EP0968198A1 - Heterocyclische verbindungen und ihre anwendung zur inhibierung des beta-amiloid peptids - Google Patents
Heterocyclische verbindungen und ihre anwendung zur inhibierung des beta-amiloid peptidsInfo
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- EP0968198A1 EP0968198A1 EP98908637A EP98908637A EP0968198A1 EP 0968198 A1 EP0968198 A1 EP 0968198A1 EP 98908637 A EP98908637 A EP 98908637A EP 98908637 A EP98908637 A EP 98908637A EP 0968198 A1 EP0968198 A1 EP 0968198A1
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- alkyl
- substimted
- cycloalkyl
- aryl
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D277/10—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
Definitions
- This invention relates to compounds which inhibit cellular ⁇ -amyloid peptide release and/or its synthesis, and, accordingly, have utility in treating
- Amyloid Precursor Protein Gene with Familial Alzheimer's Disease Nature, 349:704-706 (1990). 5 Chartier-Harlan, et al. , "Early-Onset Alzheimer's Disease Caused by Mutations at Codon 717 of the ⁇ - Amyloid Precursor Proteing Gene", Nature, 353:844-846 (1989).
- AD Alzheimer's Disease
- AD failureia
- AD in aged humans and is believed to represent the fourth most common medical cause of death in the United States.
- AD has been observed in races and ethnic groups worldwide and presents a major present and future public health problem. The disease is currently estimated to affect about two to three million individuals in the United States alone. AD is at present incurable. No treatment that effectively prevents AD or reverses its symptoms and course is currently known.
- the brains of individuals with AD exhibit characteristic lesions termed senile (or amyloid) plaques, amyloid angiopathy (amyloid deposits in blood vessels) and neurofibrillary tangles.
- senile or amyloid
- amyloid angiopathy amyloid deposits in blood vessels
- neurofibrillary tangles Large numbers of these lesions, particularly amyloid plaques and neurofibrillary tangles, are generally found in several areas of the human brain important for memory and cognitive function in patients with AD. Smaller numbers of these lesions in a more restrictive anatomical distribution are also found in the brains of most aged humans who do not have clinical AD .
- Amyloid plaques and amyloid angiopathy also characterize the brains of individuals with Trisomy 21 (Down's Syndrome) and Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch Type (HCHWA-D).
- a definitive diagnosis of AD usually requires observing the aforementioned lesions in the brain tissue of patients who have died with the disease or, rarely, in small biopsied samples of brain tissue taken during an invasive neurosurgical procedure.
- amyloid angiopathy amyloid angiopathy characteristic of AD and the other disorders mentioned above is an approximately 4.2 kilodalton (kD) protein of about 39-43 amino acids designated the /3-amyloid peptide ( AP)-or sometimes A ⁇ , AjSP or ⁇ lA4.
- AP /3-amyloid peptide
- ⁇ - Amyloid peptide was first purified and a partial amino acid sequence was provided by Glenner, et al. 1 The isolation procedure and the sequence data for the first 28 amino acids are described in U.S. Patent No. 4,666,829 2 .
- jS-amyloid peptide is a small fragment of a much larger precursor protein (APP), that is normally produced by cells in many tissues of various animals, including humans.
- APP precursor protein
- Knowledge of the structure of the gene encoding the APP has demonstrated that -amyloid peptide arises as a peptide fragment that is cleaved from APP by protease enzyme(s).
- protease enzyme(s) The precise biochemical mechanism by which the ⁇ -amyloid peptide fragment is cleaved from APP and subsequently deposited as amyloid plaques in the cerebral tissue and in the walls of the cerebral and meningeal blood vessels is currently unknown.
- a mutation at amino acid 693 of the 770-amino acid isoform of APP has been identified as the cause of the /3-amyloid peptide deposition disease, HCHWA-D, and a change from alanine to glycine at amino acid 692 appears to cause a phenotype that resembles AD is some patients but HCHWA-D in others.
- the discovery of these and other mutations in APP in genetically based cases of AD prove that alteration of APP and subsequent deposition of its /3-amyloid peptide fragment can cause AD.
- the treatment methods would advantageously be based on drugs which are capable of inhibiting ⁇ -amyloid peptide release and/or its synthesis in vivo.
- This invention is directed to the discovery of a class of compounds which inhibit -amyloid peptide release and/or its synthesis and, therefore, are useful in the prevention of AD in patients susceptable to AD and/or in the treatment of patients with AD in order to inhibit further deterioration in their condition.
- the class of compounds having the described properties are defined by formula I below:
- A is selected from the group consisting of:
- R 1 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic;
- Z is selected from the group consisting of
- T is selected from the group consisting of oxygen, sulfur and -NR 3 where R 3 is hydrogen, acyl, alkyl, aryl or heteroaryl group; X' is hydrogen or fluoro, X" is hydrogen, hydroxy or fluoro, or X' and X" together form an oxo group; and
- T is selected from the group consisting of oxygen, sulfur and -NR 3 where R 3 is hydrogen, acyl, alkyl, aryl or heteroaryl group; X' is hydrogen or fluoro, X" is hydrogen, hydroxy or fluoro, or X' and X" together form an oxo group;
- R 2 is selected from the group consisting of alkyl, substimted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic;
- R 6 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substimted alkenyl, alkynyl, substimted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic;
- m is an integer equal to 0 or 1 ;
- R 1 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substimted alkyl, substimted alkenyl, substituted alkynyl, substimted cycloalkyl, substimted cycloalkenyl, aryl, heteroaryl and heterocyclic;
- T' is selected from the group consisting of a bond covalently linking R 1 to -CX'X"-, oxygen, sulfur and -NR 3 where R 3 is hydrogen, " acyl, alkyl, aryl or heteroaryl group;
- W and X are independently selected from the group consisting of -(CR 7 R 7 ) 9 -, oxygen, sulfur and -NR 8 where q is an integer equal to one or two, and each R 7 and R 8 is independently selected from the group consisting of hydrogen, alkyl, substimted alkyl, cycloalkyl, aryl, heteroaryl, acyl, acyloxy, carboxyl, carboxyl esters and heterocyclic and further, when q is 2, an R 7 group on each of the carbon atoms can optionally be fused to form an aryl, heteroaryl, heterocyclic or cycloalkyl group with the ethylene group with the proviso that when unsaturated, the remaining R 7 group on each carbon atom participates in the unsaturation; and with the further proviso that when W is oxygen, then X is not also oxygen;
- X' is hydrogen, hydroxy or fluoro
- X" is hydrogen, hydroxy or fluoro
- X' and X" together form an oxo group
- R 4 is selected from the group consisting of hydrogen, alkyl, substimted alkyl, alkenyl, substimted alkenyl, alkynyl, substimted alkynyl, cycloalkyl, substimted cycloalkyl, aryl, heteroaryl and heterocyclic;
- R 1 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substimted alkyl, substimted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic;
- T' is selected from the group consisting of a bond covaleritly linking R 1 to -CX'X"-, oxygen, sulfur and -NR 3 where R 3 is hydrogen, acyl, alkyl, aryl or heteroaryl group;
- W and X are independently selected from the group consisting of -(CR 7 R 7 ) (? -, oxygen, sulfur and -NR 8 where q is an integer equal to one or two and each R 7 and R 8 is independently selected from the group consisting of hydrogen, alkyl, substimted alkyl, cycloalkyl, aryl, heteroaryl, acyl, acyloxy, carboxyl, carboxyl esters, and heterocyclic and further, when q is 2, an R 7 group on each of the carbon atoms can optionally be fused to form an aryl, heteroaryl, heterocyclic or cycloalkyl group with the ethylene group with the proviso that when unsaturated, the remaining R 7 group on each carbon atom participates in the unsaturation;
- X' is hydrogen, hydroxy or fluoro
- X" is hydrogen, hydroxy or fluoro
- R 4 is selected from the group consisting of hydrogen, alkyl, substimted alkyl, alkenyl, substimted alkenyl, alkynyl, substimted alkynyl, cycloalkyl, substimted cycloalkyl, aryl, heteroaryl and heterocyclic;
- B is selected from the group consisting of:
- R 5 is selected from the group consisting of alkyl, substimted alkyl, alkenyl, substimted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substimted cycloalkyl, aryl, heteroaryl and heterocyclic;
- W and X are independently selected from the group consisting of -(CR 7 R 7 ) q -, oxygen, sulfur and -NR 8 where q is an integer equal to one or two, and each R 7 and R 8 is independently selected from the group consisting of hydrogen, alkyl, substimted alkyl, cycloalkyl, aryl, heteroaryl, acyl, acyloxy, carboxyl, carboxyl esters, and heterocyclic and further, when q is 2, an R 7 group on each of the carbon atoms can optionally be fused to form an aryl, heteroaryl, heterocyclic or cycloalkyl group with the ethylene group with the proviso that when unsaturated, the remaining R 7 group on each carbon atom participates in the unsaturation; and with the further proviso that when W is oxygen, then X is not also oxygen;
- R 4 is selected from the group consisting of hydrogen, alkyl, substimted alkyl, alkenyl, substimted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substimted cycloalkyl, aryl, heteroaryl and heterocyclic;
- W and X are independently selected from the group consisting of -(CR 7 R 7 ) q -, oxygen, sulfur and -NR 8 where q is an integer equal to 1 or 2 and each R 7 and R 8 is independently selected from the group consisting of hydrogen, alkyl, substimted alkyl, cycloalkyl, aryl, heteroaryl, acyl, acyloxy, and heterocyclic and further, when q is 2, an R 7 group on each of the carbon atoms can optionally be fused to form an aryl, heteroaryl, heterocyclic or cycloalkyl group with the ethylene group with the proviso that when unsaturated, the remaining R 7 group on each carbon atom participates in the unsaturation;
- R 4 is selected from the group consisting of hydrogen, alkyl, substimted alkyl, alkenyl, substimted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalky
- B can also be a covalent bond linking A to C;
- C is selected from the group consisting of:
- R' and R" are independently selected from hydrogen, alkyl, alkenyl, alkynyl, substimted alkyl, substimted alkenyl, substimted alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic, where one of R' or R" is hydroxy or alkoxy, and where R' and R" are joined to form a cyclic group having from 2 to 8 carbon atoms optionally containing 1 to 2 additional heteroatoms selected from oxygen, sulfur and nitrogen and optionally substimted with one or more alkyl, alkoxy or carboxylalkyl groups,
- R 8 is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic
- R 9 is hydrogen or alkyl
- each R 10 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substimted alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic, and
- each R 11 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substimted cycloalkyl, aryl, heteroaryfand heterocyclic and Y' is selected from the group consisting of hydroxyl, alkoxy, amino, thiol, substituted alkoxy, thioalkoxy, substimted thioalkoxy, -OC(O)R 9 , -SSR 9 , and -SSC(O)R 9 where R 9 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic; and
- N-heterocyclic amino, N,N-diheterocyclic amino and mixed N,N-amino groups comprising a first and second substituent on said amino group which substituents are selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substimted cycloalkyl, aryl, heteroaryl, and heterocyclic provided that said first and second substituents are not the same; with the proviso that when A has structure (i) and B has strucmre (i), then C does not have strucmre (i) or (ii); with the further provisos that
- B when /I has structure (i) with R 1 being 3,5-difluorophenyl, Z being -CH 2 C(0)-, R 2 being methyl, and ? being zero, B has strucmre (ii) with W being > NC(O)OC(CH 3 ) 3 , X being -CH , and R 4 being phenyl, then C is not -C(O)OCH 3 ; and
- A has structure (ii) wherein R l is 3,5-difluorophenyl, T' is a bond linking R 1 to -CX'X"-, X' and X" are hydrogen, W is sulfur, X is methylene and R 4 is methyl, and B is a covalent bond linking A to C, then C is not -C(O)OCH 3 .
- the compounds of formula I are further characterized by formula II below:
- R 1 , R 2 , R 5 , R 6 , A, Z, m and /? are as defined above.
- Z is preferably -CX'X"C(O)- where X" is preferably hydrogen, X' is preferably hydrogen or fluoro or X' and X" form an oxo group.
- preferred R 1 unsubstituted aryl groups include, for example, phenyl, 1-naphthyl, 2-naphthyl, and the like.
- R 1 substituted aryl groups in formula II include, for example, monosubstituted phenyls (preferably 3 or 5 substituents); disubstituted phenyls (preferably 3,5 substituents); and trisubstiruted phenyls (preferably 3,4,5 substituents).
- the substimted phenyl groups do not include more than 3 substituents.
- R 1 phenyls preferred in formula II include, for instance, 2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl, 2-hydroxyphenyl, 2- nitrophenyl, 2-methylphenyl, 2-methoxyphenyl, 2-phenoxyphenyl, 2- trifluoromethylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4- nitrophenyl, 4-methylphenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4- ethoxyphenyl, 4-butoxyphenyl, 4-z.r ⁇ -propylphenyl, 4-phenoxyphenyl, 4- trifluoromethylphenyl, 4-hydroxymethylphenyl, 3-methoxyphenyl, 3- hydroxyphenyl, 3-nitrophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-phenoxyphenyl, 3-thiomethoxyphenyl, 3-methyl
- R 1 alkaryl groups in formula II include, by way of example, benzyl, 2-phenylethyl, 3-phenyl-n-propyl, and the like.
- R 1 heteroaryls and substimted heteroaryls in formula II include, by way of example, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, fluoropyridyls (including 5-fluoropyrid-3-yl), chloropyridyls (including 5-chloropyrid-3-yl), thiophen-2-yl, thiophen-3-yl, benzothiazol-4-yl, 2-phenylbenzoxazol-5-yl, furan-
- R 2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic.
- Particularly preferred R 2 substituents include, by way of example, methyl, ethyl, n-propyl, iso-propyl, /? -butyl, iso-butyl, sec-butyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, -CH 2 CH 2 SCH 3 , and the like.
- R 2 , as well as R 5 and R 6 are preferably the side chain of an L-amino acid.
- R 5 and/or R 6 substituents in formula II are independently selected from the group consisting of include, for example, hydrogen, methyl, ethyl, rt-propyl, iso-propyl, /.-butyl, iso-butyl, sec-butyl, tert-butyl, -CH 2 CH(CH 2 CH 3 ) 2 , 2-methyl- ⁇ -butyl, 6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, so-but-2-enyl, 3-methylpentyl,
- each R 10 is independently selected from the group consisting of alkyl, substimted alkyl, or aryl.
- Preferred heterocyclic structures include, by way of example, 3-methyl- l ,2,4-oxadiazol-5-yl, thiazolin-2-yl, 3-phenyl-l,2,4-oxadiazol-5-yl, 3-(p- methoxy-benzyl)-l ,2,4-oxadiazol-5-yl, and the like.
- Preferred compounds of formula II include the following:
- the compounds of formula I are further characterized by formula III and IV below:
- R 1 , R 2 , R 4 , R 6 , W, X, Y, Z, m and p are as defined above.
- Z is preferably -CX'X"C(O)- where X" is preferably hydrogen, X' is preferably hydrogen or fluoro and where X' and X" form an oxo group.
- preferred R 1 unsubstituted aryl groups include, for example, phenyl, 1-naphthyl, 2-naphthyl, and the like.
- R 1 substimted aryl groups in formula III and IV include, for example, monosubstimted phenyls (preferably 3 or 5 substiments); disubstituted phenyls (preferably 3,5 substituents); and trisubstituted phenyls (preferably 3,4,5 substiments).
- the substituted phenyl groups do not include more than 3 substituents.
- R 1 phenyls preferred in formula III and IV include, for instance, 2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl, 2-hydroxyphenyl, 2-nitrophenyl, 2-methy lphenyl, 2-methoxyphenyl, 2-phenoxyphenyl, 2-trifluoromethy lphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-methy lphenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-butoxyphenyl, 4- so-propylphenyl,
- R 1 alkaryl groups in formula III and IV include,- by way of example, benzyl, 2-phenylethyl, 3-phenyl- «-propyl, and the like.
- R 1 heteroaryls and substimted heteroaryls in formula III and IV include, by way of example, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, fluoropyridyls (including 5-fluoropyrid-3-yl), chloropyridyls (including 5- chloropyrid-3-yl), thiophen-2-yl, thiophen-3-yl, benzothiazol-4-yl,
- R 2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic.
- Particularly preferred R 2 substituents include, by way of example, methyl, ethyl, tz-propyl, .s ⁇ -propyl, «-butyl, .s ⁇ -butyl, sec-butyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, -CH 2 CH 2 SCH 3 , and the like.
- R 2 (as well as R 6 ) are preferably the side chain of an L- amino acid.
- R° substiments in formula III and IV include, for example, hydrogen, methyl, ethyl, r ⁇ -propyl, t ' s ⁇ -propyl, -butyl, ts ⁇ -butyl, sec-butyl, tert-butyl, -CH 2 CH(CH 2 CH 3 ) 2 , 2-methyl-n-butyl, 6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, s ⁇ -but-2-enyl, 3-methylpentyl, -CH 2 -cyclopropyl, -CH 2 -cyclohexyl, -CH 2 CH 2 -cyclopropyl, -CH 2 CH 2 -cyclohexyl, -CH 2 -indol-3-yl, /?-(phenyl)phenyl, ⁇ -ff
- Y in Formula III or IV is hydroxy, alkoxy, substituted alkoxy and -NR'R" where R' and R" are as defined above.
- Preferred alkoxy and substituted alkoxy groups include methoxy, ethyoxy, ⁇ -propoxy, z ' s ⁇ -propoxy,
- -butoxy is ⁇ -butoxy, t-butoxy, ne ⁇ -pentoxy, benzyloxy, 2-phenylethoxy, 3- phenyl-tz-propoxy, 3-iodo-n-propoxy, 4-bromo-n-butoxy, and the like.
- Preferred -NR'R" groups include, by way of example, amino (-NH 2 ), -NH(Zs ⁇ -butyl), -NH (sec-butyl), N-methylamino, N,N-dimethylamino, N-benzylamino, N-morpholino, azetidino, N-thiomorpholino, N-piperidinyl,
- Still another preferred Y group is an alkyl group such as -CH 2 CH 2 CH(CH 3 ) 2 , and the like.
- Preferred heterocyclic strucmres defined by W and X include, by way of example, 4,5-dihydrothiazoles, 3,4-dihydro-l,3-isodiazoles, 3,4-dihydro-3-N-t- butoxy-3-isodiazoles, 4,5-dihydrooxazoles, and the like.
- Preferred compounds of formula III and IV include the following:
- the compounds of formula I are further characterized by formula V and VI below:
- R 1 , R 4 , R 6 , T ⁇ X', X", W, X, and Y are as defined above.
- Z is preferably -CX'X"C(O)- where X" is preferably hydrogen, X' is preferably hydrogen or fluoro or where X' and X" form an oxo group.
- preferred R 1 unsubstituted aryl groups include, for example, phenyl, 1-naphthyl, 2-naphthyl, and the like.
- R 1 substimted aryl groups in formula V and VI include, for example, monosubstimted phenyls (preferably 3 or 5 substiments); disubstimted phenyls (preferably 3,5 substiments); and trisubstituted phenyls (preferably 3,4,5 substiments).
- the substimted phenyl groups do not include more than 3 substiments.
- R 1 phenyls preferred in formula IV and VI include, for instance, 2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl, 2-hydroxyphenyl, 2-nitrophenyl, 2-methy lphenyl, 2-methoxyphenyl, 2-phenoxyphenyl, 2 -trifluoromethy lphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-methy lphenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-butoxyphenyl, 4-zs ⁇ -propy lphenyl,
- R 1 alkaryl groups in formula IV and VI include, by way of example, benzyl, 2-phenylethyl, 3-phenyl-fl-propyl,
- R 1 alkyl, substituted alkyl, alkenyl, cycloalkyl and cycloalkenyl groups in formula V and VI include, by way of example,
- R 1 heteroaryls and substimted heteroaryls in formula III and IV include, by way of example, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, fluoropyridyls (including 5-fluoropyrid-3-yl), chloropyridyls (including 5- chloropyrid-3-yl), thiophen-2-yl, thiophen-3-yl, benzothiazol-4-yl,
- R 4 substituents in formula III and IV include, for example, hydrogen, methyl, phenyl, benzyl and the like.
- R 6 substituents in formula V and VI include, for example, hydrogen, methyl, ethyl, «-propyl, /s ⁇ -propyl, « -butyl, s ⁇ -butyl, sec-butyl, tert-butyl, -CH 2 CH(CH 2 CH 3 ) 2 , 2-methyl- ⁇ -butyl, 6-fluoro-/ ⁇ -hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, s ⁇ -but-2-enyl, 3-methylpentyl, -CH 2 -cyclopropyl, -CH 2 -cyclohexyl, -CH 2 CH 2 -cyclopropyl, -CH 2 CH 2 -cyclohexyl, -CH 2 -indol-3-yl, /?-(phenyl)phenyl, ⁇ - fluorophenyl
- -CH 2 -naphthyl e.g. , 1-naphthyl and 2-naphthyl
- -CH 2 -(N-mo ⁇ holino) /?-(N-morpholino-CH 2 CH 2 O)-benzyl
- benzo[b]thiophen-2-yl, 5 -chlorobenzo [b] thiophen-2-y 1 , 4,5,6,7 -tetrahydrobenzo [b] thiophen-2-y 1 benzo [b] thiophen-3 -y 1 , 5 -chlorobenzo [b] thiophen-3 -y 1
- Y in Formula V or VI is hydroxy, alkoxy, substimted alkoxy and -NR'R" where R' and R" are as defined above.
- Preferred alkoxy and substimted alkoxy groups include methoxy, ethyoxy, Az-propoxy, z ' s ⁇ -propoxy, tz-butoxy, s ⁇ -butoxy, t-butoxy, ne ⁇ -pentoxy, benzyloxy, 2-phenylethoxy, 3- phenyl-n-propoxy, 3-iodo-n-propoxy, 4-bromo-/?-butoxy, and the like.
- Preferred -NR'R" groups include, by way of example, amino (-NH 2 ), -NH ' s ⁇ -butyl), -NH(sec-butyl), N-methylamino, N,N-dimethylamino, N-benzylamino, N-morpholino, azetidino, N-thiomorpholino, N-piperidinyl, N-hexamethyleneimino, N-heptamethylene-imino, N-pyrrolidinyl,
- Still another preferred Y group is an alkyl group such as -CH 2 CH 2 CH(CH 3 ) 2 , and the like.
- Preferred heterocyclic strucmres defined by W and X include, by way of example, 4-methylthiazolin-4-yl.
- Preferred compounds of formula V and VI include the following:
- Yet another preferred compound of this invention includes lactams and related compounds of formula VII and VIII
- R ⁇ R 4 , R 6 , T', X' , X", W and X are as defined above;
- X is preferably hydrogen
- X' is preferably hydrogen or fluoro or X' and X" form an oxo group
- T' is preferably " a covalent bond linking R 1 to -CX'X"-.
- preferred R 1 unsubstituted aryl groups include, for example, phenyl, 1-naphthyl, 2-naphthyl, and the like.
- R 1 substituted aryl groups in formula VII and VIII include, for example, monosubstimted phenyls (preferably 3 or 5 substituents); disubstimted phenyls (preferably 3,5 substiments); and trisubstituted phenyls (preferably 3,4,5 substiments).
- the substimted phenyl groups do not include more than 3 substituents.
- R 1 phenyls preferred in formula VII and VIII include 2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl, 2-hydroxyphenyl,
- R 1 alkaryl groups in formula VII and VIII include, by way of example, benzyl, 2-phenylethyl, 3-phenyl-/.-propyl, and the like.
- R 1 heteroaryls and substituted heteroaryls in formula VII and VIII include, by way of example, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, fluoropyridyls (including 5-fluoropyrid-3-yl), chloropyridyls (including 5-chloropyrid-3-yl), thiophen-2-yl, thiophen-3-yl, benzothiazol-4-yl,
- R 4 substituents in formula VII and VIII include, for example, hydrogen, methyl, phenyl, benzyl and the like.
- R 6 substituents in formula VII and VIII include, for example, hydrogen, methyl, ethyl, n-propyl, z ' s ⁇ -propyl, ⁇ -butyl, /s ⁇ -butyl, sec-butyl, tert-butyl, -CH 2 CH(CH 2 CH 3 ) 2 , 2-methyl-rz-butyl, 6-fluoro-rz-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, z ' s ⁇ -but-2-enyl, 3-methylpentyl, -CH 2 -cyclopropyl, -CH 2 -cyclohexyl, -CH 2 CH 2 -cyclopropyl, -CH 2 CH 2 -cyclohexyl, -CH 2 -indol-3-yl, ?-(phenyl)phenyl,
- T is selected from the group consisting of alkylene and substimted alkylene.
- a preferred cycloalkyl group is represented by the formula:
- each V is independently selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, substimted alkyl, alkoxy, substimted alkoxy, alkenyl, substimted alkenyl, alkynyl, substimted alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxy lalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substimted thioalkoxy, trihalomethyl and the like;
- R a is selected from the group consisting of alkyl, substimted alkyl, alkoxy, substimted alkoxy, amino, carboxyl, carboxyl alkyl, cyano, halo, and the like;
- t is an integer from 0 to 2 and, more preferably, is an integer equal to 0 or 1.
- T" is selected from the group consisting of alkylene, substimted alkylene, alkenylene, substimted alkenylene, -(R 13 Z) q R 13 - and -ZR 13 - where Z is a substituent selected from the group consisting of -O-, -S- and
- each R 12 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substimted alkyl, substimted alkenyl, substimted alkynyl, aryl, heteroaryl and heterocyclic
- each R 13 is independently alkylene, substimted alkylene, alkenylene and substimted alkenylene with the proviso that when Z is -O- or -S-, any unsaturation in the alkenylene and substimted alkenylene does not involve participation of the -O- or -S-
- q is an integer of from 1 to 3.
- Particularly preferred alcohol or thiol substituted groups include
- each V is independently selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, substimted alkyl, alkoxy, substimted alkoxy, alkenyl, substimted alkenyl, alkynyl, substimted alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxy lalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substimted thioalkoxy, trihalomethyl and the like;
- R a is selected from the group consisting of alkyl, substimted alkyl, alkoxy, substimted alkoxy, amino, carboxyl, carboxyl alkyl, cyano, halo, and the like;
- t is an integer from
- t is an integer from 0 to 2 and, more preferably, is an integer equal to 0 or 1.
- T" is selected from the group consisting of alkylene, substimted alkylene, alkenylene, substituted alkenylene, -(R 13 Z) q R 13 - and -ZR 13 - where Z is a substituent selected from the group consisting of -O-, -S- and > NR 12
- each R 12 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substimted alkyl, substimted alkenyl, substimted alkynyl, aryl, heteroaryl and heterocyclic
- each R 13 is independently alkylene, substituted alkylene, alkenylene and substituted alkenylene with the proviso that when Z is -O- or -S-, any unsaturation in the alkenylene and substimted alkenylene does not involve participation of the -O- or -S-,
- Particularly preferred cyclic ketone and thioketone groups include:
- t is an integer from 0 to 2 and, more preferably, is an integer equal to 0 or 1.
- T" is selected from the group consisting of alkylene, substimted alkylene, alkenylene, substimted alkenylene, -(R 13 Z) q R 13 - and -ZR 13 - where Z is a substituent selected from the group consisting of -O-, -S- and > NR 12
- each R 12 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substimted alkyl, substimted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic
- each R 13 is independently alkylene, substimted alkylene, alkenylene and substimted alkenylene with the proviso that when Z is -O- or -S-, any unsaturation in the alkenylene and substimted alkenylene does not involve participation of the -O- or
- lactone and thiolactone groups include:
- each V is independently selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, substimted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substimted alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxy lalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substimted thioalkoxy, trihalomethyl and the like;
- R a is selected from the group consisting of alkyl, substimted alkyl, alkoxy, substimted alkoxy, amino, carboxyl, carboxyl alkyl, cyano, halo, and the like;
- t is an integer from 0 to 2 and, more preferably, is an integer equal to 0 or 1.
- T is selected from the group consisting " of alkylene, substituted alkylene, alkenylene, substimted alkenylene, -(R 13 Z) q R 13 - and -ZR 13 - where Z is a substituent selected from the group consisting of -O-, -S- and > NR 12
- each R 12 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substimted alkyl, substimted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic
- each R 13 is independently alkylene, substimted alkylene, alkenylene and substimted alkenylene with the proviso that when Z is -O- or -S-, any unsaturation in the alkenylene and substimted alkenylene does not involve participation of the -O- or -
- lactam and thiolactam groups include:
- Q' is oxygen or sulfur;
- each V is independently selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substimted alkenyl, alkynyl, substituted alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxy lalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substimted thioalkoxy, trihalomethyl and the like;
- R a is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substimted alkoxy, amino, carboxyl, carboxyl alkyl, cyano, halo, and the like;
- t is an integer from 0 to 2 and, more preferably, is an integer equal to 0 or 1.
- T" is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substimted alkenylene, -(R 13 Z) q R 13 - and -ZR 13 - where Z is a substituent selected from the group consisting of -O-, -S- and >NR 12
- each R 12 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substimted alkyl, substimted alkenyl, substimted alkynyl, aryl, heteroaryl and heterocyclic
- each R 13 is independently alkylene, substimted alkylene, alkenylene and substituted alkenylene with the proviso that when Z is -O- or -S-, any unsaturation in the alkenylene and substimted alkenylene does not involve participation of the -O- or -S-
- T" is selected from the group consisting of alkylene, substimted alkylene, alkenylene, substimted alkenylene, -(R 13 Z) q R 13 - and -ZR 13 - where Z is a substituent selected from the group consisting of -O-, -S- and > NR 12
- each R 12 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substimted alkyl, substimted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic
- each R 13 is independently alkylene, substimted alkylene, alkenylene and substimted alkenylene with the proviso that when Z is -O- or -S-, any unsaturation in the alkenylene and substimted alkenylene does not involve participation of the -O- or
- Yet another preferred compound of this invention includes lactams and related compounds of formula IX and X:
- R 1 , R 2 , R 4 , Z, U, W, W', X, m and s are as defined above.
- R 1 , R 2 , R 4 , Z, W and W' are also as defined above.
- this invention is directed to a method for inhibiting ⁇ -amyloid peptide release and/or its synthesis in a cell which method comprises administering to such a cell an amount of a compound or a mixture of compounds of formula I, VII and VIII above effective in inhibiting the cellular release and/or synthesis of -amyloid peptide.
- this invention is directed to a prophylactic method for preventing the onset of AD in a patient at risk for developing AD which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically inert carrier and an effective amount of a compound or a mixture of compounds of formula I, VII and VIII above.
- this invention is directed to a therapeutic method for treating a patient with AD in order to inhibit further deterioration in the condition of that patient which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically inert carrier and an effective amount of a compound or a mixture of compounds of formula I, " VII and VIII above.
- This invention also provides for novel pharmaceutical compositions comprising a pharmaceutically inert carrier and a compound of the formula I, VII or VIII above.
- this invention provides for novel compounds of formula I, VII or VIII.
- this invention relates to compounds which inhibit /3-amyloid peptide release and/or its synthesis, and, accordingly, have utility in treating Alzheimer's disease.
- this invention relates to compounds which inhibit /3-amyloid peptide release and/or its synthesis, and, accordingly, have utility in treating Alzheimer's disease.
- -amyloid peptide refers to a 39-43 amino acid peptide having a molecular weight of about 4.2 kD, which peptide is substantially homologous to the form of the protein described by Glenner, et al. 1 including mutations and post- translational modifications of the normal -amyloid peptide.
- the ⁇ -amyloid peptide is an approximate 39-43 amino acid fragment of a large membrane-spanning glycoprotein, referred to as the -amyloid precursor protein
- Alkyl refers to monovalent alkyl groups preferably having from 1 to 10 carbon atoms and more preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, z ' s ⁇ -propyl, /.-butyl, z ' s ⁇ -butyl, /z-hexyl, and the like.
- “Substimted alkyl” refers to an alkyl group, preferably of from 1 to 10 carbon atoms, having from 1 to 3 substiments selected from the group consisting of alkoxy, " substimted alkoxy, acyl, acylamino, amino, aminoacyl, aminocarboxy esters, cyano, cycloalkyl, halogen, hydroxyl, carboxyl, carboxy lalkyl, oxyacyl, oxyacylamino, thiol, thioalkoxy, substimted thioalkoxy, aryl, heteroaryl, heterocyclic, aryloxy, thioaryloxy, heteroaryloxy, thioheteroaryloxy, nitro, and mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and diary lamino, mono- and di-heteroarylamino, mono- and di-heterocyclic amino, and un
- Alkylene refers to divalent alkylene groups preferably having from 1 to 10 carbon atoms and more preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), the propylene isomers (e.g. , -CH 2 CH 2 CH 2 - and -CH(CH 3 )CH 2 -), and the like.
- Alkaryl refers to -alkylene-aryl groups preferably having from 1 to 10 carbon atoms in the alkylene moiety and from 6 to 10 carbon atoms in the aryl moiety. Such alkaryl groups are exemplified by benzyl, phenethyl and the like.
- Alkoxy refers to the group “alkyl-O-”. Preferred alkoxy groups include, by way of example, methoxy, ethoxy, zz-propoxy, zs ⁇ -propoxy, zz-butoxy, tert-butoxy, sec-butoxy, zz-pentoxy, zz-hexoxy, 1 ,2-dimethylbutoxy, and the like.
- Substituted alkoxy refers to the group “substituted alkyl-O-" where substituted alkyl is as defined above.
- alkenyl refers to alkenyl groups preferably having from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1 -2 sites of alkenyl unsaturation.
- Substituted alkenyl refers to an alkenyl group as defined above having from 1 to 3 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, amino, aminoacyl, aminocarboxy esters, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, cycloalkyl, oxyacyl, oxyacylamino, thiol, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic, nitro, and mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic
- Substituted alkenylene refers to an alkenylene group, preferably of from 2 to 8 carbon atoms, having from 1 to 3 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, thiol, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic, nitro, and mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic.
- substituted alkylene groups include those where 2 substituents on the alkylene group are fused to form one or more cycloalkyl, aryl, heterocyclic or heteroaryl groups fused to the alkylene group.
- Alkynyl refers to alkynyl groups preferably having from ⁇ 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1 and preferably " from 1-2 sites of alkynyl unsaturation.
- Preferred alkynyl groups include ethynyl (-G ⁇ CH), propargyl (-CH 2 C ⁇ CH) and the like.
- Substituted alkynyl refers to an alkynyl group as defined above having from 1 to 3 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, amino, aminoacyl, aminocarboxy esters, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, cycloalkyl, oxyacyl, oxyacylamino, thiol, thioalkoxy, substituted thioalkyoxy, aryl, heteroaryl, heterocyclic, nitro, and mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and
- Acyl refers to the groups alkyl-C(O)-, substituted alkyl-C(O)-, cycloalkyl- C(O)-, aryl-C(O)-, heteroaryl-C(O)- and heterocyclic-C(O)- where alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic are as defined herein.
- Acylamino refers to the group -C(O)NRR where each R is independently hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic and where each of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic are as defined herein.
- Aminoacyl refers to the group -NRC(O)R where each R is independently hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl. and heterocyclic and where each of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic are as defined herein.
- Oxyacyl refers to the groups -OC(O)-alkyl, -OC(O)-aryi, -C(O)0- heteroaryl-, and -C(O)O-heterocyclic where alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
- Oxyacylamino refers to the groups -OC(O)NR-alkyl, -OC(O)NR- substituted alkyl, -OC(O)NR-aryl, -OC(O)NR-heteroaryl-, and -OC(O)NR- heterocyclic where R is hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic and where each of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic are as defined herein.
- Aminocarboxy esters refers to the groups -NRC(O)0-alkyl, -NRC(0)0-substituted alkyl, -NRC(O)0-aryl, -NRC(0)0-heteroaryl, and -NRC(O)O-heterocyclic where R is hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic and where each of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic are as defined herein.
- Aryl refers to an unsaturated aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl). Preferred aryls include phenyl, naphthyl and the like.
- such aryl groups can optionally be substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, acyl, alkyl, alkoxy, alkenyl, alkynyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, amino, aminoacyl, aminocarboxy esters, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, acylamino, cyano, halo, nitro, heteroaryl, heterocyclic, oxyacyl, oxyacylamino, thioalkoxy, substituted thioalkoxy, trihalomethyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di- heteroarylamino, mono- and di-heterocyclic amino, and un
- Aryloxy refers to the group aryl-O- wherein the aryl group is as defined above including optionally substituted aryl groups as also defined above.
- Carboxy alkyl refers to the groups -C(O)O-alkyl and -C(0)0-substituted alkyl where alkyl and substituted alkyl are as defined above.
- Cycloalkyl refers to cyclic alkyl groups of from 3 to 8 carbon atoms having a single cyclic ring or multiple condensed rings which can be optionally substituted with from 1 to 3 alkyl groups.
- Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, 1 -methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, and the like, or multiple ring structures such as adamantanyl, and the like.
- Substituted cycloalkyl refers to cycloalkyl groups having from 1 to 5 (preferably 1 to 3) substituents selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substituted thioalkoxy, trihalomethyl and the like.
- Cycloalkenyl refers to cyclic alkenyl groups of from 4 to 8 carbon atoms having a single cyclic ring and at least one point of internal unsaturation which can be optionally substituted with from 1 to 3 alkyl groups.
- suitable cycloalkenyl groups include, for instance, cyclobut-2-enyl, cyclopent-3-enyl, cyclooct-3-enyl and the like.
- Substituted cycloalkenyl refers to cycloalkenyl groups having from 1 to 5 substituents selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substituted thioalkoxy, trihalomethyl and the like.
- Halo or halogen refers to fluoro, chloro, bromo and iodo and preferably is either chloro or bromo.
- Heteroaryl refers to a monovalent aromatic carbocyclic group of from 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within the ring.
- heteroaryl groups can be optionally substituted with 1 to 3 substituents selected from the group consisting of hydroxy, acyl, alkyl, alkoxy, alkenyl, alkynyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, amino, aminoacyl, aminocarboxy esters, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, aminoacyl, cyano, halo, nitro, heteroaryl, heterocyclic, oxyacyl, oxyacylamino, thioalkoxy, substituted thioalkoxy, trihalomethyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di- heteroarylamino, mono- and di-heterocyclic amino, and unsymmetric di-
- heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzo thienyl).
- Preferred heteroaryls include pyridyl, pyrrolyl and furyl.
- Heterocycle or “heterocyclic” refers to a monovalent saturated or unsaturated group having a single ring or multiple condensed rings, from 1 to 8 carbon atoms and from 1 to 4 hetero atoms selected from nitrogen, sulfur or oxygen within the ring.
- heterocyclic groups can be optionally substituted with 1 to 3 substituents selected from the group consisting of hydroxy, acyl, alkyl, alkoxy, alkenyl, alkynyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, amino, aminoacyl, aminocarboxy esters, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, aminoacyl, cyano, halo, nitro, heteroaryl, heterocyclic, oxyacyl, oxyacylamino, thioalkoxy, substituted thioalkoxy, trihalomethyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclic amino, and unsymmetric
- heterocycles and heteroaryls include, but are not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7- tetrahydrobenzo[b]thi
- Oxyacyl refers to the groups -OC(0)-alkyl, -OC(O)-aryl, -C(O)0- heteroaryl-, and -C(O)O-heterocyclic where alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
- Oxyacylamino refers to the groups -OC(O)NH-alkyl, -OC(O)NH- substituted alkyl, -OC(0)NH-aryl, -OC(O)NH-heteroaryl-, and -OC(O)NH- heterocycllc where alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
- Thiol refers to the group -SH.
- Thioalkoxy refers to the group -S-alkyl.
- Substituted thioalkoxy refers to the group -S-substituted alkyl.
- Thioaryloxy refers to the group aryl-S- wherein the aryl group is as defined above including optionally substituted aryl groups also defined above.
- Thioheteroaryloxy refers to the group heteroaryl-S- wherein the heteroaryl group is as defined above including optionally substituted aryl groups as also defined above.
- “Pharmaceutically acceptable salt” refers to pharmaceutically acceptable salts of a compound of formula I, VII or VIII which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
- the compounds of formula I are readily prepared via several divergent synthetic routes with the particular route selected relative to the ease of compound preparation, commercial availability of starting materials, etc.
- the heterocyclic ring(s) in the compounds of formula I above can be prepared by use or adaptation of known chemical syntheses and methods, which synthesis and methods are well known in the art. For example, the synthesis of various heterocycles is illustrated in detail in the examples set forth below. Using these procedures, other suitable heterocycles can be prepared by modifying the starting materials employed in these procedures.
- the compounds of formula I above are prepared by coupling a suitable heterocycle having one or more pendant functional groups to the other components necessary to form the A-B-C structure of formula I.
- Typical functional groups used for such couplings include, by way of example, carboxylic acid and amino groups.
- the coupling reaction is generally conducted using conventional coupling reagents such as carbodiimides with or without the use of well known additives such as N-hydroxysuccinimide, 1-hydroxybenzotriazole, etc. can be used to facilitate coupling.
- the reaction is typically conducted in an inert aprotic polar diluent such as dimethylformamide, dichloromethane, chloroform, acetonitrile, tetrahydrofuran and the like.
- R ⁇ R 4 , R ⁇ T ⁇ X', X", W, X, W', U, t and s are as defined above.
- the reaction is conventionally conducted by using at least a stoichiometric amount of carboxylic acid la or lb and amine 2.
- This reaction is conventionally conducted for peptide synthesis and synthetic methods used therein can also be employed to prepare compounds VII and VIII.
- well known coupling reagents such as carbodiimides with or without the use of well known additives such as ⁇ -hydroxysuccinimide, 1-hydroxybenzotriazole, etc. can be used to facilitate coupling.
- reaction is conventionally conducted in an inert aprotic polar diluent such as dimethylformamide, dichloromethane, chloroform, acetonitrile, tetrahydrofuran and the like.
- aprotic polar diluent such as dimethylformamide, dichloromethane, chloroform, acetonitrile, tetrahydrofuran and the like.
- the acid halide of compound la or lb can be employed in reaction (1) and, when so employed, it is typically employed in the presence of a suitable base to scavenge the acid generated during the reaction.
- Suitable bases include, by way of example, triethylamine, diisopropylethylamine, ⁇ -methylmorpholine and the like.
- Carboxylic acids la and lb can be prepared by several divergent synthetic routes with the particular route selected relative to the ease of compound preparation, commercial availability of starting materials, whether t is zero or one.
- One method for preparing these compounds (when t is one) is the hydrolysis of esters of compounds of formula V and VI above. Similar methods can be employed to prepare related compounds when t is zero.
- Carboxylic acids 1 having m equal to 1 and n equal to 1 or 2 can also be prepared by use of polymer supported forms of carbodiimide peptide coupling reagents.
- a polymer supported form of EDC for example, has been described (Tetrahedron Letters, 34(48), 7685 (1993)) 10 .
- a new carbodiimide coupling reagent, PEPC, and its corresponding polymer supported forms have been discovered and are very useful for the preparation of such compounds.
- Polymers suitable for use in making a polymer supported coupling reagent are either commercially available or may be prepared by methods well known to (he artisan skilled in the polymer arts.
- a suitable polymer must possess pendant sidechains bearing moieties reactive with the terminal amine of the carbodiimide.
- Such reactive moieties include chloro, bromo, iodo and methanesulfonyl.
- the reactive moiety is a chloromethyl group.
- the polymer's backbone must be inert to both the carbodiimide and reaction conditions under which the ultimate polymer bound coupling reagents will be used.
- hydroxymethylated resins may be converted into chloromethylated resins useful for the preparation of polymer supported coupling reagents.
- hydroxylated resins include the 4-hydroxymethylphenylacetamidomethyl resin (Pam Resin) and 4- benzyloxy benzyl alcohol resin (Wang Resin) available from Advanced Materials
- Preferred resins are the chloromethylated styrene/divinylbenzene resins because of their ready commercial availability. As the name suggests, these resins are already chloromethylated and require no chemical modification prior to use. These resins are commercially known as Merrifield's resins and are available from Aldrich Chemical Company of Milwaukee, Wisconsin, USA (see
- PEPC is prepared by first reacting ethyl isocyanate with l-(3-aminopropyl)pyrrolidine. The resulting urea is treated with 4-toluenesulfonyl chloride to provide PEPC.
- the polymer supported form is prepared by reaction of PEPC with an appropriate resin under standard conditions to give the desired reagent. The carboxylic acid coupling reactions employing these reagents are performed at about ambient to about 45 °C, for from about 3 to 120 hours.
- the product may be isolated by washing the reaction with CHC1 3 and concentrating the remaining organics under reduced pressure.
- isolation of products from reactions where a polymer bound reagent has been used is greatly simplified, requiring only filtration of the reaction mixture and then concentration of the filtrate under reduced pressure.
- Cyclic amino compounds 2 employed in reaction (1) above are generally aminolactams, aminolactones, aminothiolactones and aminocycloalkyl compounds which can be represented by the formula:
- Q is preferably selected from the group consisting of -O-, -S-, > NR 16 , and > CR 17 R 18 where each of R 16 , R 17 and R 18 are independently selected from the group consisting of hydrogen, alkyl, substimted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic with the proviso that if Q is -O-, -S- or > NR 16 , then X is oxo or dihydro.
- aminolactams, aminolactones and aminothiolactones of the formula above can be prepared by use or adaptation of known chemical syntheses which syntheses are well described in the literature. See, e.g. , Ogliaruso and Wolfe, Synthesis ofLactones and Lactams, Patai, et al. Editor, J. Wiley & Sons, New
- 3-amino substituted lactams 13 with 5, 6 or 7 ring atoms may be prepared by the direct cyclization of a suitable alpha, omega-diamino acid ester " 12 as shown in reaction (5) below:
- L is a linking group (typically an alkylene group) of from 2-4 atoms
- Pr is a suitable protecting group such as t-butoxycarbonyl, carbobenzyloxy, or the like and R 19 is an alkoxy or aryloxy group such as methoxy, ethoxy, /?-nitrophenoxy, N-succinimidoxy, and the like.
- the reaction may be carried out in a solvent such as water, methanol, ethanol, pyridine, and the like.
- Such reactions are exemplied by cyclization of a lysine ester to a caprolactam as described by Ugi, et al. , Tetrahedron, 52(35): 11657-11664 (1996).
- such a cyclization can also be conducted in the presence of dehydrating agents such as alumina or silica to form lactams as described by
- R 16 is as defined above.
- reaction (7) is presented by Semple, et al. , supra. , and Freidinger, et al. , J. Org. Chem. , 47: 104-109 (1982) where a dimethylsulfomum leaving group is generated from methyl iodide treatment of an alkyl methyl sulfide 17 to provide for lactam 18.
- a similar approach using a Mitsunobu reaction on an omega alcohol is found Holladay, et al. , J. Org.
- lactams 20 can be prepared from cyclic ketones 19 using either the well known Beckmann rearrangement (e.g. , Donaruma, et al., Organic Reactions, 11 : 1-156 (I960)) or the well known Schmidt reaction
- lactams especially lactams having two hydrogen atoms on the carbon alpha to the lactam carbonyl which lactams form a preferred group of lactams in the synthesis of the compounds of formula I above.
- the L group can be highly variable including, for example, alkylene, substituted alkylene and hetero containing alkylene with the proviso that a heteroatom is not adjacent to the carbonyl group of compound 19.
- the Beckmann rearrangement can be applied to bicyclic ketones as described in Krow, et al. , J. Org. Chem. , 61:5574-5580 (1996).
- lactones can be similarly conducted using peracids in a Baeyer-Villiger reaction on ketones.
- thiolactones can be prepared by cyclization of an omega -SH group to a carboxylic acid and thiolactams can be prepared by conversion of the oxo group to the thiooxo group by P 2 S 5 or by use of the commercially available La wesson's Reagent, Tetrahedron, 35:2433 (1979).
- R 10 is exemplified by alkyl, substimted alkyl, alkoxy, substimted alkoxy, aryl, heteroaryl, cycloalkyl and heterocyclic.
- ketone 21 is converted to an ⁇ -( ⁇ -alkyl)ketone 22 which is cyclized to form bicyclic lactam 23.
- Such intramolecular reactions are useful in forming bicyclic lactams having 5-7 members and the lactam ring of 6-13 members.
- the use of hetero atoms at non-reactive sites in these rings is feasible in preparing heterobicyclic lactams.
- R 6 and Pr are as defined above and R 11 is exemplified by halo, alkyl, substimted alkyl, alkoxy, substimted alkoxy, aryl, heteroaryl, cycloalkyl and heterocyclic wherein the aryl, heteroaryl, cycloalkyl and heterocyclic group is optionally fused to the lactam ring structure.
- lactam 26 is formed from an appropriate unsaturated amide (e.g. , 24) through a ruthenium or molybdenum complexes catalysed olefin metathesis reaction to form unsaturated lactam 25 which can be used herein without further modification.
- unsaturation in 25 permits a myriad of techniques such as hydroboration, Sha less or Jacobsen epoxidations, Sha ⁇ less dihydroxylations, Diels-Alder additions, dipolar cycloaddition reactions and many more chemistries to provide for a wide range of substiments on the lactam ring.
- subsequent transformations of the formed substitution leads to other additional substiments (e.g.
- proline derivative 27 is cyclized via a tributyltin-radical cyclization to provide for lactam 28.
- lactams described above contain the requisite amino group alpha to the lactam carbonyl whereas others did not.
- the introduction of the required amino group can be achieved by any of several routes delineated below which merely catalogue several recent literature references for this synthesis.
- azide or amine displacement of a leaving group alpha to the carbonyl group of the lactam leads to the alpha-aminolactams.
- Such general synthetic procedures are exemplified by the introduction of a halogen atom followed by displacement with phthalimide anion or azide and subsequent conversion to the amine typically by hydrogenation for the azide as described in Rogriguez, et al. , Tetrahedron,
- Still another example of this first general procedure uses a Mitsunobu reaction of an alcohol and a nitrogen equivalent (either -NH 2 or a phthalimido group) in the presence of an azodicarboxylate and a triarylphosphine as described in Wada, et al. , Bull. Chem. Soc. Japan, 46:2833-2835 (1973) using an open chain reagent.
- Yet another example of this first general procedure involves reaction of alpha-chlorolactams with anilines or alkyl amines in a neat mixmre at 120°C to provide for 2-(N-aryl or N-alkyl)lactams as described by Gaetzi, Chem. Abs. , 66:28690m.
- reaction of an enolate with an alkyl nitrite ester to prepare the alpha oxime followed by reduction yields the alpha- aminolactam compound.
- This general synthetic procedure is exemplified by Wheeler, et al. , Organic Syntheses, Coll. Vol. VI, p. 840 which describes the reaction of isoamyl nitrite with a ketone to prepare the desired oxime.
- the reduction of the oxime methyl ester (prepared from the oxime by reaction with methyl iodide) is described in the J. Med. Chem.
- Pr is as defined above and R 12 is typically hydrogen, an alkyl or an aryl group.
- the alpha-aminolactams employed as the cyclic amino compounds 2 in reaction (1) above include ring N-substituted lactams in addition to ring N-H lactams. Some methods for preparing ring N-substituted lactams have been described above. More generally, however, the preparation of these compounds range from the direct introduction of the substituent after lactam formation to essentially introduction before lactam formation.
- the former methods typically employ a base and an primary alkyl halide although it is contemplated that a secondary alkyl halide can also be employed although yields may suffer.
- a first general method for preparing N-substituted lactams is achieved via reaction of the lactam with base and alkyl halide (or acrylates in some cases).
- bases such as sodamide, sodium hydride, LDA, LiHMDS in appropriate solvents such as THF, DMF, etc. are employed provided that the selected base is compatible with the solvent.
- bases such as sodamide, sodium hydride, LDA, LiHMDS in appropriate solvents such as THF, DMF, etc. are employed provided that the selected base is compatible with the solvent. See for example: K. Orito, et al. , Tetrahedron, 36: 1017-1021 (1980) and J.E. Semple, et al. , J. Med. Chem. , 39:4531-4536 (1996) (use of LiHMDS with either R-X or acrylates as electrophiles).
- a second general method employs reductive amination on an amino function which is then cyclized to an appropriate ester or other carbonyl function.
- a third general method achieves production of the N-substitution during lactam formation.
- Literature citations report such production from either photolytic or thermal rearrangement of oxaziridines, particularly of N-aryl compounds. See, for example, Krimm, Chem. Ber. , 91 : 1057 (1958) and Suda, et al. , J. Chem. Soc Chem Comm. , 949-950, (1994). Also, the use of methyl hydroxylamine for the formation of nitrones and their rearrangement to the N- methyl derivatives is reported by Barton, et al. , /. Chem. Soc , 1764-1767 (1975). Additionally, the use of the oxaziridine process in chiral synthesis has been reported by Kitagawa, et al. , J. Am. Chem. Soc , 117:5169-5178 (1975).
- lactams and appropriate corresponding lactones
- Similar alcohol functions at the carbonyl position are derivative of either amine ring opening of cyclic epoxides, ring opening of aziridines, displacement of appropriate halides with amine or alcohol nucleophiles, or most likely reduction of appropriate ketones. These ketones are also of interest to the present invention.
- R 1 and R 2 are exemplified by alkyl, aryl or alkenyl (e.g. , allyl).
- Monocyclic lactams containing a second nitrogen ring atom as described by Sakakida, et al., Bull. Chem. Soc. Japan, 44:478-480 (1971) and represented by the formula:
- R is exemplified by CH 3 - or PhCH 2 -.
- R is exemplified by benzyl (includes both the cis and trans hydroxy lactams).
- R is alkyl, alkenyl, alkynyl, cycloalkyl, or benzyl.
- N-methoxylactams prepared from cyclohexanone and dimethoxyamine are described by Vedejs, et al. , Tet. Lett. , 33:3261-3264 (1992). These structures are represented by the formula:
- R 1 and R 2 are independently selected from alkyl, substimted alkyl, alkenyl, substituted alkenyl, aryl, heteroaryl, heterocyclic or are fused to form a cyclic group.
- Ring substituted lactams are described by Lowe, et al., Bioorg. Med. Chem. Lett. , 4:2877-2882 (1994) and are represented by the formula:
- R 2 and R 3 are exemplified by aryl and substimted aryl and R 1 is exemplified by alkyl or hydrogen.
- R 1 is aryl or heteroaryl and R 2 corresponds to any substiment for which the corresponding amine R 2 -NH 2 exists.
- R H or CH 3 -;
- R 1 is substimted aryl or cyclohexyl
- X is a suitable substiment
- R 2 can be H or alkyl.
- X is -OH, -NH 2 or -NR°R 6 where R 6 is as defined above.
- the reported ketone is a versatile synthetic intermediate which can be modified by conventional methods such as reductive amination, reduction, etc.
- saturated bicyclic alpha-aminolactams are also contemplated for use in the synthesis of compounds of formula I.
- Such samrated bicyclic alpha-aminolactams are well known in the art.
- Edwards, et al. Can. J. Chem. , 49: 1648-1658 (1971) describes several syntheses of bicyclic lactams of the formula:
- R 1 and R 2 are H or -CH 3
- ring A can have from 6-13 members and ring B can have from 5-7 members.
- R can be alkyl, aryl, cycloalkyl and the like.
- Lactams having further heteroatom(s) in the cyclic lactam structure are described by Cornille, et al. , J. Am. Chem. Soc , 117:909-917 (1995), who describe lactams of the formula:
- R is, for example, alkyl, substimted alkyl, aryl, heteroaryl, heterocyclic, and the like.
- R is acyl, alkyl, substimted alkyl, aryl, heteroaryl or heterocyclic provided that R is not an acid labile group such as t-Boc; and R' is hydrogen, alkyl, substituted alkyl, alkoxy, substimted alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclicoxy, halo, cyano, nitro, trihalomethyl, and the like.
- R is as defined in this reference.
- the dislosure of Yokoo, et al. can be extended to cover R being alkyl, substituted alkyl, aryl, alkoxy, substimted alkoxy, heteroaryl, cycloalkyl, heterocyclic, alkenyl, substimted alkenyl, and the like.
- R is as defined in the reference and R can be alkyl, substituted alkyl, aryl, alkoxy, substituted alkoxy, heteroaryl, cycloalkyl, heterocyclic, alkenyl, substituted " alkenyl, and the like.
- thialactams (generally oxalactams can be made by the same methodology) has been reported by Freidinger, et al. , J. Org. Chem. , 47: 104-109 (1982), who prepared thialactams of the formula:
- the coupling agent is any standard reagent used in the formation of typical peptide or amide bonds, for example, carbodiimide reagents. See, also, Karanewsky, U.S. Patent No. 4,460,579 and Kametani, et al. , Heterocycles, 9:831-840 (1978).
- the thiolactam ring is prepared as follows:
- R 2 will be limited to aryl and heteroaryl groups and sterically hindered alkyl groups such as t-butyl.
- R 1 can be highly variable and is limited only by subsequent reaction steps.
- the Kametani procedure allows for a wide selection of R 1 and R 2 groups limited primarily by stability to the reaction conditions.
- the first synthetic route is:
- R 2 can be highly variable (e.g. , alkyl, substimted alkyl, aryl, heteroaryl, heterocyclic and the like) since a number of well documented routes exist for the synthesis " of nitroethylene derivatives from aldehydes and nitromethane (Henry reaction) followed by dehydration.
- R 1 is limited to groups that can undergo alkylation reactions.
- R 2 can be highly variable.
- the starting component required to introduce R 2 can be readily derived by the reduction of any known alpha- BOC-amino acid to the alcohol derivative followed by formation of the mesylate.
- the primary approaches to the preparation of lactams is the Beckmann/Schmidt ring expansion reaction using either inter- or intramolecular approaches serves to prepare lactams of various ring sizes.
- the intramolecular approach generates bicyclic materials with the lactam nitrogen incorporated into the ring fusion.
- Additional approaches set forth above are at the base of the methodology are internal cyclization of omega-amino acids/esters where the construction of the substiment pattern takes place prior to cyclization, and internal cyclization of an electrophilic center onto a nucleophilic functional group as in the Friedel Crafts type cyclization at the center of the Ben-Ishal procedure for making benzazepinones. This latter procedure is ' applicable to a wide variety of heteroaromatics as well as benzenoid rings, and may also be applied to non-aromatic double or triple bonds to generate a wide array of substituents or ring fusions.
- the 5,7-dihydro-6H-diben[b,d]azepin-6-one derivatives employed in this invention can be prepared using conventional procedures and reagents.
- an appropriately substituted N-tert-Boc-2-amino-2'- methylbiphenyl compound can be cyclized to form the corresponding 5,7- dihydro-6H-diben[b,d]azepin-6-one derivative by first treating the biphenyl compound with about 2.1 to about 2.5 equivalents of a strong base, such as sec- butyl lithium. This reaction is typically conducted at a temperature ranging from about -80°C to about -60°C in an inert diluent such as THF.
- the amide nitrogen can be readily alkylated by first treating the dibenazepinone with about 1.1 to about 1.5 equivalents of a strong base, such as sodium hydride, in an inert diluent, such as DMF. This reaction is typically conducted at a temperamre ranging from about -10°C to about 80 °C for about 0.5 " to about 6 hours. The resulting anion is then contacted with an excess, preferably about 1.1 to about " 3.0 equivalents, of an alkyl halide, typically an alkyl chloride, bromide or iodide. Generally, this reaction is conducted at a temperamre of about 0°C to about 100°C for about 1 to about 48 hours.
- a strong base such as sodium hydride
- an inert diluent such as DMF.
- This reaction is typically conducted at a temperamre ranging from about -10°C to about 80 °C for about 0.5 " to about 6 hours.
- the resulting anion is then
- An amino group can then be introduced at the 5-position of the 7-alkyl- 5,7-dihydro-6H-diben[b,d]azepin-6-one using conventional procedures and reagents.
- a strong base such as potassium 1 , 1,1,3,3,3-hexamethyldisilazane (KHMDS)
- KHMDS potassium 1 , 1,1,3,3,3-hexamethyldisilazane
- benzodiazepine derivatives suitable for use in this invention can be prepared using conventional procedures and reagents.
- a 2-aminobenzophenone can be readily coupled to ⁇ -(isopropylthio)- N-(benzyloxycarbonyl)glycine by first forming the acid chloride of the glycine derivative with oxayl chloride, and then coupling the acid chloride with the 2- aminobenzophenone in the presence of a base, such as 4-methylmorpholine, to afford the 2-[c.-(isopropylthio)-N-(benzyloxycarbonyl)glycinyl]- aminobenzophenone.
- a base such as 4-methylmorpholine
- 2,3-dihydro-5-phenyl-lH-l,4-benzodiazepin-2-ones can be readily aminated at the 3-position using conventional azide transfer reactions followed by reduction of the resulting azido group to form the corresponding amino group. The conditions for these and related reactions are described in the examples set forth below. Additionally, 2,3-dihydro-5-phenyl-lH-l,4- benzodiazepin-2-ones are readily alkylated at the 1 -position using conventional procedures and reagents.
- this reaction is typically conducted by first treating the benzodiazepinone with about 1.1 to about 1.5 equivalents of a base, such as sodium hydride, potassium tert-butoxide, potassium 1,1,1,3,3,3- hexamethyldisilazane, cesium carbonate, in an inert diluent, such as DMF.
- a base such as sodium hydride, potassium tert-butoxide, potassium 1,1,1,3,3,3- hexamethyldisilazane, cesium carbonate
- an inert diluent such as DMF.
- This reaction is typically conducted at a temperamre ranging from about -78 °C to about 80°C for about 0.5 to about 6 hours.
- the resulting anion is then contacted with an excess, preferably about 1.1 to about 3.0 equivalents, of an alkyl halide, typically an alkyl chloride, bromide or iodide.
- this reaction is conducted at a temperamre of about 0
- 3-amino-2,4-dioxo-2,3,4,5-tetrahydro-lH-l,5- benzodiazepines employed in this invention are typically prepared by first coupling malonic acid with a 1,2-phenylenediamine. Conditions for this reaction are well known in the art and are described, for example, in PCT Application WO 96-US8400 960603. Subsequent alkylation and amination using conventional procedures and reagents affords various 3-amino-l,5- bis(alkyl)-2,4-dioxo-2,3,4,5-tetrahydro-lH-l,5-benzodiazepines. Such procedures are described in further detail in the example set forth below.
- the starting materials can contain a chiral center (e.g. , alanine) and, when a racemic starting material is employed, the resulting product is a mixmre of R,S enantiomers.
- a chiral isomer of the starting material can be employed and, if the reaction protocol employed does not racemize this starting material, a chiral product is obtained.
- Such reaction protocols can involve inversion of the chiral center during synthesis.
- the products of this invention are a mixmre of diastereomers or R,S enantiomers.
- the chiral product corresponds to the L-amino acid derivative.
- chiral products can be obtained via purification techniques which separates diastereomers or enantiomers to provide for one or the other stereoisomer. Such techniques are well known in the art.
- compositions When employed as pharmaceuticals, the compounds of formula I are usually administered in the form of pharmaceutical compositions. These compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. These compounds are effective as both injectable and oral compositions. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.
- compositions which contain, as the active ingredient, one or more of the compounds of formula I above associated with pharmaceutically acceptable carriers.
- the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container.
- the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
- compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
- the active compound In preparing a formulation, it may be necessary to mill the active compound to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it ordinarily is milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.
- excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose.
- the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy- benzoates; sweetening agents; and flavoring agents.
- compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
- the compositions are preferably formulated in a unit dosage form, each dosage containing from about 5 to about 100 mg, more usually about 10 to about 30 mg of the active ingredient.
- unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
- the compound of formula I above is employed at no more than about 20 weight percent of the pharmaceutical composition, more preferably no more than about 15 weight percent, with the balance being pharmaceutically inert carrier(s).
- the active compound is effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It, will be understood, however, that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
- the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
- a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
- the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
- This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, 0.1 to about 500 mg of the active ingredient of the present invention.
- the tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
- the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
- the two components can separated by enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
- enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
- liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
- compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
- the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra.
- the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
- Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device may be attached to a face masks tent, or intermittent positive pressure breathing machine.
- Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.
- the following formulation examples illustrate the pharmaceutical compositions of the present invention.
- Quantity Ingredient (mg/capsule)
- the above ingredients are mixed and filled into hard gelatin capsules in 340 mg quantities.
- a tablet formula is prepared using the ingredients below:
- Quantity Ingredient (mg/tablet)
- the components are blended and compressed to form tablets, each weighing 240 mg.
- a dry powder inhaler formulation is prepared containing the following components:
- Lactose 95 The active ingredient is mixed with the lactose and the mixmre is added to a dry powder inhaling appliance.
- Formulation Example 4 Tablets, each containing 30 mg of active ingredient, are prepared as follows:
- the active ingredient, starch and cellulose are passed through a No. 20 mesh U.S. sieve and mixed thoroughly.
- the solution of polyvinyl-pyrrolidone is mixed with the resultant powders, which are then passed through a 16 mesh
- the active ingredient, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 150 mg quantities.
- Suppositories each containing 25 mg of active ingredient are made as follows:
- the active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the samrated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2.0 g capacity and allowed to cool.
- the active ingredient, sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystalline cellulose and sodium carboxymethyl cellulose in water.
- the sodium benzoate, flavor, and color are diluted with some of the water and added with stirring. Sufficient water is then added to produce the required volume.
- a subcutaneous formulation may be prepared as follows:
- a topical formulation may be prepared as follows: Ingredient Quantity
- the white soft paraffin is heated until molten.
- the liquid paraffin and emulsifying wax are inco ⁇ orated and stirred until dissolved.
- the active ingredient is added and stirring is continued until dispersed.
- the mixmre is then cooled until solid.
- transdermal delivery devices Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts.
- the construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g. , U.S. Patent 5,023,252, issued June 11, 1991, herein incorporated by reference.
- patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents. Frequently, it will be desirable or necessary to introduce the pharmaceutical composition to the brain, either directly or indirectly. Direct techniques usually involve placement of a drug delivery catheter into the host's ventricular system to bypass the blood-brain barrier.
- One such implantable delivery system used for the transport of biological factors to specific anatomical regions of the body is described in U.S. Patent 5,011,472 which is herein incorporated by reference.
- Indirect techniques usually involve formulating the compositions to provide for drug latentiation by the conversion of hydrophilic drugs into lip id-soluble drugs.
- Latentiation is generally achieved through blocking of the hydroxy, carbonyl, sulfate, and primary amine groups present on the drug to render the drug more lipid soluble and amenable to transportation across the blood-brain barrier.
- the delivery of hydrophilic drugs may be enhanced by intra-arterial infusion of hypertonic solutions which can transiently open the blood-brain barrier.
- the compounds and pharmaceutical compositions of the invention are useful in inhibiting ⁇ -amyloid peptide release and/or its synthesis, and, accordingly, have utility in diagnosing and treating Alzheimer's disease in mammals including humans.
- the compounds described herein are suitable for use in a variety of drug delivery systems described above. Additionally, in order to enhance the in vivo serum half-life of the administered compound, the compounds may be encapsulated, introduced into the lumen of liposomes, prepared as a colloid, or other conventional techniques may be employed which provide an extended serum half-life of the compounds.
- a variety of methods are available for preparing liposomes, as described in, e.g., Szoka, et al. , U.S. Patent Nos. 4,235,871 , 4,501,728 and 4,837,028 each of which is incorporated herein by reference.
- compositions are administered to a patient already suffering from AD in an amount sufficient to at least partially arrest further onset of the symptoms of the disease and its complications.
- An amount adequate to accomplish this is defined as "therapeutically effective dose.
- Amounts effective for this use will depend on the judgment of the attending clinician depending upon factors such as the degree or severity of AD in the patient, the age, weight and general condition of the patient, and the like.
- the compounds described herein are administered at dosages ranging from about 1 to about 500 mg/kg/day.
- compositions are administered to a patient at risk of developing AD (determined for example by genetic screening or familial trait) in an amount sufficient to inhibit the onset of symptoms of the disease.
- An amount adequate to accomplish this is defined as "prophylactically effective dose. " Amounts effective for this use will depend on the judgment of the attending clinician depending upon factors such as the age, weight and general condition of the patient, and the like.
- the compounds described herein are administered at dosages ranging from about 1 to about 500 mg/kg/day.
- the compounds administered to a patient are in the form of pharmaceutical compositions described above. These compositions may be sterilized by conventional sterilization techniques, or may be sterile -filtered. The resulting aqueous solutions may be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration.
- the pH of the compound preparations typically will be between 3 and 11 , more preferably from 5 to 9 and most preferably from 7 and
- the compounds described herein are also suitable for use in the administration of the compounds to a cell for diagnostic and drug discovery purposes. Specifically, the compounds may be used in the diagnosis of cells releasing and/or synthesizing ⁇ -amyloid peptide. In addition the compounds described herein are useful for the measurement and evaluation of the activity of other candidate drugs on the inhibition of the cellular release and/or synthesis of /3-amyloid peptide.
- BEMP 2-tert-butylimino-2-diethylamino- 1,3- dimethylperhydro- 1 , 3 ,2-diazaphosphorine
- HOBT 1-hydroxybenzotriazole hydrate
- Hunig's base diisopropylethylamine
- PEPC l-(3-(l-pyrrolidinyl)propyl)-3-ethylcarbodiimide
- ⁇ L microliter
- Aldrich Aldrich Chemical Company, Inc. , 1001 West Saint Paul Avenue, Milwaukee, WI 53233 USA
- Fluka Fluka Chemical Corp. , 980 South 2nd Street, Ronkonkoma NY 11779 USA
- Chemservice Chemservice Inc. , Westchester, PA
- Bachem Bachem Biosciences Inc. , 3700 Horizon Drive, Renaissance at Gulph Mills, King of Prussia, PA 19406 USA
- Maybridge Maybridge Chemical Co. Trevillett, Tintagel, Cornwall PL34 OHW United Kingdom
- GENERAL PROCEDURE B EDC Coupling — Procedure II A carboxylic acid (1 eq.) was stirred in a suitable solvent (such as THF, dioxane or DMF) and an alcohol or oxime (1 - 5 eq.) was added. To this mixmre was added l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.2 eq.) and 1-hydroxybenzotriazole hydrate (1 eq.) followed by a suitable base, such as 4-methy lmorpholine, triethylamine, or Hunig's base (0 - 1 eq.).
- a suitable solvent such as THF, dioxane or DMF
- an alcohol or oxime (1 - 5 eq.
- a catalytic amount (0.1 eq.) of 4-dimethylaminopyridine was then added and the mixmre was stirred at ambient temperamre and under a dry atmosphere of nitrogen. After 20 hours, the mixture was concentrated under reduced pressure and the resulting concentrate was partitioned between ethyl acetate and water. The organic portion was separated and washed with aqueous sodium bicarbonate and brine, and then dried (sodium sulfate) and concentrated under reduced pressure. The crude product was either used without further purification or was purified using standard procedures, such as silica gel chromatography and/or recrystallization.
- N-tert-BOC Protecting Group - Procedure II The N-tert-Boc-amine was dissolved in a suitable dry solvent (such as 1 ,4- dioxane or ethyl acetate) and the solution was cooled in an ice bath. Gaseous HCl was introduced into the solution until the mixmre was samrated with HCl and the mixmre was then stirred until the starting material was consumed. The resulting mixmre was concentrated under reduced pressure to yield the amine hydrochloride. The amine hydrochloride was either used without further purification or was trimrated in diethyl ether and the resulting solid collected by filtration.
- a suitable dry solvent such as 1 ,4- dioxane or ethyl acetate
- N-tert-Boc-protected amino acid and an amidoxime are reacted according to General Procedure B above to provide the corresponding O- acyloxime.
- the O-acyloxime is then heated at reflux in xylenes with the azeotropic removal of water to provide the N-tert-Boc-protected 5-aminoalkyl- 1,2,4-oxadiazole derivative, which is then typically purified by silica gel chromatography.
- the tert-Boc protecting group is then removed according to General Procedure E above to afford the 5-aminoalkyl-l,2,4-oxadiazole.
- Step B Synthesis of (2S)-2-[l-(N-Carbobenzyloxy)aminoethyl]-5(R,S)- ethoxycarbonyl-2-oxazoIine
- triphenylphosphine (2 eq.)
- the mixture was cooled to 0°C and a solution of diethyl azodicarboxylate (2 eq.) in THF was added dropwise.
- the resulting mixture was allowed to warm to room temperamre and, after 20 hours, the mixture was concentrated under reduced pressure.
- the resulting oil was purified by silica gel chromatography to yield the title compound as an oil which was used without further purification.
- Step B Synthesis of (S)-2-(l-Aminoethyl)-4(R,S)-ethoxycarbonyl-2- thiazoline Hydrochloride
- Step C Synthesis of 2-[l-(N-Carbobenzyloxy)aminoethyl)-4- methoxycarbonyl-4-phenylmethyl-2-imidazoline
- the product from Step A above (1 equivalent) in iodomethane (35 equivalents) was heated to reflux under nitrogen for 8 hours.
- the dark yellow solution was concentrated z ' zz vacuo to a golden yellow foam, then azeotroped with methanol (2x) to remove any residual iodomethane.
- the residue was dissolved in methanol (0.2 M) and the product from Step B above (1 equivalent) was added.
- the resulting clear colorless solution was heated to reflux for 1 hour under nitrogen and then stirred at ambient temperature for 14 hours, and again heated to reflux for an additional 1 hour.
- Step D Synthesis of l-tert-Butoxycarbonyl-2-[l-(N- carbobenzyloxy)aminoethyl]-4-methoxycarbonyI-4-phenylmethyl-2- imidazoline
- Step E Synthesis of l-tert-ButoxycarbonyI-2-(l-aminoethyl)-4- methoxycarbonyl-4-phenylmethyl-2-imidazoline A mixture of the racemic N-Cbz-protected amine from Step D above and
- Step B Synthesis of 2-[l-(N-Carbobenzyloxy)aminoethyl)-4- methoxycarbonyl-4-phenyl-2-imidazoline
- the product from Example J — Step A (5.206 g, 1.1 eq.) in iodomethane (36.5 mL, 38 eq.) was heated to reflux under nitrogen for 16 hours.
- the dark yellow solution was concentrated in vacuo to a golden yellow foam, then azeotroped once with methanol (30 mL) to remove any residual iodomethane.
- the residue was dissolved in methanol (30 mL) and the product from Step A above (3.00 g, 1 eq.) was added.
- Step C Synthesis of l-tert-Butoxycarbonyl-2-[l-(N- carbobenzyloxy)aminoethyl]-4-methoxycarbonyl-4-phenyl-2-imidazoline
- THF 35 mL
- H 2 O 35 mL
- NaHC0 3 2.00 g, 1.84 eq.
- di-tert- butyl dicarbonate 7.50 g, 2.65 eq.
- Step D Synthesis of l-tert-Butoxycarbonyl-2-(l-aminoethyl)-4- methoxycarbonyl-4-phenyl-2-imidazoline
- the title compound was prepared as a viscous oil in five steps (35% overall yield) from D-(S)-cysteine methyl ester hydrochloride as described in G. Pattenden, et al., Tetrahedron, 1993, 49, 2131-2138 and references cited therein.
- D-(S)-cysteine methyl ester hydrochloride was prepared in one step (98% yield) from D-cysteine hydrochloride monohydrate (Aldrich) as described in J. E.
- the solution was concentrated in vacuo to a volume of approximately 5 mL and the concentrate was diluted with ethyl acetate and washed with 1 N aqueous HCl (2x), and water (lx); then dried over Na 2 SO 4 , filtered, and concentrated in vacuo to a give the title compound (0.6111 g, 88% yield) as a white solid having a melting point of 119.5-122.0°C.
- Method B The amino acid ester was dissolved in dioxane/water (4:1) to which was added LiOH ( ⁇ 2 eq.) that was dissolved in water such that the total solvent after addition was about 2:1 dioxane: water.
- the reaction mixture was stirred until reaction completion and the dioxane was removed under reduced pressure.
- the residue was dissolved in water and washed with ether.
- the layers were separated and the aqueous layer was acidified to pH 2.
- the aqueous layer was extracted with ethyl acetate. The ethyl acetate extracts were dried over
- the mixture was washed with water, saturated aqueous NaHCO 3 , IN HCl and saturated aqueous NaCl, and then dried over MgS0 4 .
- the resulting solution was stripped free of solvent on a rotary evaporator to yield the crude product.
- Example II-A Synthesis of N-(Phenylacetyl)-L-alanine Using General Procedure II-C, the title compound was prepared from phenylacetyl chloride (Aldrich) and L-alanine (Aldrich) as a solid having a melting point of 102-104°C. NMR data was as follows:
- Example II-B Synthesis of N-(3,5-Difluorophenylacetyl)-L-alanine Using General Procedure II-C, the title compound was prepared from 3,5- difluorophenylacetyl chloride (General Procedure II-B) and L-alanine (Aldrich). NMR data was as follows:
- Step A Preparation of N-(Cyclopentylacetyl)-L-alanine Methyl Ester Following General Procedure II-E above using cyclopentylacetic acid (Aldrich) and L-alanine methyl ester hydrochloride (Sigma), the title compound was prepared as a solid having a melting point of 43-46°C. Purification was by recrystallization from ethyl acetate/hexanes. NMR data was as follows:
- Step B ⁇ - Preparation of N-(Cvclopentylacetyl)-L-phenylglvcine
- Methyl ( ⁇ )-3,5-difluoromandelate was separated via preparative chiral HPLC to give a white solid having a melting point of 70-71 °C.
- Anal, calcd for C 9 H 8 F 2 O 3 C, 53.47; H, 3.99. Found: C, 53.40; H, 3.89.
- Step C Preparation of S-(+)-3.5-Difluoromandelic acid A solution of methyl S-(+)-3,5-difluoromandelate (1 eq.) in 74% aqueous
- THF was cooled to 0 °C and treated with lithium hydroxide. After 40 minutes at 0 °C the reaction was complete by TLC. The contents were transferred to a separatory funnel and partitioned between CH 2 C1 2 and saturated aqueous NaHC0 3 . The aqueous layer was acidified with 0.5 N NaHSO 4 and extracted thrice with ethyl acetate. The combined extracts were washed with brine, dried over Na 2 S0 4 , filtered, and concentrated to a white solid having a melting point of 1 19-122 °C. The ⁇ NMR was consistent with known 3,5-difluoromandelic acid.
- Step A To a three-necked flask equipped with a mechanical stirrer and a nitrogen inlet tube was added 3,5-difluorophenylacetic acid (Aldrich) and THF. The reaction mixture was cooled to -78°C and 1.2 eq. of triethylamine was added, followed by dropwise addition of trimethylacetyl chloride (1.05 eq.) (Aldrich). During the addition, the temperature was maintained at -78°C. The cold bath was then removed and replaced with an ice bath. The temperature was allowed to warm to 0°C and stirring was continued for 1 hour. The reaction mixture was then re-cooled to -78 °C. To a second flask charged with 3,5-difluorophenylacetic acid (Aldrich) and THF. The reaction mixture was cooled to -78°C and 1.2 eq. of triethylamine was added, followed by dropwise addition of trimethylacetyl chloride (1.05 e
- Step B To (S)-(-)-3-(3,5-difluorophenyacetyl)-4-benzyl-2-oxazolidione (3.0 mM) in 20 mL of dry THF cooled to -78°C was added LiHMDS (1.05 eq.) dropwise while maintaining the temperature at -78°C. The reaction mixture was allowed to stir at -78°C for 15 min. and then a pre-cooled (-60°C) solution of trisyl azide (1.12 eq.) in 10 mL of THF was added. The reaction mixture was allowed to stir an additional 10 min. and then was quenched with 4.4 eq. of acetic acid.
- Step C To a solution of methyl 2-azido-2-(3,5-difluorophenyl)acetate in
- Step A To (S)-(-)-4-benzyl-2-oxazolidanone (Aldrich) in THF cooled to -50°C was added zz-butyllithium 1.1 eq. (1.6 M in hexane) dropwise-. The reaction mixture was allowed to warm to -20°C and then was re-cooled to -78°C and propionyl chloride (1.1 eq) was added in one portion. The reaction mixture was allowed to stir an additional 15 min. at -78°C and then was allowed to warm to room temperature. The reaction was then quenched with a saturated solution of sodium bicarbonate and extracted with ethyl acetate. The organic extracts were washed with water, followed by brine and then dried over sodium sulfate, filtered and concentrated to give (S)-(-)-3-propionyl-4-benzyl-2- oxazolidanone.
- Step B To a solution of (S)-(-)-3-propionyl-4-benzyl-2-oxazolidanone in THF at -78°C was added KHMDS (1.05 eq.) (Aldrich) dropwise. The reaction mixture was allowed to stir at -78°C for 30 min. and then a precooled solution of di-tert-butyl-azodicarboxylate (Aldrich) was added via a cannula. After 5 min. 2.6 eq. of acetic acid was added. The reaction mixture was then extracted with dichloromethane and the organic layer was washed with IM potassium phosphate.
- KHMDS 1.05 eq.
- Aldrich di-tert-butyl-azodicarboxylate
- Step C To (S)-(-)-3-[(R)-N,N'-di-BOC-2-hydrazinopropionyl]-4-benzyl-2- oxazolidanone (0.49 moles) at 0°C in 8 mL of THF and 3 mL of water was added LiOH (1.7 eq.) and H 2 O 2 (3.0 eq.) and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was then poured into a seraratory funnel and diluted with water. The aqueous mixture was extracted with ethyl acetate and then acidified to pH 2.0 with IN HCl and extracted with ethyl acetate. The organic layer was then dried over sodium sulfate, filtered and solvent removed to give (R)-N,N'-di-BOC-2-hydrazinopropionic acid which was used without further purification.
- Step A Ethyl 3,5-difluorophenyl- ⁇ -oxoacetate was prepared from 1-bromo-
- Step B Ethyl 3,5-difluorophenyl- ⁇ -oxoacetate was hydrolyzed using
- the title compound (CAS No. 6053-71-0) was prepared in two steps from cyclopentylmethanal (CAS No. 872-53-7, Wiley) using the procedure described by Gibby, W. A.; Gubler, C. J. Biochemical Medicine 1982, 27, 15-25.
- N-(3,4-dichlorophenyl)alanine was prepared. Specifically, to a solution of 3,4- dichloroaniline (1 equivalent) (Aldrich) in isopropanol (about 500 mL per mole of 3,4-dichloroaniline) is added water (about 0.06 mL per mL of isopropanol) and 2-chloropropionic acid (2 equivalents) (Aldrich). This mixture is warmed to
- N-(3,5-difluorophenyl)alanine was prepared using 3,5-difluoroaniline (Aldrich) and 2-chloropropionic acid (Aldrich).
- ⁇ MR data was as follows: 'H-nmr (DMSO- 6 ): ⁇ - 4.30 (m, IH), 5.26 (m, IH).
- Step B Synthesis of 2-(3,5-Difluorophenylmethy ⁇ )-4-ethoxycarbonyl-4- methyl-2-imidazoline
- the reaction was allowed to slowly warm to room temperature and stir overnight. The mixture was then filtered through a sintered glass funnel and the filtrate was concentrated on the rotary evaporator. The residue was partitioned between 50 mL of 1.0 N sodium hydroxide and 50 mL of dichloromethane.
- Step C Synthesis of 1-tert-Butoxycarbonyl- 2-(3,5-difluorophenylmethyl)-4-ethoxycarbonyI-4-methyI-2-imidazoline
- reaction was monitored using thin layer chromatography, and when the reaction was complete, the reaction mixture was partitioned between 250 mL of ethyl acetate and 250 mL of saturated brine. The organic layer was washed twice with a 250 mL of saturated brine and then dried over sodium sulfate. Filtration followed by concentration on the rotary evaporator yielded a yellow oil which was purified by flash chromatography on silica gel 60 (230-
- NMK data was as follows:
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Publication number | Priority date | Publication date | Assignee | Title |
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US6635632B1 (en) | 1996-12-23 | 2003-10-21 | Athena Neurosciences, Inc. | Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds |
HUP0100294A3 (en) * | 1997-12-22 | 2003-04-28 | Lilly Co Eli | Polycyclic alpha-amino-sigma-caprolactams and related compounds |
US6552013B1 (en) | 1998-06-22 | 2003-04-22 | Elan Pharmaceuticals, Inc. | Deoxyamino acid compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds |
JP2002518481A (ja) * | 1998-06-22 | 2002-06-25 | エラン ファーマシューティカルズ,インコーポレイテッド | β−アミロイドペプチドの放出および/またはその合成を阻害するための化合物 |
US6509331B1 (en) | 1998-06-22 | 2003-01-21 | Elan Pharmaceuticals, Inc. | Deoxyamino acid compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds |
US6528505B1 (en) | 1998-06-22 | 2003-03-04 | Elan Pharmaceuticals, Inc. | Cyclic amino acid compounds pharmaceutical compositions comprising same and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds |
US6569851B1 (en) | 1998-06-22 | 2003-05-27 | Elan Pharmaceutials, Inc. | Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds |
US6774125B2 (en) | 1998-06-22 | 2004-08-10 | Elan Pharmaceuticals, Inc. | Deoxyamino acid compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds |
US6737038B1 (en) | 1998-11-12 | 2004-05-18 | Bristol-Myers Squibb Company | Use of small molecule radioligands to discover inhibitors of amyloid-beta peptide production and for diagnostic imaging |
WO2000051998A1 (en) | 1999-03-02 | 2000-09-08 | Boehringer Ingelheim Pharmaceuticals, Inc. | Compounds useful as reversible inhibitors of cathepsin s |
US7160880B1 (en) | 1999-05-14 | 2007-01-09 | Cenes Limited | Short-acting benzodiazepines |
GB9911803D0 (en) * | 1999-05-20 | 1999-07-21 | Merck Sharp & Dohme | Therapeutic combination |
MXPA02001340A (es) * | 1999-08-05 | 2004-07-16 | Prescient Neuropharma Inc | Compuestos novedosos 1,4-benzodiazepina y derivados de los mismos. |
US6420364B1 (en) | 1999-09-13 | 2002-07-16 | Boehringer Ingelheim Pharmaceuticals, Inc. | Compound useful as reversible inhibitors of cysteine proteases |
US6878363B2 (en) | 2000-05-17 | 2005-04-12 | Bristol-Myers Squibb Pharma Company | Use of small molecule radioligands to discover inhibitors of amyloid-beta peptide production and for diagnostic imaging |
CN1386118A (zh) | 2000-06-01 | 2002-12-18 | 布里斯托尔-迈尔斯斯奎布药品公司 | 作为Aβ蛋白产生抑制剂的被环状琥珀酸酯取代的内酰胺类化合物 |
DE10029077A1 (de) * | 2000-06-13 | 2001-12-20 | Bayer Ag | Thiazolylsubstituierte Heterocyclen |
US6432944B1 (en) | 2000-07-06 | 2002-08-13 | Bristol-Myers Squibb Company | Benzodiazepinone β-amyloid inhibitors: arylacetamidoalanyl derivatives |
FR2840899B1 (fr) * | 2002-06-12 | 2005-02-25 | Sanofi Synthelabo | Derives d'acylaminothiazole, leur preparation et leur utilisation en therapeutique |
AR039059A1 (es) | 2001-08-06 | 2005-02-09 | Sanofi Aventis | Compuesto derivado de acilaminotiazol, su utilizacion, procedimientos para prepararlo, composicion farmaceutica que lo comprende, y compuestos intermediarios |
KR20050010826A (ko) | 2002-06-05 | 2005-01-28 | 가부시키가이샤 가네카 | 광학 활성 α-메틸시스테인 유도체의 제조 방법 |
NZ588431A (en) | 2004-09-17 | 2012-02-24 | Whitehead Biomedical Inst | Using Benzimidazole or Indole compounds with a 1,2-diazole group to Inhibit Alpha-Synuclein Toxicity |
US7449486B2 (en) | 2004-10-19 | 2008-11-11 | Array Biopharma Inc. | Mitotic kinesin inhibitors and methods of use thereof |
UA95907C2 (en) | 2005-05-02 | 2011-09-26 | Эррей Биофарма Инк. | Mitotic kinesin inhibitors and methods of use thereof |
EP1757290A1 (de) | 2005-08-16 | 2007-02-28 | Zentaris GmbH | Triazolderivate als Liganden der Wachstumshormonrezeptoren |
WO2008042928A2 (en) | 2006-10-03 | 2008-04-10 | Array Biopharma, Inc. | Oxadiazole and thiadiazole derivatives as mitotic kinesin inhibitors and methods of use thereof |
ES2700613T3 (es) * | 2008-07-16 | 2019-02-18 | Bitop Ag | Síntesis de amidinas cíclicas |
AR081626A1 (es) | 2010-04-23 | 2012-10-10 | Cytokinetics Inc | Compuestos amino-piridazinicos, composiciones farmaceuticas que los contienen y uso de los mismos para tratar trastornos musculares cardiacos y esqueleticos |
AR081331A1 (es) | 2010-04-23 | 2012-08-08 | Cytokinetics Inc | Amino- pirimidinas composiciones de las mismas y metodos para el uso de los mismos |
EP2560488B1 (de) | 2010-04-23 | 2015-10-28 | Cytokinetics, Inc. | Bestimmte aminopyrimidine und aminotriazine, zusammensetzungen daraus und verfahren zu ihrer verwendung |
EP2431035A1 (de) | 2010-09-16 | 2012-03-21 | Æterna Zentaris GmbH | Neue Triazolderivate mit verbesserter Rezeptoraktivität und Bioverfügbarkeitseigenschaften als Ghrelin-Antagonisten der Wachstumshormon-Sekretagogum-Rezeptoren |
US8759380B2 (en) | 2011-04-22 | 2014-06-24 | Cytokinetics, Inc. | Certain heterocycles, compositions thereof, and methods for their use |
US8809372B2 (en) | 2011-09-30 | 2014-08-19 | Asana Biosciences, Llc | Pyridine derivatives |
CN103435549A (zh) * | 2013-08-14 | 2013-12-11 | 无锡惠飞生物医药技术有限公司 | 5-甲基-7-氨基-5H,7H-二苯并[b,d]氮杂环庚-6-酮的制备方法 |
CN105646208B (zh) * | 2016-02-24 | 2018-10-16 | 潍坊晶润化工股份有限公司 | 丙酮酸甲酯的制备方法 |
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ZA981627B (en) | 1999-10-05 |
PL335424A1 (en) | 2000-04-25 |
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CO4920244A1 (es) | 2000-05-29 |
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