the temperature below -5°C. The solution was maintained at -5 to -15°C for
1.5 hours then treated with the dried zinc chloride solution and allowed to warm to room temperature. In a separate flask, 4-iodotoluene (20.17 g, 92.5 mmol, 1.2 eq) and bis-(triphenylphosphine)nickel (II) dichloride (1.5 g, 2.3 mmol, 0.03 eq) were dissolved in 60 mL of tetrahydrofuran, then degassed and left under an atmosphere of nitrogen. The mixture was cooled to 5°C and treated with 1.5 mL of 3.0 M solution of methylmagnesium chloride in tetrahydrofuran (4.5 mmol, 0.06 eq) so as to keep the temperature below 10°C. The solution was warmed to room temperature and added, under nitrogen purge, to the arylzinc solution. The reaction mixture was stirred vigorously for 8 hours at room temperature then quenched by the slow addition of a solution of 10 mL of glacial acetic acid (1.6 mmol, 0.02 eq) in 60 mL of tetrahydrofuran at a rate so that the temperature was maintained below 40°C. The mixture was stirred for 30 minutes and 150 mL of 80% saturated aqueous sodium
chloride was added; the reaction mixture was extracted for 30 minutes and the layers allowed to separate. The organic layer was removed and washed with 150 mL of 80% saturated aqueous sodium chloride buffered to pH>10 by the addition of ammonium hydroxide. The organic phase was removed and concentrated under vacuum to approximately 50 mL then 250 mL of acetonitrile was added. The mixture was again concentrated under vacuum to 50 mL and acetonitrile added to make the final volume 150 mL. The resulting slurry was cooled at 5°C for 1 hour then filtered and washed with 50 mL of cold acetonitrile followed by 150 mL of distilled water. The filter cake was air dried to a free flowing solid then further dried under vacuum at 50°C for 12 hours to afford 30.0 g (62.8 mmol, 81%) of the product. lH NMR (200 MHz, CDCI3): 2.28 (s, 3H), 6.9-7.05 (m, 10H), 7.2-7.5 (m, 12H), 7.9 (m, IH).
Step J: N-Triρhenylmethyl-5-[2-(4'-bromomethylbiphen-4-yl)] tetrazole
A solution of 3.15 g (6.6 mmol) of N-triphenylmethyl-5-[2- (4'-methylbiphen-4-yl)j tetrazole (Step I) in 25 mL of methylene chloride was treated with 1.29 g (7.25 mmol, 1.1 eq) of N-bromo-succinimide, 80 mg (0.5 mmol, 0.07 eq) of AIBN, 200 mg of sodium acetate and 200 mg of acetic acid. The mixture was heated at reflux for 2 to 16 hours then cooled and washed with saturated aqueous sodium bicarbonate. The organic layer was removed, dried over sodium sulfate, filtered and concentrated to a minimum volume by atmospheric distillation. Methyl t- butyl ether was added and distillation continued until almost all the methylene chloride was removed the the total volume reduce to approximately 12 mL and 12 mL of hexanes was then added. The mixture was kept at room temperature for 2 hours and the product isolated by filtration, washed with hexanes then dried under vacuum at 50°C to give 2.81g (5.04 mmol, 76%) of the product. lH NMR (200 MHz, CDCI3): 4.38 (s, 2H), 6.9-8.0 (m, 23H). NMR indicates presence of approximately 1% of the starting material and 7% of the dibromo derivative.
_
- 40 -
Step K: 3-Benzyloxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro- 2-oxo- l-[[2'-(N-triphenylmethyl)-tetrazol-5-yl][ 1 , 1 '- biphenyl]-4-yl]methyl- IH- 1 -benzazepin-3(R)-yl]- butanamide To a solution of 437 mg ( 1.07 mmol) of the intermediate obtained in Step F in 2 mL of dry dimethylformamide at room temperature under nitrogen was added 55 mg of 60% sodium hydride oil dispersion (33 mg NaH, 1.38 mmol, 1.3 eq). After 15 minutes, a solution of 715 mg (1.28 mmol, 1.2 eq) N-triphenyl-methyl-5-[2-(4'- bromomethylbiphen-4-yl)] tetrazole (Step J) in 1.5 mL of dry dimethyl¬ formamide was added and the mixture stirred for 90 minutes. The reaction mixture was added to 100 mL of ethyl acetate and washed with water (2x) and brine. The organic layer was removed, dried over magnesium sulfate, filtered and solvents removed under vacuum. Purification by medium pressure liquid chromatography on silica, eluting with ethyl acetate/hexane (1 : 1), afforded 902 mg (1.02 mmol, 95%) of the product. lH NMR (200 MHz, CDCI3): 1.38 (s, 3H), 1.39 (s, 3H), 1.68 (m, IH), 2.2-2.5 (m, 5H), 4.44 (m, IH), 4.67 (d, 14Hz, IH), 5.06 (s, 2H), 5.12 (d, 14Hz, IH), 5.63 (br 1, IH), 6.65 (d, 8Hz, IH), 6.9-7.5 (m, 31H), 7.85 (m, IH).
Step L: 3-Amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-l-[[2'-(lH- tetrazol-5-yl] [1,1 '-biphenyl]-4-yl]methyl- 1 H- 1 -benzazepin-
3(RVyl1-butanamide. trifluoroacetate A solution of 902 mg (1.02 mmol) of the intermediate obtained in Step H in 5 mL methanol was hydrogenated at room temperature and one atmosphere over 160 mg of 20% Pd(OH)2/C for 14 hours. The mixture was filtered through Celite and concentrated under vacuum. The residue was purified by reverse phase HPLC on C-18, eluting with methanol/0.1% aqueous trifluoroacetic acid (linear gradient: 60% methanol increased to 80% methanol over 10 minutes) to afford 568 mg (0.91 mmol, 89%) of the title compound. *H NMR (200 MHz, CD3OD): 1.33 (s, 3H), 1.37 (s, 3H), 2.0-2.6 (m, 6H), 4.35 (dd; 7, 11 Hz; IH), 4.86 (d, 15 Hz, IH), 5.20 (d, 15 Hz, IH), 7.00 (d, 8 Hz, 2H), 7.15-
7.35 (m, 6H), 7.45-7.70 (m, 4H). FAB-MS: calculated for C29H31N7O2 509; found 510 (M+H, 100%).
EXAMPLE 2
3-[(2(R)-Hydroxyρropyl)amino]-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo- l-[[2'-(lH-tetrazol-5-yl)[l,l-biphenyl]-4-yl]methyl]-lH-l-benzazepin- 3(RVyl1-butanamide
Step A: 3-[(2-(R)-Benzyloxypropyl)amino]-3-methyl-N-[2,3,4,5- tetrahydro-2-oxo- 1 -[[2'-( 1 H-tetrazol-5-yl)[ 1 , 1 '-biphenyl] -4- yl] methyl] - 1 H- 1 -benzazepin-3 (R)-y l]butanamide, trifluoroacetate
The title compound was prepared from 3-amino-3-methyl-N- [2,3,4,5-tetrahydro-2-oxo-l-[[2'-(lH-tetrazol-5-yl)[l,l'-biphenyl]-4- yl]methyl]-lH-l-benzazepin-3(R)-yl]butanamide, trifluoroacetate (Example 1) and (R)-2-benzyloxlpropanal (prepared from ethyl-D-lactate according to the procedure of Hanessian and Kloss, Tetrahedron Lett.. 26. 1261-1264 (1985) by the procedure described in U.S. Patent No. 5,206,235, Example 86, Step A. lH NMR (200MHz, CD3OD): 1.25 (d, 6Hz, 3H), 1.35 (s, 6H), 2.11 (m, IH), 2.32 (m, IH), 2.5-2.7 (m, 4H), 2.95 (m, IH), 3.17 (m, IH), 3.80 (m, IH), 4.40 (m, IH), 4.44 (d, 11Hz, IH), 4.64 (d, 11Hz, IH), 4.90 (d, 15Hz, IH), 5.02 (d, 15Hz, IH), 6.99 (d, 8Hz, 2H), 7.1-7.7 (m, 15H). FAB-MS: calculated for C39H43N7O3 657; found 658 (M+H, 100%).
Step B: 3-[(2(R)-Hydroxypropyl)amino]-3-methyl-N-[2,3,4,5- tetrahydro-2-oxo- 1 -[[2'-( 1 H-tetrazol-5-yl)[ 1 , 1 '-biphenyl]-4- yl]methyl]- 1 H- 1 -benzazepin-3(R)-yl]butanamide, trifluoroacetate
The title compound was prepared from the intermediate obtained in Step A by the procedure described in U.S. Patent No.
5,206,235, Example 86, Step B. *H NMR (400MHz, CD3OD): 1.22 (d,
6Hz, 3H), 1.37 (s, 3H), 1.39 (s, 3H), 2.10 (m, IH), 2.31 (m, IH), 2.45-
2.70 (m, 4H), 2.81 (dd; 10, 12Hz; IH), 3.08 (dd; 4, 12Hz; IH), 3.92 (m, IH), 4.36 (dd; 7, 11Hz; IH), 4.93 (d, 15Hz, IH), 5.17 (d, 15Hz, IH), 7.04 (d, 8Hz, 2H), 7.19 (d, 8Hz, 2H), 7.20-7.35 (m, 4H), 7.54 (m, 2H), 7.65 (m, 2H). FAB-MS: calculated for C32H37N7O3 567; found 568 (M+H, 45%).
EXAMPLE 3 (METHOD n
N-[l(R)-[(l,2-Dihydro-l-methanesulfonylspiro[3H-indole-3,4'-piperdin]- 1 '-yl)carbonyl]-2-(phenylmethyloxy)ethyl]-2-amino-2- methylpropanamide
Step A: l,2-Dihydro-l-methanesulfonylspiro[3H-indole-3,4'- piperdinelhydrochloride To a solution of 1.20 g (5.8mmol) of 1 '-methyl- 1,2-dihydro- spiro[3H-indole-3,4'-piperdine] (prepared as described by H. Ong, et al., J. Med. Chem.. 22, 981-986 (1983)) in 20 mL of dry dichloromethane at 0°C was added triethylamine (0.90 mL; 6.4 mmol) and methanesulfonyl chloride (0.49 mL; 6.35 mmol) and stirred for 30 min. The reaction mixture was poured into 15 mL of saturated aqueous sodium bicarbonate solution and extracted with dichloromethane (2X10 mL). The combined organics were washed with brine (20 mL), dried over anhydrous potassium carbonate, filtered and the solvent removed under reduced pressure to yield 1.44 g of the methanesulfonamide derivative as pale yellow oil which was used without purification.
To a solution of above crude product in 20 mL of dry 1,2- dichloroethane at 0°C was added 1.0 mL (9.30 mmol) of 1 -chloroethyl chloroformate, and then stirred at RT for 30 min and finally at reflux for lh. The reaction mixture was concentrated to approximately one third of the volume and then diluted with 20 mL of dry methanol and refluxed for 1.5h. The reaction was cooled to RT and concentrated to approximately one half of the volume. The precipitate was filtered and washed with a small volume of cold methanol. This yielded 1.0 g of the piperidine HCl salt as a white solid. The filtrate was concentrated and a small volume of
methanol was added followed by ether. The precipitated material was once again filtered, washed with cold methanol, and dried. This gave an additional 0.49 g of the desired product. Total yield 1.49 g (70%). lH NMR (CDC13, 200MHz) δ 7.43-7.20 (m, 3H), 7.10 (dd, IH), 3.98 (bs, 2H), 3.55-3.40 (bd, 2H), 3.35-3.10 (m, 2H), 2.99 (s, 3H), 2.15 (t, 2H), 2.00 (t, 2H).
Step B: N-[ 1 (R)-[( 1 ,2-Dihydro- l-methanesulfonylspiro[3H-indole- 3,4'-piρerdin]- 1 '-yl)carbonyl]-2-(phenylmethyloxy)ethyl]-2- [(l,l-dimethylethoxy)carbonyl]amino-2-methyl- propanamide
To 0.35g (1.15 mmol) of (2R)-2-[(l,l-dimethylethoxy)- carbonyl]amino-3-[2-(phenylmethyloxy)ethyl]-l-propanoic acid in 13 mL of dichloromethane was added 1 ,2-dihydro- l-methanesulfonylspiro-[3H- indole-3,4'-piperdine] hydrochloride (0.325 g; 1.07 mmol), 0.18 mL (1.63 mmol) of N-methylmoφholine, 0.159 g (1.18 mmol) of 1- hydroxybenztriazole(HOBT) and stirred for 15 min. EDC (0.31 g; 1.62 mol) was added and stirring was continued for lh. An additional 60 μL of N-methylmoφholine was added and stirred for 45 min. The reaction mixture was poured into 5 mL of water and the organic layer was separated. The organic layer was washed with 5 mL of 0.5N aqueous hydrochloric acid and 5 mL of saturated aqueous sodium bicarbonate solution. The combined organics were dried over anhydrous magnesium sulfate, and concentrated to yield 0.627 g of the product as a yellow foam which was used without purification.
To a 0.627 g (1.07 mmol) of the above product in 5 mL of dichloromethane was added 1.0 mL of trifluoroacetic acid and stirred at RT for 75 min. An additional 1.00 mL of trifluoroacetic acid was added and stirred for 10 min. The reaction mixture was concentrated, diluted with 5.0 mL of dichloromethane and carefully basified by pouring into 10 mL of 10% aqueous sodium carbonate solution. The organic layer was separated and the aqueous layer was further extracted with 2X15 mL of dichloromethane. The combined organics were washed with 5 mL of water, dried over potassium carbonate, filtered and concentrated to give
the 0.486 g of the amine as a light yellow foam which was used without purification.
To 0.486 g (1.01 mmol) of the amine and 10 mL of dichloromethane was added 0.26g (1.28 mmol) of 2-[(l,l-dimethyl- ethoxy )carbonyl]amino-2-methyl-propanoic acid, 0.173 g (1.28 mmol) of 1-hydroxybenztriazole (HOBT) and EDC (0.245 g; 1.28 mol) and stirried at RT overnight. The reaction mixture was poured into 5.0 mL of water and the organic layer was separated. The aqueous layer was back extracted with 5 mL of dichloromethane. The combined organics were washed with 5.0 mL of 0.5N aqueous hydrochloric acid, 5 mL of saturated aqueous sodium bicarbonate solution dried over anhydrous magnesium sulfate, and concentrated to yield 0.751 g of the crude product as a yellow foam. A solution of this crude product in dichloromethane was chromatographed on 25 g of silica gel and eluted first with hexanes/acetone/dichloromethane (70/25/5) and then with hexanes/acetone/dichloromethane (65/30/5). This gave 0.63 g of the title compound as a white solid. *H NMR (CDCI3, 400MHz) Compound exists as a 3:2 mixture of rotamers δ 7.40-7.10 (m, 6H), 7.06 (d, 1/3H), 7.02 (t, 1/3H), 6.90 (t, 1/3H), 6.55 (d, 1/3H), 5.15 (m, IH), 4.95 (bs, IH), 4.63 (bd, 1/3H), 4.57-4.40 (m, 2 2/3 H), 4.10 (bd, 1/3H), 4.00 (bd, 1/3H), 3.82 (t, IH), 3.78-3.62 (m, 2H), 3.60-3.50 (m, IH), 3.04 (q, IH), 2.87 (s, IH), 2.86 (s, 2H), 2.80-2.60 (m, IH), 1.90 (bs, IH), 2.85-2.75 (m, IH), 1.82-1.60 (m, 3H), 1.55-1.45 (m, IH), 1.45 (s, 4H), 1.42 (s, 2H), 1.39 (s, 9H).
Step C: N- [ 1 (R)-[( 1 ,2-Dihydro- 1 -methanesulfonylspiro[3H-indole- 3,4'-piperidin]- 1 '-yl)carbonyl]-2-(phenylmethyloxy)ethyl]-2- amino-2-methylpropanamide hydrochloride
To 0.637 g (0.101 mmol) of the intermediate from Step B in 5 mL of dichloromethane was added 2.5 mL of trifluoroacetic acid and stirred at RT for 30 min. The reaction mixture was concentrated to an oil, taken up in 10 mL of ethyl acetate and washed with 8 mL of 10% aqueous sodium carbonate solution. The aqueous layer was further extracted with 5 mL of ethyl acetate. The combined organics were
washed widi 10 mL of water, dried over magnesium sulfate, filtered and concentrated to give the 0.512 g of the free base as a white foam.
To 0.512 g of the free base in 5 mL of ethyl acetate at 0°C was added 0.2 mL of saturated hydrochloric acid in ethyl acetate and stirred for 1.5 h. The white precipitate was filtered under nitrogen, washed with ether, and dried to give 0.50 g of the title compound as a white solid lH NMR (400MHz, CD3OD) Compound exists as 3:2 mixture of rotamers. δ 7.40-7.28 (m, 4H), 7.25-7.17 (m, 2H), 7.08 (t, 1/3H), 7.00 (t, 1/3H), 6.80 (d, 1/3H), 5.16 (ddd, IH), 4.60-4.42 (m, 3H), 4.05 (t, IH), 3.90 (bs, 2H), 3.83-3.70 (m, 2H), 3.30-3.15 (m, 1H0, 2.97 (s, IH), 2.95 (s, 2H), 2.90-2.78 (m, IH), 1.96 (t, 1/3H), 1.85-1.65 (m, 4H), 1.63 (s, 2H), 1.60 (s, 4H).
EXAMPLE 3 (METHOD 2)
N- [ 1 (R)-[( 1 ,2-Dihydro- 1 -methanesulfonylspiro[3H-indole-3 ,4'-piperdin] - 1 '-yl) carbonyl]-2-(phenylmethyloxy)ethyl]-2-amino-2- methylpropanamide
Step A: (2R)-[[[-2-(l,l-dimethylethoxy)carbonyl]amino]-2,2- dimethyl- 1 -oxoethyl]amino-2-(phenylmethoxy)ethyl]- 1 - propanoic acid allyl ester
Prepared from (2R)-2-[(l,l-dimethylethoxy)carbonyl]- amino-3-(phenylmethyloxy)ethyl-propanoic acid and allyl alcohol by carrying out the coupling reaction in CH2CI2 in the presence of EDC and DMAP. lH NMR (400MHz, CDCI3) δ 7.25 (s, 5H), 5.8 (m, IH), 5.2 (dd, 2H), 5.0 (bs, IH), 4.7 (m, IH), 4.6 (m, 2H), 4.4 (dd, 2H), 3.9 (dd, IH), 3.6 (dd, IH), 1.45 (d, 6H), 1.39 (s, 9H).
Step B: (2R)-[[[-2-(l,l-dimethylethoxy)carbonyl]amino]-2,2- dimethyl- l-oxoethyl]amino-2-(phenylmethyloxy)ethyl)- 1 - propanoic acid
To a stirred solution of the crude intermediate obtained in Step A (6.7 g, 15.9 mmol), tetrakis (triphenylρhosphine)-palladium (1.8 g, 0.1 eq) and, triphenyl phosphine (1.25 g, 0.3 eq) was added a solution
of potassium-2-ethyl hexanoate (35 mL, 0.5M solution in EtOAc). The reaction mixture was stirred at room temperature under nitrogen atmosphere for lh and then diluted with ether (100 mL) and poured into ice- water. The organic layer was seperated and the aqueous fraction was acidified with citric acid (20%), then extracted with EtOAc. The EtOAc extracts were washed with brine, dried over magnesium sulfate, filtered and evaporated to give the title compound as a solid. 1 H NMR (400Hz, CD30D) δ 7.3 (s, 5H), 4.7 (m, IH), 4.5 (s, 2H), 4.0 (m, IH), 3.6 (m, IH), 1.4 (d, 6H), 1.3 (s, 9H).
Step C: N- [ 1 (R)- [( 1 ,2-Dihydro- 1 -methanesulfonylspiro[3H-indole- 3,4'-piperdin]- 1 '-yl)carbonyl]-2-(phenylmethyloxy)ethyl]-2- [(1,1 -dimethyl-ethoxy)carbonyl]amino-2-methyl- propanamide To a solution of 1.0 g (3.44 mmol) of 1-methanesulfonyl- spiro[indoline-3,4'-piperidine] hydrochloride, 1.44 g (3.78 mmol) of (2R)-[[-2-( 1 , l-dimethylethoxy)carbonyl)amino]-2,2-dimethyl- 1-oxo- ethyl]-amino-2-(phenylmethyloxy)ethyl)- 1 -propanoic acid, N-methyl moφholine (0.58 mL; 5.20 mmol), and 1-hydroxybenztriazole (HOBT) (0.58 g; 3.78 mmol), in 50 mL of dichloromethane was added EDC ( 1.03 g; 5.20 mmol) and stirred at RT for 16h. The reaction mixture was diluted with an additional 50 mL of dichloromethane and washed with aqueous sodium bicarbonate solution (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated. Flash chromatography (50 g silica gel) of the crude oily residue gave 2.148 g (90%) of the desired material as a colorless foam. *H NMR (CDCI3, 400MHz) Compound exists as a 3:2 mixture of rotamers δ 7.40-7.10 (m, 6H), 7.06 (d, 1/3H), 7.02 (t, 1/3H), 6.90 (t, 1/3H), 6.55 (d, 1/3H), 5.15 (m, IH), 4.95 (bs, IH), 4.63 (bd, 1/3H), 4.57-4.40 (m, 2 2/3 H), 4.10 (bd, 1/3H), 4.00 (bd, 1/3H), 3.82 (t, IH), 3.78-3.62 (m, 2H), 3.60-3.50 (m, IH), 3.04 (q, IH), 2.87 (s, IH), 2.86 (s, 2H), 2.80-2.60 (m, IH), 1.90 (bs, IH), 2.85-2.75 (m, IH), 1.82-1.60 (m, 3H), 1.55-1.45 (m, IH), 1.45 (s, 4H), 1.42 (s, 2H), 1.39 (s, 9H).
Step D: N-[l(R)-[(l,2-Dihydro-l-methanesulfonylspiro[3H-indole- 3,4'-piperdin]- 1 '-yl)carbonyl]-2-(phenylmethyloxy)ethyl]-2ι amino-2-methylpropanamide hydrochloride
To a solution of 2.148 g (3.41 mmol) of the intermediate from Step C in 10 mL of dichloromethane was added 5 mL of trifluoroacetic acid and stirred for lh. The reaction mixture was concentrated and basified with 100 mL of 5% aqueous sodium carbonate solution and extracted with dichloromethane (3X50 mL). The combined organics were washed with brine (50 mL), dried over anhydrous potassium carbonate, filtered, and concentrated to yield a colorless foam. To a solution of the foam in 25 mL of ethyl acetate at 0°C was added 4 mL of IM solution of hydrochloric acid in ethyl acetate. The precipitate was filtered and washed first with ethyl acetate and then with ethyl acetate-ether (1:1), dried to yield 1.79 g (93%) of the title compound as a colorless solid. lH NMR (400MHz, CD3OD) Compound exists as 3:2 mixture of rotamers. δ 7.40-7.28 (m, 4H), 7.25-7.17 (m, 2H), 7.08 (t, 1/3H), 7.00 (t, 1/3H), 6.80 (d, 1/3H), 5.16 (ddd, IH), 4.60-4.42 (m, 3H), 4.05 (t, IH), 3.90 (bs, 2H), 3.83-3.70 (m, 2H), 3.30-3.15 (m, 1H0, 2.97 (s, IH), 2.95 (s, 2H), 2.90-2.78 (m, IH), 1.96 (t, 1/3H), 1.85-1.65 (m, 4H), 1.63 (s, 2H), 1.60 (s, 4H).
EXAMPLE 4
N- [ 1 (R)-[( 1 ,2-Dihydro- 1 -methanesulfonylspiro[3H-indole-3,4'-piperdin] - 1 '-yl)carbonyl]-2-(phenylmemyloxy)ethyl]-2-amino-2-methyl- propanamide methanesulfonate
This compound was prepared by the treating the free base obtained in Example 4, Step D, with methane sulfonic acid. The title compound was obtained by recrystallizing it from ethyl acetate-ethanol- water, m.p. = 166°-168°C.
EXAMPLE 5
Procedure for Manufacturing Tablets of 5.0 mg Potency Active Ingredient
Ingredient Per Tablet Per 25.000Tablets
Active Ingredient 5.91 mg 147.8 g
(N- [ 1 (R)- [( 1 ,2-dihydro- 1 -methane- sulfonylspiro[3H-indole-3,4'-piperdin]- r-yl)carbonyl]-2-(phenylmethyloxy)- ethyl]-2-amino-2-methylρropanamide methanesulfonate)
Calcium Phosphate Dibasic 188.10 mg 4.70 kg
Starch Pregelatinized 120.00 mg 3.00 kg
NF 1500
Microcrystalline Cellulose NF 60.00 mg 1.50 kg
Avicel PH 101
Magnesium Stearate Impalpable 2.00 mg 50.0 g
Powder NF
Croscarmellose Sodium NF 24.00 mg 600 g
Ethanol 95% 30 μl 750 ml
Water purified 90 μl 2.25 1
(Tablet Weight = 400 g)
The active ingredient (equivalent to 5.0 mg anhydrous free base per tablet) was mixed with the calcium phosphate dibasic, the starch pregelatinized NF 1000, the microcrystalline cellulose NF, and half of the croscarmellose sodium NF in a high Fielder 10/25 mixer for about 6 minutes. The 25% ethanol/water granulating solution was slowly added to the powder mixture with the mixer running over a period of about 1.5 minutes then granulated for about 8 minutes to form granules. The wet granules were dried at about 47°C (range 46 to 48°C) in a tray dryer or a fluid bed dryer for approximately 3.0 hours. The dried granules were then milled using a Quadro Comill to achieve fine granules. After milling, the remainder of the croscarmellose sodium NFS was added to the fine granules and mixed in a V blender for about 10 minutes.
Magnesium stearate impalpable powder NF was added to this blend through a 60 mesh stainless steel screen and blended in the V blender for about 1 minute. The lubricated mixture was compressed to provide tablets of 5.0 mg active ingredient (free base equivalent).
EXAMPLE 6
Procedure for Manufacturing Coated Tablets of 5.0 mg Potency Active
Ingredient
Ingredient Per Tablet Per 25.000 Tablets
Hydroxypropyl Methylcellulose 3.2 mg 80 g
USP (HPMC)
Hydroxypropyl Cellulose NF 3.2 mg 80.0 g with < 0.3% Silica (HPC)
Titanium Dioxide USP 1.28 mg 32.0 g
Talc USP Purified 0.32 mg 8.0 g
Water Purified To 80 μl To 200 ml
(Film Coated Tablet Weight = 408 g)
The titanium dioxide and talc, USP were mixed and passed through a 60 mesh stainless steel screen. This mixture was mixed with HPMC and HPC to form a dry blend. The dry blend was added to water (20 ml) which was previously heated to 90°C with mild agitation to ensure that the blend is wetted to form a slurry. The remainder of the water (up to 32 ml) was added to the slurry at ambient temperature with gentle agitation to form a suspension. The suspension was then applied to the tablets from the previous Example using the following guidelines to provide the coated tablets. Pan: suitable size
Pan Speed: 20 RPM Nozzles: 2850 liquid/120 air Inlet Temperature: 85°C Bed Temperature: 47°C Spray Rate: ca. 2.0 g/minute/kg Tablets
EXAMPLE 7
Procedure for Manufacturing Tablets of 25 mg Potency Active Ingredient
Ingredient Per Tablet Per 25.000Tablets
Active Ingredient 29.55 mg 738.75 g
(N-[ 1 (R)-[( 1 ,2-dihydro- 1 -methane- sulfonylspiro[3H-indole-3,4'-piperdin]- r-yl)carbonyl]-2-(phenylmethyloxy)- ethyl]-2-amino-2-methylpropanamide methanesulfonate)
Calcium Phosphate Dibasic 174.46 mg 4.361 kg
Starch Pregelatinized 113.00 mg 2.825 kg NF 1500
Microcrystalline Cellulose NF 57.00 mg 1.425 kg Avicel PH 101
Magnesium Stearate Impalpable 2.00 mg 50.0 g Powder NF
Croscarmellose Sodium NF 24.00 mg 600 g
Ethanol 95% 30 μl 750 ml
Water purified 90 μl 2.25 1
(Tablet Weight = 400 g)
The active ingredient (equivalent to 25 mg anhydrous free base per tablet) was mixed with the calcium phosphate dibasic, the starch pregelatinized NF 1000, the microcrystalline cellulose NF, and half of the croscarmellose sodium NF in a high shear granulator Fielder 10/25 mixer for about 6 minutes. The 25% ethanol/water granulating solution was slowly added to the powder mixture with the mixer running over a period of about 1.5 minutes then granulated for about 8 minutes to form
granules. The wet granules were dried at about 47°C (range 46 to 48°C) in a tray dryer or a fluid bed dryer for approximately 3.0 hours. The dried granules were then milled using a Quadro Comill to achieve fine granules. After milling, the remainder of the croscarmellose sodium NFS was added to the fine granules and mixed in a V blender for about 10 minutes. Magnesium stearate impalpable powder NF was added to this blend through a 60 mesh stainless steel screen and blended in the V blender for about 1 minute. The lubricated mixture was compressed to provide tablets of 25 mg active ingredient (free base equivalent).
EXAMPLE 8
Procedure for Manufacturing Coated Tablets of 25 mg Potency Active Ingredient
Ingredient Per Tablet Per 25.000 Tablets
Hydroxypropyl Methylcellulose 3.2 mg 80 g
USP (HPMC)
Hydroxypropyl Cellulose NF 3.2 mg 80.0 g with < 0.3% Silica (HPC)
Titanium Dioxide USP 1.28 mg 32.0 g Talc USP Purified 0.32 mg 8.0 g
Water Purified To 80 μl To 200 ml
(Film Coated Tablet Weight = 408 g)
Using essentially the procedure of Example 9 and applying the suspension to the tablets from the previous Example, 25 mg potency coated tablets were formed.
EXAMPLE 12
Clinical Study of N-[l(R)-[(l,2-Dihydro-l-methane-sulfonylspiro[3H- indole-3 ,4'-piperidin]- 1 '-yl)carbonyl]-2-(phenyl-methyloxy)ethyl]-2- amino-2-methylρropanamide methanesulfonate in Healthy Young Adults In this study, 9 healthy young men (ages 18 to 30 years) who did not suffer sleep complaints were randomly assigned to a sequence of 3 treatment periods. In each period the subjects received a single oral dose of either placebo, 5 mg of N-[l(R)-[(l,2-dihydro-l-memane- sulfonylspiro[3H-indole-3,4'-piperidin]- 1 '-yl)carbonyl]-2-(phenylmethyl- oxy)ethyl]-2-amino-2-methyl-propanamide methanesulfonate or 25 mg of N-[l(R)-[(l,2-dihydro-l-methanesulfonylspiro[3H-indole-3,4'-piperidin]- r-yl)carbonyl]-2-(phenylmethyloxy)ethyl]-2-amino-2-methyl- propanamide methanesulfonate once daily for 7 days. Sleep was recorded for 2 nights: a habituation night and a blood sampling night
(Days 6 and 7 of study drug administration). On average, the durations of Stages 1, 2, and 3 were similar in the three study conditions. After 7 days of treatment, however, Stage 4 sleep duration was significantly higher after administration of 25 mg of N-[l(R)-[(l,2-dihydro-l-methane- sulfonyl-spiro[3H-indole-3,4'-piperidin]- 1 '-yl)carbonyl]-2-(phenylmethyl- oxy)ethyl]-2-amino-2-methylpropanamide methanesulfonate than after treatment with placebo (54 + 27 min versus 37 ± 19 min, N = 8, p < 0.05). Moreover, when compared to placebo, there was a significant increase in REM sleep in the 25 mg treatment group on the blood sampling night (103 ± 9 min versus 88 ± 19 min, N = 9, p < 0.05) and there was a reduction in sleep latency, a reduction in the amount of time spent awake, as well as a decrease in the number of sleep disturbances in the 25 mg treatment group. Accordingly, the group treated with 25 mg of growth hormone secretagogue exhibited improved sleep efficiency and sleep maintenance. This study suggests that use of a growth hormone secretagogue may have a beneficial effect in enhancing the quality of sleep in humans.
While the invention has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the art will appreciate that various adaptations, changes, modifications, substitutions, deletions, or additions of procedures and protocols may be made without departing from the spirit and scope of the invention. For example, effective dosages other than the particular dosages as set forth herein above may be applicable as a consequence of variations in the responsiveness of the mammal being treated for any of the indications with the compounds of the invention indicated above. Likewise, the specific pharmacological responses observed may vary according to and depending upon the particular active compounds selected or whether there are present pharmaceutical carriers, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present invention. It is intended, therefore, that the invention be defined by the scope of the claims which follow and that such claims be inteφreted as broadly as is reasonable.
Claims (13)
1. A method for enhancing the quality of sleep in a mammal which comprises administering an effective amount of a growth hormone secretagogue.
2. The method of Claim 1 wherein the growth hormone secretagogue is an orally active growth hormone secretagogue.
3. The method of Claim 2 wherein the growth hormone secretagogue is orally administered.
4. The method of Claim 1 wherein the growth hormone secretagogue is a non-peptidal growth hormone secretagogue.
5. The method of Claim 1 wherein the mammal is a human.
6. The method of Claim 4 wherein the growth horomone secretagogue is able to induce the engogenous release of growth hormone or growth hormone-releasing hormone in the first few hours following sleep onset, or alternatively in the period immediately preceding sleep onset.
7. The method of Claim 1 wherein tlie growth hormone secretagogue is selected from the group consisting of:
Formula I Formula II wherein:
Rl is selected from the group consisting of: -Cl-ClO alkyl, -aryl, -aryl-(Ci-C6 alkyl),
-C3-C7 cycloalkyl-(Cl-C6alkyl), -C 1 -C5alkyl-K-C 1 -C5 alkyl, -aryl(Cθ- C5aIkyI)-K-(Ci-C5 alkyl), -C3-C7 cycloalkyl(C0-C5 alkyl)-K-(Cl-C5 alkyl), wherein K is O, S(0)m, N(R2>C(0), C(0)N(R2), OC(O), C(0)0, or -CR2=CR2-, or -C≡C-, and wherein die aryl groups are as defined below and the R2 and alkyl groups may be futher substituted by 1 to 9 halogen, S(0)mR2a, 1 to 3 OR2a» or C(0)OR2a- and the aryl groups may be further substituted by phenyl, phenoxy, halophenyl, 1-3 C1-C6 alkyl, 1 to 3 halogen, 1 to 2 -OR2, methylenedioxy, -S(0)mR2, 1 to 2 -CF3, -OCF3, nitro, -N(R2)(R2), -N(R2)C(0)R2, -C(0)OR2, -C(0)N(R2)(R2). -Sθ2N(R2)(R2), -N(R2)S(0)2 aryl, and -N(R2)Sθ2R2; R2 is selected from the group consisting of: hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, and where two C1-C6 alkyl groups are present on one atom, they may be optionally joined to form a C3-C8 cyclic ring optionally including oxygen, sulfur or NR2a; R2a is hydrogen, or C 1 -Cβ alkyl;
R3a and R3b are independently selected from the group consisting of: hydrogen, halogen, -C1-C6 alkyl, -OR2, cyano, -OCF3, methylenedioxy, nitro, -S(0)mR, -CF3 or -C(0)OR2 and when R3a and R3b are in an ortho arrangement, they may be joined to form a C5 to C8 aliphatic or aromatic ring optionally including 1 or 2 heteroatoms selected from oxygen, sulfur or nitrogen;
R4 and R5 are independently selected from the group consisting of: hydrogen, -C1-C6 alkyl, substituted C1-C6 alkyl wherein the substituents are selected from 1 to 5 halo, 1 to 3 hydroxy, 1 to 3
Cl-Cio alkanoyloxy, 1 to 3 C1-C6 alkoxy, phenyl, phenoxy, 2-furyl, Cl-
C6 alkoxycarbonyl, -S(0)m(Cl-C6 alkyl); or R4 and R5 can be taken together to form -(CH2)rLa (CH2)s- where La is -C(R2)2-, -O-, -S(0)m-, or -N(R2)-, where r and s are independently 1 to 3 and R2 is as defined above;
R6 is hydrogen or C1-C6 alkyl;
A is:
R 7 (CH2) -C— (CH2)y—
R 7a or
— Z-(CH2)X-C — (CH2) R7a wherein x and y are independently 0-3; Z is N-R2 or O;
R7 and R7a are independently selected from the group consisting of: hydrogen, -C1-C6 alkyl, -OR2, trifluoromethyl, phenyl, substituted
C1-C6 alkyl where the substituents are selected from imidazolyl, phenyl, indolyl, p-hydroxyphenyl, -OR2, 1 to 3 fluoro, -S(0)mR2, -C(0)OR2, -C3-C7 cycloalkyl, -N(R2)(R2), -C(0)N(R2)(R2); or R7 and R7a can independently be joined to one or both of R4 and R5 groups to form alkylene bridges between the terminal nitrogen and the alkyl portion of the R7 or R7a groups, wherein the bridge contains 1 to 5 carbons atoms;
B, D, E, and F are independently selected from the group consisting of:
-C(R8)(RlθK -0-, C=0, -S(0)m-. or -NR9-, such that one or two of B, D, E, or F may be optionally absent to provide a 5, 6, or 7 membered ring; and provided that B, D, E and F can be -C(R8)(Rl0)- or C=0 only when one of the remaining B, D, E and F groups is simultaneously -O-,
-S(0)m-, or -NR9-, or
B and D, or D and E taken together may be -N=CRlθ- or -CRlθ=N-, or B and D, or D and E taken together may be -CR8=CRl0-, provided one of the other of B and E or F is simultaneously -O-, -S(0)m-. or -NR9;
R8 and RlO are independently selected from the group consisting of: hydrogen, -R2, -OR2, (-CH2)q-aryl, -(CH2)q-C(0)OR2, -(CH2)q- C(0)0(CH2)q-aryl, or -(CH2)q-( 1 H-tetrazol-5-yl), where the aryl may be optionally substituted by 1 to 3 halo, 1 to 2 C1-C8 alkyl, 1 to 3 -OR2 or 1 to 2 -C(0)OR2;
R9 is selected from the group consisting of: -R2, -(CH2)q-aryl, -C(0)R2, -C(0)(CH2)q-aryl, -SO2R2,
-S02(CH2)q-aryl, -C(0)N(R2)(R2), -C(0)N(R2)(CH2)q-aryl, -C(0)OR2, l-H-tetrazol-5-yl, -SO3H, -Sθ2NHC≡N, -Sθ2N(R2)aryl, -S02N(R2)(R2), and wherein the (CH2)q may be optionally substituted by 1 to 2 C1-C4 alkyl, and the R2 and aryl may be optionally further substituted by 1 to 3 -OR2a, -0(CH2)q aryl, 1 to 2 -C(0)OR2a, 1 to 2 -C(0)0(CH2)q aryl, 1 to 2 -C(0)N(R2a)(R2aX 1 to 2 -C(0)N(R2a)(CH2)q aryl, 1 to 5 halogen, 1 to 3 C1-C4 alkyl, 1,2,4-triazolyl, l-H-tetrazol-5-yl, -C(0)NHSθ2R2a. -S(0)mR2a, -C(0)NHS02(CH2)q-aryl, -Sθ2NHC≡N, -Sθ2NHC(0)R2a, -S02NHC(0)(CH2)qaryl, -N(R2)C(0)N(R2a)(R2a), -N(R2a)C(0)N(R2a)(CH2)q-aryl, -N(R2a)(R2a), -N(R2a)C(0)R2a, -N(R2a)C(0)(CH2)q aryl, -OC(0)N(R2a)(R2a). -OC(0)N(R2a)(CH2)q aryl, -Sθ2(CH2)qCONH-(CH2)wNHC(0)Rl \ , wherein w is 2-6 and Rl 1 may be biotin, aryl, or aryl substituted by 1 or 2 OR2, 1-2 halogen, azido or nitro;
m is 0, 1 or 2;
n is 1, or 2;
q may optionally be 0, 1, 2, 3, or 4; and
G, H, I and J are carbon, nitrogen, sulfur or oxygen atoms, such that at least one is a heteroatom and one of G, H, I or J may be optionally missing to afford a 5 or 6 membered heterocyclic aromatic ring; and pharmaceutically acceptable salts and individual diastereomers thereof.
8. The method of Claim 1 wherein the growth hormone secretagogue is selected from the group consisting of:
1) N-[l(R)-[(l,2-Dihydro-l-methanesulfonylspiro[3H-indole-3,4'- piperidin]- r-yl)carbonyl]-2-(lH-indol-3-yl)ethyl]-2-amino-2-methyl- propanamide;
2) N-[l(R)-[(l,2-Dihydro-l-methanecarbonylspiro[3H-indole-3,4'- piperidin]-r-yl)carbonyl]-2-(lH-indol-3-yl)ethyl]-2-amino-2-methyl- propanamide;
3) N-[ 1 (R)-[( 1 ,2-Dihydro- 1 -benzenesulfonylspiro[3H-indole-3,4'- piperidin]-r-yl)carbonyl]-2-(lH-indol-3-yl)ethyl]-2-amino-2-methyl- propanamide;
4) N-[l (R)-[(3,4-Dihydro-spiro[2H- l-benzopyran-2,4'-piperidin]- 1 '-yl) carbonyl]-2-( 1 H-indol-3-yl)ethyl]-2-amino-2-methylpropanamide;
5) N-[l (R)-[(2- Acetyl- l,2,3,4-tetrahydrospiro[isoquinolin-4,4'- piperidin]- 1 '-yl)carbonyl]-2-(indol-3-yl)ethyl]-2-amino-2-methyl- propanamide;
6) N-[ 1 (R)-[( 1 ,2-Dihydro- 1 -methanesulfonylspiro[3H-indole-3,4'- piperidin]- 1 '-yl)carbonyl]-2-(phenylmethyloxy)ethyl]-2-amino-2~ methy lpropanamide;
7) N-[l(R)-[(l,2-Dihydro- l-methanesulfonylspiro[3H-indole-3,4'- piperidin]- 1 '-yl)carbonyl]-2-(phenylmethyloxy)ethyl]-2-amino-2- methylpropanamide methanesulfonate;
8) N-[l(R)-[(l,2-Dihydro-l-methanesulfonylspiro[3H-indole-3,4'- piρeridin]-r-yl)carbonyl]-2-(2',6'-difluorophenylmethyloxy)ethyl]-2- amino-2-methylpropanamide; 9) N- [ 1 (R)- [( 1 ,2-Dihydro- 1 -methanesulfony 1-5-fluorospiro [3 H-indole-
3,4'-piperidin]-r-yl)carbonyl]-2-(phenylmethyloxy)ethyl]-2-amino-2- methylpropanamide;
10) N-[l(S)-[(l,2-Dihydro-l-methanesulfonylspiro[3H-indole-3,4'- piperidin]- 1 '-yl) carbonyl]-2-(phenylmethylthio)ethyl]-2-amino-2- methy lpropanamide ;
11) N-[ 1 (R)-[( 1 ,2-Dihydro- 1 -methanesulfonylspiro[3H-indole-3,4'- piperidin]- 1 '-yl)carbonyl]-3-phenylpropyl]-2-amino-2-methyl- propanamide;
12) N- [ 1 (R)-[( 1 ,2-Dihydro- 1 -methanesulfonylspiro[3H-indole-3 ,4'- piperidin]-l'-yl)carbonyl]-3-cyclohexylpropyl]-2-amino-2-methyl- propanamide;
13) N-[l(R)-[(l,2-Dihydro-l-methanesulfonylspiro[3H-indole-3,4'- piperidin]- 1 '-yl)carbonyl]-4-phenylbutyl]-2-amino-2-methyl- propanamide;
14) N-[l(R)-[(l,2-Dihydro-l-methanesulfonylspiro[3H-indole-3,4'- piperidin]-r-yl)carbonyl]-2-(5-fluoro-lH-indol-3-yl)ethyl]-2-amino-2- methy lpropanamide ;
15) N-[l(R)-[(l,2-Dihydro-l-methanesulfonyl-5-fluorospiro[3H-indole- 3,4'-piperidin]-r-yl)carbonyl]-2-(5-fluoro-lH-indol-3-yl)ethyl]-2-amino- 2-methylpropanamide;
16) N- [ 1 (R)- [( 1 ,2-Dihydro- 1 - (2-ethoxycarbony l)methylsulfonylspiro- [3H-indole-3,4'-piperidin]-l*-yl)carbonyl]-2-(lH-indol-3-yl)ethyl]-2- amino-2-methylpropanamide ; 17) N- [ 1 (R)- [( 1 ,2-Dihydro- 1 , 1 -dioxospiro[3H-benzothiophene-3 ,4'- piperidin]- 1 '-yl)carbonyl]-2-(phenylmethyloxy)ethyl]-2-amino-2- methy lpropanamide ;
and pharmaceutically acceptable salts thereof.
9. The method of Claim 4 wherein the compound is administered in conjunction with an additional growth hormone secretagogue which is selected from the group consisting of: GHRP-6, GHRP- 1, GHRP-2, growth hormone releasing factor; an analog of growth hormone releasing factor; IGF-1; and IGF-2.
10. A method for enhancing the quality of sleep in a mammal which comprises administering an effective amount of a growth hormone secretagogue in combination with a compound which is selected from the group consisting of: adinazolam, allobarbital, alonimid, alprazolam, amitriptyline, amobarbital, amoxapine, bentazepam, benzoctamine, brotizolam, bupropion, busprione, butabarbital, butalbital, capuride, carbocloral, chloral betaine, chloral hydrate, chlordiazepoxide, clomipramine, cloperidone, clorazepate, clorethate, clozapine, cyprazepam, desipramine, dexclamol, diazepam, dichloralphenazone, divalproex, diphenhydramine, doxepin, estazolam, ethchlorvynol, etomidate, fenobam, flunitrazepam, flurazepam, fluvoxamine, fluoxetine, fosazepam, glutethimide, halazepam, hydroxyzine, imipramine, lithium, lorazepam, lormetazepam, maprotiline, mecloqualone, melatonin, mephobarbital, meprobamate, methaqualone, midaflur, midazolam, nefazodone, nisobamate, nitrazepam, nortriptyline, oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine, peφhenazine, phenelzine, phenobarbital, prazepam, promethazine, propofol, protriptyline, quazepam, reclazepam, roletamide, secobarbital, sertraline, suproclone, temazepam, thioridazine, tracazolate, tranylcypromaine, trazodone, triazolam, trepipam, tricetamide, triclofos, trifluoperazine, trimetozine, trimipramine, uldazepam, venlafaxine, zaleplon, zolazepam, zolpidem, and salts thereof.
11. The method of Claim 10 wherein the mammal is a human.
12. The method of Claim 10 wherein the growth hormone secretagogue is selected from the group consisting of:
Formula Formula II wherein:
Rl is selected from the group consisting of: -Cl-ClO alkyl, -aryl, -aryl-(Cl-C6 alkyl),
-C3-C7 cycloalkyl-(Cl-C6alkyl), -Cι-C5alkyl-K-Cι-C5 alkyl, -aryKQ)- C5alkyl)-K-(Cl-C5 alkyl), -C3-C7 cycloalkyl(Cθ-C5 alkyl)-K-(Cl-C5 alkyl), wherein K is O, S(0)m, N(R2>C(0), C(0)N(R2), OC(O), C(0)0, or -CR2=CR2-, or -C≡C-, and wherein the aryl groups are as defined below and the R2 and alkyl groups may be futher substituted by 1 to 9 halogen, S(0)mR2a. 1 to 3 OR2a» or C(0)OR2a. and the aryl groups may be further substituted by phenyl, phenoxy, halophenyl, 1-3 C1-C6 alkyl, 1 to 3 halogen, 1 to 2 -OR2, methylenedioxy, -S(0)mR2, 1 to 2 -CF3, -OCF3, nitro, -N(R2)(R2), -N(R2)C(0)R2, -C(0)OR2, -C(0)N(R2)(R2), -Sθ2N(R2)(R2), -N(R2)S(0)2 aryl, and -N(R2)Sθ2R2;
R2 is selected from the group consisting of: hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, and where two C1-C6 alkyl groups are present on one atom, they may be optionally joined to form a C3-C8 cyclic ring optionally including oxygen, sulfur or NR2a. R2a is hydrogen, or C1-C6 alkyl;
R3a and R3b are independently selected from the group consisting of: hydrogen, halogen, -C1-C6 alkyl, -OR2, cyano, -OCF3, methylenedioxy, nitro, -S(0)mR, -CF3 or -C(0)OR2 and when R3a and R3b are in an ortho arrangement, they may be joined to form a C5 to C8 aliphatic or aromatic ring optionally including 1 or 2 heteroatoms selected from oxygen, sulfur or nitrogen;
R4 and R5 are independently selected from the group consisting of: hydrogen, -C1-C6 alkyl, substituted Cl-Cό alkyl wherein the substituents are selected from 1 to 5 halo, 1 to 3 hydroxy, 1 to 3 Cl-ClO alkanoyloxy, 1 to 3 Cl-Cό alkoxy, phenyl, phenoxy, 2-furyl, Cl- C6 alkoxycarbonyl, -S(0)m(Cl-C6 alkyl); or R4 and R5 can be taken together to form -(CH2)rLa (CH2)s- where La is -C(R2)2-, -O-, -S(0)m-, or -N(R2)-, where r and s are independently 1 to 3 and R2 is as defined above; R6 is hydrogen or C 1 -Cβ alkyl ;
A is:
RΪ
(CH2) -C— (CH2)y—
R7a or
— Z-(CH2)X-C — (CH2)y—
R7a wherein x and y are independently 0-3; Z is N-R2 or O;
R7 and R7a are independently selected from the group consisting of: hydrogen, -Cl-C6 alkyl, -OR2, trifluoromethyl, phenyl, substituted C1-C6 alkyl where the substituents are selected from imidazolyl, phenyl, indolyl, p-hydroxyphenyl, -OR2, 1 to 3 fluoro, -S(0)mR2. -C(0)OR2, -C3-C7 cycloalkyl, -N(R2)(R2), -C(0)N(R2)(R2); or R7 and R7a can independently be joined to one or both of R4 and R5 groups to form alkylene bridges between the terminal nitrogen and the alkyl portion of the R7 or R7a groups, wherein the bridge contains 1 to 5 carbons atoms;
B, D, E, and F are independently selected from the group consisting of: -C(R8)(RlθK -O-, C=0, -S(0)m-, or -NR9-, such that one or two of B, D, E, or F may be optionally absent to provide a 5, 6, or 7 membered ring; and provided that B, D, E and F can be -C(R8)(RlO)- or C=0 only when one of the remaining B, D, E and F groups is simultaneously -O-, -S(0)m-. or -NR9-, or
B and D, or D and E taken together may be -N=CRl0- or -CRio=N-, or B and D, or D and E taken together may be -CR8=CRlθ-, provided one of the other of B and E or F is simultaneously -O-, -S(0)πr. or -NR9; R8 and RlO are independently selected from the group consisting of: hydrogen, -R2, -OR2, (-CH2)q-aryl, -(CH2)q-C(0)OR2, -(CH2)q- C(0)0(CH2)q-aryl, or -(CH2)q-(lH-tetrazol-5-yl), where the aryl may be optionally substituted by 1 to 3 halo, 1 to 2 Cl-C8 alkyl, 1 to 3 -OR2 or 1 to 2 -C(0)OR2;
R9 is selected from the group consisting of: -R2. -(CH2)q-aryl, -C(0)R2, -C(0)(CH2)q-aryl, -SO2R2, -Sθ2(CH2)q-aryl, -C(0)N(R2)(R2), -C(0)N(R2)(CH2)q-aryl, -C(0)OR2, l-H-tetrazol-5-yl, -SO3H, -Sθ2NHC≡N, -Sθ2N(R2)aryl,
-S02N(R2)(R2), and wherein die (CH2)q may be optionally substituted by 1 to 2 C1-C4 alkyl, and the R2 and aryl may be optionally further substituted by 1 to 3 -OR2a, -0(CH2)q aryl, 1 to 2 -C(0)OR2a, 1 to 2 -C(0)0(CH2)q aryl, 1 to 2 -C(0)N(R2a)(R2aX 1 to 2 -C(0)N(R2a)(CH2)q aryl, 1 to 5 halogen, 1 to 3 C1-C4 alkyl, 1,2,4-triazolyl, l-H-tetrazol-5-yl, -C(0)NHSθ2R2a> -S(0)mR2a, -C(0)NHS02(CH2)q-aryl, -Sθ2NHC≡N, -Sθ2NHC(0)R2a, -S02NHC(0)(CH2)qaryl, -N(R2)C(0)N(R2a)(R2a), -N(R2a)C(0)N(R2a)(CH2)q-aryl, -N(R2a)(R2a), -N(R2a)C(0)R2a, -N(R2a)C(0)(CH2)q aryl, -OC(0)N(R2a)(R2a), -OC(0)N(R2a)(CH2)q aryl, -Sθ2(CH2)qCONH-(CH2)wNHC(0)Rl 1, wherein w is 2-6 and Rl l may be biotin, aryl, or aryl substituted by 1 or 2 OR2, 1-2 halogen, azido or nitro;
m is 0, 1 or 2; n is 1, or 2; q may optionally be 0, 1, 2, 3, or 4; and
G, H, I and J are carbon, nitrogen, sulfur or oxygen atoms, such that at least one is a heteroatom and one of G, H, I or J may be optionally missing to afford a 5 or 6 membered heterocyclic aromatic ring;
and pharmaceutically acceptable salts and individual diastereomers thereof.
13. The method of Claim 10 wherein the growth hormone secretagogue is selected from the group consisting of:
1 ) N-[l (R)-[(l ,2-Dihydro- 1 -methanesulfonylspiro[3H-indole-3,4'- piperidin]-r-yl)carbonyl]-2-(lH-indol-3-yl)ethyl]-2-amino-2-methyl- propanamide;
2) N-[ 1 (R)-[( 1 ,2-Dihydro- 1 -methanecarbonylspiro[3H-indole-3,4'- piperidin]- 1 '-yl)carbonyl]-2-( lH-indol-3-yl)ethyl]-2-amino-2-methyl- propanamide;
3) N-[l(R)-[(l,2-Dihydro-l-benzenesulfonylspiro[3H-indole-3,4'- piperidin]-r-yl)carbonyl]-2-(lH-indol-3-yl)ethyl]-2-amino-2-methyl- propanamide;
4) N-[l(R)-[(3,4-Dihydro-spiro[2H-l-benzopyran-2,4'-piperidin]-l'-yl) carbonyl]-2-( 1 H-indol-3-yl)ethyl]-2-amino-2-methylpropanamide;
5) N-[ 1 (R)-[(2- Acetyl- 1 ,2,3,4-tetrahydrospiro[isoquinoϊin-4,4'- piperidin]- 1 '-yl)carbonyl]-2-(indol-3-yl)ethyl]-2-amino-2-methyl- propanamide;
6) N-[l(R)-[(l,2-Dihydro-l-methanesulfonylspiro[3H-indole-3,4'- piperidin]- 1 '-yl)carbonyl]-2-(phenylmethyloxy)ethyl]-2-amino-2- methy lpropanamide;
7) N-[ 1 (R)-[( 1 ,2-Dihydro- 1 -methanesulfonylspiro[3H-indole-3,4'- piperidin]- 1 '-yl)carbonyl]-2-(phenylmethyloxy)ethyl]-2-amino-2- methylpropanamide methanesulfonate;
8) N-[l(R)-[(l,2-Dihydro-l-methanesulfonylspiro[3H-indole-3,4*- piperidin]-r-yl)carbonyl]-2-(2',6'-difluorophenylmethyloxy)ethyl]-2- amino-2-methylpropanamide; 9) N-[ 1 (R)-[( 1 ,2-Dihydro- 1 -methanesulfonyl-5-fluorospiro[3H-indole-
3,4,-piperidin]-r-yl)carbonyl]-2-(ρhenylmethyloxy)ethyl]-2-amino-2- methylpropanamide;
10) N-[l(S)-[(l,2-Dihydro-l-methanesulfonylspiro[3H-indole-3,4'- piperidin]- 1 '-yl) carbonyl]-2-(phenylmethylmio)ethyl]-2-amino-2- methylpropanamide;
11) N-[ 1 (R)-[( 1 ,2-Dihydro- 1 -methanesulfonylspiro[3H-indole-3,4'- piperidin]- 1 -yl)carbonyl]-3-phenylpropyl]-2-amino-2-methyl- propanamide;
12) N- [ 1 (R)- [( 1 ,2-Dihydro- 1 -methanesulf onylspiro[3H-indole-3 ,4'- piperidin]-l'-yl)carbonyl]-3-cyclohexylpropyl]-2-amino-2-methyl- propanamide;
13) N-[l(R)-[(l,2-Dihydro-l-methanesulfonylsρiro[3H-indole-3,4'- piperidin]- 1 '-yl)carbonyl]-4-phenylbutyl]-2-amino-2-methyl- propanamide;
14) N-[l(R)-[(l,2-Dihydro-l-methanesulfonylspiro[3H-indole-3,4'- piperidin]-r-yl)carbonyl]-2-(5-fluoro-lH-indol-3-yl)ethyl]-2-amino-2- methylpropanamide;
15) N-[ 1 (R)-[( 1 ,2-Dihydro- 1 -methanesulfonyl-5-fluorospiro[3H-indole- 3,4'-piperidin]-r-yl)carbonyl]-2-(5-fluoro-lH-indol-3-yl)ethyl]-2-amino- 2-methylpropanamide;
16) N- [ 1 (R)-[( 1 ,2-Dihydro- 1 -(2-ethoxycarbonyl)methylsulfony lspiro- [3H-indole-3,4'-piperidin]-l'-yl)carbonyl]-2-(lH-indol-3-yl)ethyl]-2- amino-2-methylpropanamide ; W
- 68 -
17) N-[ 1 (R)-[( 1 ,2-Dihydro- 1 , 1 -dioxospiro[3H-benzothiophene-3 ,4'- piperidin]- 1 '-yl)carbonyl]-2-(phenylmethyloxy)ethyl]-2-amino-2- methy lpropanamide ;
5 and pharmaceutically acceptable salts thereof.
Applications Claiming Priority (5)
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US1678796P | 1996-05-07 | 1996-05-07 | |
US60/016787 | 1996-05-07 | ||
GB9611002 | 1996-05-24 | ||
GBGB9611002.8A GB9611002D0 (en) | 1996-05-24 | 1996-05-24 | Enhancement of sleep with a growth hormone secreragogue |
PCT/US1997/007516 WO1997041879A1 (en) | 1996-05-07 | 1997-05-05 | Enhancement of sleep with a growth hormone secretagogue |
Publications (2)
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AU2996397A true AU2996397A (en) | 1997-11-26 |
AU711884B2 AU711884B2 (en) | 1999-10-21 |
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EP (1) | EP0900086A4 (en) |
JP (1) | JP2000511885A (en) |
AU (1) | AU711884B2 (en) |
CA (1) | CA2253390A1 (en) |
WO (1) | WO1997041879A1 (en) |
Families Citing this family (20)
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US6071926A (en) * | 1996-05-22 | 2000-06-06 | Arch Development Corporation | Sleep quality improvement using a growth hormone secretagogue |
KR100699404B1 (en) | 1999-02-18 | 2007-03-23 | 가켄 세야쿠 가부시키가이샤 | Novel Amide Derivatives as Growth Hormone Secretagogues |
IL143690A0 (en) * | 2000-06-19 | 2002-04-21 | Pfizer Prod Inc | The use of growth hormone secretagogues to treat systemic lupus erythematosus and inflammatory bowel disease |
IL144468A0 (en) * | 2000-07-27 | 2002-05-23 | Pfizer Prod Inc | Use of growth hormone secretagogues for improvement of functional health status |
JP4731031B2 (en) * | 2001-03-30 | 2011-07-20 | 株式会社デンソー | Sleep analysis device, program, and recording medium |
MXPA05009850A (en) * | 2003-03-14 | 2005-12-06 | Merck Sharp & Dohme | METHOD FOR TREATING MILD COGNITIVE IMPAIRMENT AND FOR PREVENTING OR DELAYING ALZHEIMERaCOES DISEASE. |
WO2004108120A1 (en) * | 2003-06-11 | 2004-12-16 | Pfizer Products Inc. | Use of growth hormone secretagogues for treatment of fibromyalgia |
US7476653B2 (en) | 2003-06-18 | 2009-01-13 | Tranzyme Pharma, Inc. | Macrocyclic modulators of the ghrelin receptor |
WO2006023852A2 (en) | 2004-08-19 | 2006-03-02 | Vertex Pharmaceuticals, Incorporated | Modulators of muscarinic receptors |
US7786141B2 (en) | 2004-08-19 | 2010-08-31 | Vertex Pharmaceuticals Incorporated | Dihydrospiroindene modulators of muscarinic receptors |
KR20070086756A (en) | 2004-11-29 | 2007-08-27 | 버텍스 파마슈티칼스 인코포레이티드 | Modulators of muscarinic receptors |
CA2634456A1 (en) | 2005-12-22 | 2007-07-05 | Vertex Pharmaceuticals Incorporated | Modulators of muscarinic receptors |
NZ570497A (en) | 2006-02-22 | 2011-09-30 | Vertex Pharma | Spiro condensed 4,4'-quinilino-piperidines derivatives as modulators of muscarinic receptors |
CN101426499A (en) | 2006-02-22 | 2009-05-06 | 弗特克斯药品有限公司 | Modulators of muscarinic receptors |
CU23558A1 (en) | 2006-02-28 | 2010-07-20 | Ct Ingenieria Genetica Biotech | COMPOUNDS ANALOG TO THE PEPTIDIC SECRETAGOGS OF THE GROWTH HORMONE |
US7858790B2 (en) | 2006-06-29 | 2010-12-28 | Vertex Pharmaceuticals Incorporated | Modulators of muscarinic receptors |
US7696201B2 (en) | 2006-08-15 | 2010-04-13 | Vertex Pharmaceuticals Incorporated | Modulators of muscarinic receptors |
EP2051715A2 (en) | 2006-08-18 | 2009-04-29 | Vertex Pharmceuticals Incorporated | Modulators of muscarinic receptors |
ES2602789T3 (en) | 2007-02-09 | 2017-02-22 | Ocera Therapeutics, Inc. | Connector intermediates for the synthesis of macrocyclic modulators of the ghrelin receptor |
JP2010540640A (en) | 2007-10-03 | 2010-12-24 | バーテックス ファーマシューティカルズ インコーポレイテッド | Muscarinic receptor modulators |
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US5206235A (en) * | 1991-03-20 | 1993-04-27 | Merck & Co., Inc. | Benzo-fused lactams that promote the release of growth hormone |
US5536716A (en) * | 1992-12-11 | 1996-07-16 | Merck & Co., Inc. | Spiro piperidines and homologs which promote release of growth hormone |
IL107836A (en) * | 1992-12-11 | 1998-01-04 | Merck & Co Inc | Spiro piperidines and homologs, their preparation and pharmaceutical compositions containing them |
US5284841A (en) * | 1993-02-04 | 1994-02-08 | Merck & Co., Inc. | Benzo-fused lactams promote release of growth hormone |
US5840331A (en) * | 1995-06-07 | 1998-11-24 | Arch Development Corporation | Use of γ-hydroxybutyrate for the stimulation of sleep-related secretion growth hormone and prolactin |
AU2334097A (en) * | 1996-03-21 | 1997-10-10 | Merck & Co., Inc. | 4-spiroindoline piperidines promote release of growth hormone |
-
1997
- 1997-05-05 CA CA002253390A patent/CA2253390A1/en not_active Abandoned
- 1997-05-05 JP JP09540091A patent/JP2000511885A/en active Pending
- 1997-05-05 EP EP97924576A patent/EP0900086A4/en not_active Withdrawn
- 1997-05-05 AU AU29963/97A patent/AU711884B2/en not_active Ceased
- 1997-05-05 WO PCT/US1997/007516 patent/WO1997041879A1/en not_active Application Discontinuation
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WO1997041879A1 (en) | 1997-11-13 |
EP0900086A1 (en) | 1999-03-10 |
AU711884B2 (en) | 1999-10-21 |
JP2000511885A (en) | 2000-09-12 |
CA2253390A1 (en) | 1997-11-13 |
EP0900086A4 (en) | 2000-01-12 |
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