CA2062755A1 - Amino acid analog cck antagonists - Google Patents
Amino acid analog cck antagonistsInfo
- Publication number
- CA2062755A1 CA2062755A1 CA002062755A CA2062755A CA2062755A1 CA 2062755 A1 CA2062755 A1 CA 2062755A1 CA 002062755 A CA002062755 A CA 002062755A CA 2062755 A CA2062755 A CA 2062755A CA 2062755 A1 CA2062755 A1 CA 2062755A1
- Authority
- CA
- Canada
- Prior art keywords
- mmol
- loweralkyl
- product
- pentylamide
- 300mhz
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
- C07C237/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/24—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the same saturated acyclic carbon skeleton
- C07C255/29—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the same saturated acyclic carbon skeleton containing cyano groups and acylated amino groups bound to the carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
- C07C255/41—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by carboxyl groups, other than cyano groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/24—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a ring other than a six-membered aromatic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/46—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylureas
- C07C275/58—Y being a hetero atom
- C07C275/62—Y being a nitrogen atom, e.g. biuret
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/14—Sulfones; Sulfoxides having sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
- C07C323/58—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/56—Amides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- C—CHEMISTRY; METALLURGY
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- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
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- C—CHEMISTRY; METALLURGY
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- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
- C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
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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
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/182—Radicals derived from carboxylic acids
- C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans 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 carbon atoms of the hetero ring
- C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
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- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes 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 carbon atoms of the hetero ring
- C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D333/70—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
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- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
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- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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Abstract
A CCK antagonist compound of formula (I) wherein G is (1) NH2 or (2) substituted amino; R9 is (1) hydrogen, (2) loweralkyl, (3) carboxy-substituted alkyl or (4) carboxyester-substituted alkyl; R10 is (1) hydrogen, (2) loweralkyl, (3) functionalized alkyl or (4) cycloalkyl; D is (1) hydrogen, (2) loweralkyl, (3) functionalized alkyl, (4) cycloalkyl, (5) aryl, (6) functionalized oxyalkyl or (7) heterocyclic; with the proviso that D is other than indolylmethyl, indolinylmethyl or oxindolylmethyl; or R10 taken together with D or R9 taken together with D forms a cyclic group; Z is (1) -C(O)-, (2) -C(S)- or (3) -S(O)2-; B is (1) absent, (2) alkylene, (3) alkenylene, (4) substituted alkenylene, (5) -R26-R27- wherein R26 is absent or -CH2- and R27 is -O-, -S-, -NH- or -N(loweralkyl)- or (6) -R27-CH2- wherein R27 is defined as above; and Ar is (1) aryl or (2) a heterocyclic group.
Description
W09l/0072~ 2 ~ S 5 PCT/US90/03630 A~INO ACID ANALOG CCK ANTAGONISTS
This is a continuation-in-part of U.S. Patent application Serial No. 376,778, filed July 7, 1989, which is a continuation-in-part of PCT patent application Serial No. PCT/US89/01412, filed April 4, 1989, which is a continuation-in-part of U.S. patent application Serial No.
177,715, filed April 5, 1988.
Technical Field The present invention relates to compounds and compositions which antagonize cholecystokinin and gastrin, processes for making such compounds, synthetic intermediates employed in these processes and a method for treating gastrointestinal disorders, central nervous system disorders, cancers of the gastrointestinal system - (i.e., pancreas, gall bladder, etc.), hypoinsulinemia, or ,; '.
- : ~ , , . :
. ..
WO9l/00725 PCT/US90/03630 ., f~.
, . v X~5 :;
potentiating analgesics, or regulating appetite disorders with such compounds.
Backaround of the Invention Cholecystokinins (CCK) are a family of polypeptide hormones. CCK and a 33 amino acid fragment of CCK (CCK33) were first isolated from hog intestine. (Mut and Jorpes, Biochem. ~. 125, 628, 1981). Recently the CCK33 fragment has been found in the brain, where it appears to be the precursor of two smaller fragments, an octapeptide CCK8 and a tetrapeptide CCK4. (Dockray, Nat~re 264, 4022, 1979)-CCK8, the carboxyl terminal octapeptide fragment ofCCK, is the smallest CCK fragment that remains fully biologically active. (Larsson and Rehfeld, Brain ~
1~, 201-218, 1979). The localization of CCK fragments in the cortex of the brain suggests that CCK may be an important neuromodulator of memory, lea-ning and control of primary sensory and motor functions. CCK and its fragments are believed to play an impor-ant role in appetite regulation and satiety. (Della-Fera, ~ ~s~
2Q6, 471, 1979; Gibbs et al., Nature ~, 599, 1981; and Smith, Eating and Its Disorders, eds., ~aven Press, New York, 67 ~984).
CCK antagonists (B.J. Gertz in Neu-oloay and ~eurobioloaY Vol 47, Cholecystokinin An-aaonists, Wang and Schoenfeld eds. Alan R. Liss, Inc., New York, NY, 327-342, 1988; Sil~erman et al., a~ J Gastroent., 82(8), 703-8, 1987) are useful in the treatment and prevention of CC~-related disorders of the gastrointestin~l (GI) (Lotti et ~ . . . - . .
. .
, . : - .
.
. . . .
WO91/00?25 PCT/US90/03630 ~ ~ ~ ? 7 SS
~. .. .
al., J Pharm E~ IhsL~ 1), 103-9, 1987), central nervous (CNS) ~Panerai et al Neuropharmacoloay, ~(9), 1285-87, 1987) and appetite regulatory systems of animals, especially man. CCK antagonists are also useful in potentiating and prolonging opiate induced analgesia and thus have utility in the treatment of pain. ~Faris et al., Science ~2~, 121S, 1984; Rovati et al., Clinical Research, 34(2), 906A, 1986; Dourish et al., European J.
Pharmacology, 147, 469-72, 1988). Disease states that may be treated with CCK antagonists are disorders of gastric emptying, gastroesophageal reflux disease ~Setnikar et al ~z~ Forsch./Drua Research, 37(II) 10, 1168-71, 1987), pancreatitis, pancreatic and gastric carcinomas (Douglas et al., Gas~roent. 2~, 4629, 1989;
Beauchamp et al., B~ Sura, 202, 313-9, 1985), disorders of bowel motility, biliary dyskinesia, anorexia nervosa, hypoglycemia (Rossetti, Diabetes, 36, 1212-15, 1987;
Reagan, ~uropean J. Pharmacoloav, 144, 241-3, 1987), gallbladder disease, and the like.
Previously four distinct chemical classes of CCK
receptor antagonists have been reported. The first class comprises derivatives of cyclic nucleotides as represented by dibutyryl cyclic GMP (N. Barlos et al., ~m_ J.
Phvsiol~ 2, G161, 1982) and references sited therein)~
The second class is represented by the C-terminal fragments of CCK tsee Jensen et al. Biochem Biophys.
~La, 757, 250 1983) and Spanarkel J. Biol. Chem. 258, 6746, 1983). The third class comprises amino acid derivatives of glutamic acid and tryptophan as indicated by proglumide (and its analogs) and benzotript (see Hahne WO9l/~0725 PCT/US90/03630 SS
et al ~oc. Natl. ~cad. ~ci. U.S.A., 78, 6304, 1981 and Jensen et al. ~i~chem. Biophys. B~S~_ 761, 269, 1983).
Tne fourth and most recent class is comprised of 3-substituted benzodiazepines, represented by L-364,718 (see: Evans et al. Proc. Natl. Acad. Sci. U.S.A., 83 4918, lg86) .
With the exception of certain substituted benzodiazepines and recently reported analogs of proglumide (Makovec et al Arzneim.-Forsch./Druq Res.
36,(I), 98-102, 1986) , all of these compounds are relatively weak antagonists of CCK usually demonstrating IC50's between 10 9 and 10 6 M. The benzodiazepine CCK
antagonists or their metabolites may have undesireable e~fects i~ v vo due to their interaction with benzodiazepine or other receptors.
The C-terminal pentapeptide fragment of CCK is the same as the C-terminal pentapeptide fragment of another polypeptide hormone, gastrin. Gastrin, like CCK, exists in the GI system. Gastrin antagonists are useful in the treatment and prevention of gastrin related disorders of the GI system such as ulcers, Zollinge--Ellison syndrome and central G cell hyperplasia. There are no effective receptor antagonists of the in vivo ef-ects of gastrin.
(Morely, Gut Pept. Ulcer Proc., Hiroshima Symp. 2nd, 1, 1983). A recent report (Bock J. ~. Chem., 32, 13-16, 1989) discloses potent n vitro gast- ~ antagonists.
: ', '. '. ' WOgl/00725 PCT/US90/03630
This is a continuation-in-part of U.S. Patent application Serial No. 376,778, filed July 7, 1989, which is a continuation-in-part of PCT patent application Serial No. PCT/US89/01412, filed April 4, 1989, which is a continuation-in-part of U.S. patent application Serial No.
177,715, filed April 5, 1988.
Technical Field The present invention relates to compounds and compositions which antagonize cholecystokinin and gastrin, processes for making such compounds, synthetic intermediates employed in these processes and a method for treating gastrointestinal disorders, central nervous system disorders, cancers of the gastrointestinal system - (i.e., pancreas, gall bladder, etc.), hypoinsulinemia, or ,; '.
- : ~ , , . :
. ..
WO9l/00725 PCT/US90/03630 ., f~.
, . v X~5 :;
potentiating analgesics, or regulating appetite disorders with such compounds.
Backaround of the Invention Cholecystokinins (CCK) are a family of polypeptide hormones. CCK and a 33 amino acid fragment of CCK (CCK33) were first isolated from hog intestine. (Mut and Jorpes, Biochem. ~. 125, 628, 1981). Recently the CCK33 fragment has been found in the brain, where it appears to be the precursor of two smaller fragments, an octapeptide CCK8 and a tetrapeptide CCK4. (Dockray, Nat~re 264, 4022, 1979)-CCK8, the carboxyl terminal octapeptide fragment ofCCK, is the smallest CCK fragment that remains fully biologically active. (Larsson and Rehfeld, Brain ~
1~, 201-218, 1979). The localization of CCK fragments in the cortex of the brain suggests that CCK may be an important neuromodulator of memory, lea-ning and control of primary sensory and motor functions. CCK and its fragments are believed to play an impor-ant role in appetite regulation and satiety. (Della-Fera, ~ ~s~
2Q6, 471, 1979; Gibbs et al., Nature ~, 599, 1981; and Smith, Eating and Its Disorders, eds., ~aven Press, New York, 67 ~984).
CCK antagonists (B.J. Gertz in Neu-oloay and ~eurobioloaY Vol 47, Cholecystokinin An-aaonists, Wang and Schoenfeld eds. Alan R. Liss, Inc., New York, NY, 327-342, 1988; Sil~erman et al., a~ J Gastroent., 82(8), 703-8, 1987) are useful in the treatment and prevention of CC~-related disorders of the gastrointestin~l (GI) (Lotti et ~ . . . - . .
. .
, . : - .
.
. . . .
WO91/00?25 PCT/US90/03630 ~ ~ ~ ? 7 SS
~. .. .
al., J Pharm E~ IhsL~ 1), 103-9, 1987), central nervous (CNS) ~Panerai et al Neuropharmacoloay, ~(9), 1285-87, 1987) and appetite regulatory systems of animals, especially man. CCK antagonists are also useful in potentiating and prolonging opiate induced analgesia and thus have utility in the treatment of pain. ~Faris et al., Science ~2~, 121S, 1984; Rovati et al., Clinical Research, 34(2), 906A, 1986; Dourish et al., European J.
Pharmacology, 147, 469-72, 1988). Disease states that may be treated with CCK antagonists are disorders of gastric emptying, gastroesophageal reflux disease ~Setnikar et al ~z~ Forsch./Drua Research, 37(II) 10, 1168-71, 1987), pancreatitis, pancreatic and gastric carcinomas (Douglas et al., Gas~roent. 2~, 4629, 1989;
Beauchamp et al., B~ Sura, 202, 313-9, 1985), disorders of bowel motility, biliary dyskinesia, anorexia nervosa, hypoglycemia (Rossetti, Diabetes, 36, 1212-15, 1987;
Reagan, ~uropean J. Pharmacoloav, 144, 241-3, 1987), gallbladder disease, and the like.
Previously four distinct chemical classes of CCK
receptor antagonists have been reported. The first class comprises derivatives of cyclic nucleotides as represented by dibutyryl cyclic GMP (N. Barlos et al., ~m_ J.
Phvsiol~ 2, G161, 1982) and references sited therein)~
The second class is represented by the C-terminal fragments of CCK tsee Jensen et al. Biochem Biophys.
~La, 757, 250 1983) and Spanarkel J. Biol. Chem. 258, 6746, 1983). The third class comprises amino acid derivatives of glutamic acid and tryptophan as indicated by proglumide (and its analogs) and benzotript (see Hahne WO9l/~0725 PCT/US90/03630 SS
et al ~oc. Natl. ~cad. ~ci. U.S.A., 78, 6304, 1981 and Jensen et al. ~i~chem. Biophys. B~S~_ 761, 269, 1983).
Tne fourth and most recent class is comprised of 3-substituted benzodiazepines, represented by L-364,718 (see: Evans et al. Proc. Natl. Acad. Sci. U.S.A., 83 4918, lg86) .
With the exception of certain substituted benzodiazepines and recently reported analogs of proglumide (Makovec et al Arzneim.-Forsch./Druq Res.
36,(I), 98-102, 1986) , all of these compounds are relatively weak antagonists of CCK usually demonstrating IC50's between 10 9 and 10 6 M. The benzodiazepine CCK
antagonists or their metabolites may have undesireable e~fects i~ v vo due to their interaction with benzodiazepine or other receptors.
The C-terminal pentapeptide fragment of CCK is the same as the C-terminal pentapeptide fragment of another polypeptide hormone, gastrin. Gastrin, like CCK, exists in the GI system. Gastrin antagonists are useful in the treatment and prevention of gastrin related disorders of the GI system such as ulcers, Zollinge--Ellison syndrome and central G cell hyperplasia. There are no effective receptor antagonists of the in vivo ef-ects of gastrin.
(Morely, Gut Pept. Ulcer Proc., Hiroshima Symp. 2nd, 1, 1983). A recent report (Bock J. ~. Chem., 32, 13-16, 1989) discloses potent n vitro gast- ~ antagonists.
: ', '. '. ' WOgl/00725 PCT/US90/03630
2~ S5 . ,. ,. `. .
~isclosure of the Tnvention In accordance with the present invention, there are cholecystokinin antagonists of the formula:
B ~ ~ r ~ G
Rg O
(I) or a pharmaceutically acceptable salt thereof.
G is (l) NH2 or (2) substituted amino.
Rg is (l) hydrogen, (2) loweralkyl,
~isclosure of the Tnvention In accordance with the present invention, there are cholecystokinin antagonists of the formula:
B ~ ~ r ~ G
Rg O
(I) or a pharmaceutically acceptable salt thereof.
G is (l) NH2 or (2) substituted amino.
Rg is (l) hydrogen, (2) loweralkyl,
(3) carboxy-substituted alkyl or
(4) carboxyester-substituted alkyl.
Rlo is (l) hydrogen, (2) loweralkyl, (3) functionalized alkyl or (4) cycloalkyl.
D is ~) hydrogen, (2) loweralkyl, , " , . . : - : . . ~ . .
... . : . : , . , . :, W091tO0725 PCT~US90/03630 ," ~, 7~5 (3) functionalized alkyl, (4) cycloalkyl,
Rlo is (l) hydrogen, (2) loweralkyl, (3) functionalized alkyl or (4) cycloalkyl.
D is ~) hydrogen, (2) loweralkyl, , " , . . : - : . . ~ . .
... . : . : , . , . :, W091tO0725 PCT~US90/03630 ," ~, 7~5 (3) functionalized alkyl, (4) cycloalkyl,
(5) aryl,
(6) functionalized oxyalkyl or
(7) heterocyclic;
or Rlo taken together with D is (1) C4 to C6 alkylene, (2) ~(CH2)q~V~(CH2)r~ wherein q is 1 to 3, r is 1 to 3 and V is (i) --O--, ( i i ) --S--, (iii) -CH2- or (iv) -N(R2s)- wherein R2s is hydrogen, loweralkyl, haloalkyl, alkoxyalkyl, arylalkyl, aryl or an N-protecting group;
or Rg taken together with D is (1) C3 to Cs alkylene or (2) -(CH2)p-V-(CH2)t- wherein p is 1 to 3, t is 1 to 3 and V is defined as above.
Z is (1) --C (O)--, (2) -C(S)- or (3) -S(0)2-.
B is (1) absent, (2) alkylene, (3) alkenylene, .
~ : , : , WO 91/0072~ PCT/US90/03630 2C~7~5~
(4) substituted alkenylene, ~5) -R26-R27- wherein R26 is absent or -CH2- and R27 is -O-, -S-, -NH- or -N(loweralkyl)- or ~6) -R27-CH2- wherein R27 is defined as above.
Ar is ~1) aryl or ~2) a heterocyclic group.
Compounds wherein D is indolylmethyl, indolinylmethyl or oxindolylmethyl are disclosed in the copending parent application PCT Patent Application Serial No.
PCT/US89/01412, filed April 4, 1989.
The term "loweralkyl" as used herein refers to straight or branched chain alkyl radicals containing from 1 to 8 carbon atoms including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n- -hexyl, 2-methylpentyl, 2,2-dimethylbutyl and the like.
The term "functionalized alkyl" as used herein includes ~1) haloalkyl, :-~2) alkenyl, (3) arylalkyl, (4) arylalkyl wherein the alkyl group is substituted by (i) -OR16 wherein R16 is hydrogen or a hydroxyl protecting group, (ii) -NHRls wherein Rls is hydrogen or an . . ~
- : . ,- . . ,................. :
:., . : ,' ~ :~. ,''. ', ' ::, ' ' : . :., , :, .
- . , . .: . .
:: ~ . , :
WO gltO0725 Pcr/ussnto3630 2~ 755 ~
N-protecting group, (iii) -OR13 wherein R13 is loweralkyl, (iv) -OR14 wherein R14 is an aryl group or (v) -SR13 wherein R13 is loweralkyl, (5) heterocyclicalkyl, (6) heterocyclicalkyl wherein the alkyl group is substituted by (i) -OR16 wherein R16 is hydrogen or a hydroxyl protecting group, (ii) -NHRls wherein Rls is hydrogen or an N-protecting group, (iii) -OR13 wherein R13 is loweralkyl, (iv) -OR14 wherein R14 is an aryl group or (v) -SR13 wherein R13 is loweralkyl, (7) loweralkyl substituted by -S-loweralkyl, -S(O)-loweralkyl or -S(0)2-loweralkyl,
or Rlo taken together with D is (1) C4 to C6 alkylene, (2) ~(CH2)q~V~(CH2)r~ wherein q is 1 to 3, r is 1 to 3 and V is (i) --O--, ( i i ) --S--, (iii) -CH2- or (iv) -N(R2s)- wherein R2s is hydrogen, loweralkyl, haloalkyl, alkoxyalkyl, arylalkyl, aryl or an N-protecting group;
or Rg taken together with D is (1) C3 to Cs alkylene or (2) -(CH2)p-V-(CH2)t- wherein p is 1 to 3, t is 1 to 3 and V is defined as above.
Z is (1) --C (O)--, (2) -C(S)- or (3) -S(0)2-.
B is (1) absent, (2) alkylene, (3) alkenylene, .
~ : , : , WO 91/0072~ PCT/US90/03630 2C~7~5~
(4) substituted alkenylene, ~5) -R26-R27- wherein R26 is absent or -CH2- and R27 is -O-, -S-, -NH- or -N(loweralkyl)- or ~6) -R27-CH2- wherein R27 is defined as above.
Ar is ~1) aryl or ~2) a heterocyclic group.
Compounds wherein D is indolylmethyl, indolinylmethyl or oxindolylmethyl are disclosed in the copending parent application PCT Patent Application Serial No.
PCT/US89/01412, filed April 4, 1989.
The term "loweralkyl" as used herein refers to straight or branched chain alkyl radicals containing from 1 to 8 carbon atoms including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n- -hexyl, 2-methylpentyl, 2,2-dimethylbutyl and the like.
The term "functionalized alkyl" as used herein includes ~1) haloalkyl, :-~2) alkenyl, (3) arylalkyl, (4) arylalkyl wherein the alkyl group is substituted by (i) -OR16 wherein R16 is hydrogen or a hydroxyl protecting group, (ii) -NHRls wherein Rls is hydrogen or an . . ~
- : . ,- . . ,................. :
:., . : ,' ~ :~. ,''. ', ' ::, ' ' : . :., , :, .
- . , . .: . .
:: ~ . , :
WO gltO0725 Pcr/ussnto3630 2~ 755 ~
N-protecting group, (iii) -OR13 wherein R13 is loweralkyl, (iv) -OR14 wherein R14 is an aryl group or (v) -SR13 wherein R13 is loweralkyl, (5) heterocyclicalkyl, (6) heterocyclicalkyl wherein the alkyl group is substituted by (i) -OR16 wherein R16 is hydrogen or a hydroxyl protecting group, (ii) -NHRls wherein Rls is hydrogen or an N-protecting group, (iii) -OR13 wherein R13 is loweralkyl, (iv) -OR14 wherein R14 is an aryl group or (v) -SR13 wherein R13 is loweralkyl, (7) loweralkyl substituted by -S-loweralkyl, -S(O)-loweralkyl or -S(0)2-loweralkyl,
(8) loweralkyl substituted by -S-aryl, -S(O)-aryl or -S(0)2- aryl and
(9) loweralkyl substituted by -NHR12 wherein R12 lS
(i) hydrogen, (ii) -C(O)R4 wherein R4 is ir.dependently selected from loweralkyl, alkenyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl, ~iii) -CO2R4 wherein R4 is independently defined as above, (iv) an N-protecting group, (v) -C(O)-A-aryl wherein A is alkenylene, substituted alkenylene, -OCH~-, -SCH2-, -NH-, -N(loweralkyl)-, -S- or -O-.
.::. , . :: :
.
.
Z~-?755 9 ; . ., ~
The term "functionalized oxyalkyl" as used herein includes -T-OR11 wherein T is (1) alkylene or (2) arylalkylene and Rll iS
(1) hydrogen, (2) loweralkyl, (3) haloalkyl, (4) alkenyl, (5) arylalkyl, ~6) hydroxyl protecting group, (7) -C(O)-(L)~-R4 wherein R4 is independently defined as above, s ~s 0 or 1 and L is (i) o, (ii) S or (iii) NH or (8) -C(O)-A-aryl wherein A is independently defined as above.
The term "haloalkyl" as used here-n refers to a loweralkyl radical in which one or more hydrogen atoms have been substituted by halo groups i~cluding, but not limited to, fluoromethyl, trifluoromet~yl, chloroethyl, 2,2-difluorethyl, 2,3-dibromopropyl and the like.
The term "alkoxyalkyl" as used he-ein refers to an alkoxy group appended to a loweralkyl =adical.
The term "cyanoalkyl" as used herein refers to a cyano group (-CN) appended to a lowerarkyl radical.
._ .... ... ~ ................. - . , .-.,, .. : ~ - . :
.. .. . . .
~=~
' ' ' , Z(~ 755 - 1 o -The term "hydroxyalkyl" as used herein refers to a hydroxy group (-OH) appended to a loweralkyl radical.
The term "cycloalkyl" as used herein refers to an alicyclic ring having 3 to 7 carbon atoms including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl and the like.
The term "cycloalkylalkyl" as used herein refers to a cycloalkyl group appended to a loweralkyl radical including, but not limited to, cyclopropylmethyl, cyclohexylethyl and the like.
The term "carboxy-substituted alkyl" as used herein refers to a carboxy group ~-COOH) appended to a loweralkyl radical.
The term "carboxyester-substituted alkyl" as used herein refers to a carboxyester group ~-COOR' wherein R' is loweralkyl, cycloalkyl, aryl or arylalkyl) appended to a loweralkyl radical.
The term "alkenyl" as used herein refers to a straight or branched chain of 2 to 8 carbon atoms containing a carbon-carbon double bond including, but not limited to, vinyl, allyl, butenyl and the like.
The term "alkylene group" as used herein refers to a straight or branched chain spacer group containing 1 to 8 carbon atoms including, but not limited to, -CH2-, -CH(CH3)-, -CH(CH3~CH2-, -(CH2)3- and the like.
The term "alkenylene group" as used herein refers to a straight or branched chain spacer group of 2 to 8 carbon atoms containing a carbon-carbon double bond including, but not limited to, -CH=CH-, -C(CH3)=C:i-, -CH2-CH=CH-, -CH(CH3)-CH2-CH=CH-CH2- and the like.
, .. . . .
:- . .: .
.
. :., WO9l/0~725 PCT/VS90/03630 . ' s5 :... .. ...
The term "substituted alkenylene" as used herein refers to an alkenylene group substituted with one or two substituents independently selected from loweralkyl, haloalkyl, halo and cyano.
The term "cycloalkylalkylene" as used herein refers to a cycloalkyl group appended to an alkylene radical.
The term "substituted amino" as used herein includes -N(Rl)(R2) wherein R1 and R2 are independently selected from (1) hydrogen, (2~ loweralkyl, (3) haloalkyl, (4) alkoxyalkyl, (5) alkenyl, (6) aryl, (7) arylalkyl, (8) cycloalkyl, (9) cycloalkylalkyl,
(i) hydrogen, (ii) -C(O)R4 wherein R4 is ir.dependently selected from loweralkyl, alkenyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl, ~iii) -CO2R4 wherein R4 is independently defined as above, (iv) an N-protecting group, (v) -C(O)-A-aryl wherein A is alkenylene, substituted alkenylene, -OCH~-, -SCH2-, -NH-, -N(loweralkyl)-, -S- or -O-.
.::. , . :: :
.
.
Z~-?755 9 ; . ., ~
The term "functionalized oxyalkyl" as used herein includes -T-OR11 wherein T is (1) alkylene or (2) arylalkylene and Rll iS
(1) hydrogen, (2) loweralkyl, (3) haloalkyl, (4) alkenyl, (5) arylalkyl, ~6) hydroxyl protecting group, (7) -C(O)-(L)~-R4 wherein R4 is independently defined as above, s ~s 0 or 1 and L is (i) o, (ii) S or (iii) NH or (8) -C(O)-A-aryl wherein A is independently defined as above.
The term "haloalkyl" as used here-n refers to a loweralkyl radical in which one or more hydrogen atoms have been substituted by halo groups i~cluding, but not limited to, fluoromethyl, trifluoromet~yl, chloroethyl, 2,2-difluorethyl, 2,3-dibromopropyl and the like.
The term "alkoxyalkyl" as used he-ein refers to an alkoxy group appended to a loweralkyl =adical.
The term "cyanoalkyl" as used herein refers to a cyano group (-CN) appended to a lowerarkyl radical.
._ .... ... ~ ................. - . , .-.,, .. : ~ - . :
.. .. . . .
~=~
' ' ' , Z(~ 755 - 1 o -The term "hydroxyalkyl" as used herein refers to a hydroxy group (-OH) appended to a loweralkyl radical.
The term "cycloalkyl" as used herein refers to an alicyclic ring having 3 to 7 carbon atoms including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl and the like.
The term "cycloalkylalkyl" as used herein refers to a cycloalkyl group appended to a loweralkyl radical including, but not limited to, cyclopropylmethyl, cyclohexylethyl and the like.
The term "carboxy-substituted alkyl" as used herein refers to a carboxy group ~-COOH) appended to a loweralkyl radical.
The term "carboxyester-substituted alkyl" as used herein refers to a carboxyester group ~-COOR' wherein R' is loweralkyl, cycloalkyl, aryl or arylalkyl) appended to a loweralkyl radical.
The term "alkenyl" as used herein refers to a straight or branched chain of 2 to 8 carbon atoms containing a carbon-carbon double bond including, but not limited to, vinyl, allyl, butenyl and the like.
The term "alkylene group" as used herein refers to a straight or branched chain spacer group containing 1 to 8 carbon atoms including, but not limited to, -CH2-, -CH(CH3)-, -CH(CH3~CH2-, -(CH2)3- and the like.
The term "alkenylene group" as used herein refers to a straight or branched chain spacer group of 2 to 8 carbon atoms containing a carbon-carbon double bond including, but not limited to, -CH=CH-, -C(CH3)=C:i-, -CH2-CH=CH-, -CH(CH3)-CH2-CH=CH-CH2- and the like.
, .. . . .
:- . .: .
.
. :., WO9l/0~725 PCT/VS90/03630 . ' s5 :... .. ...
The term "substituted alkenylene" as used herein refers to an alkenylene group substituted with one or two substituents independently selected from loweralkyl, haloalkyl, halo and cyano.
The term "cycloalkylalkylene" as used herein refers to a cycloalkyl group appended to an alkylene radical.
The term "substituted amino" as used herein includes -N(Rl)(R2) wherein R1 and R2 are independently selected from (1) hydrogen, (2~ loweralkyl, (3) haloalkyl, (4) alkoxyalkyl, (5) alkenyl, (6) aryl, (7) arylalkyl, (8) cycloalkyl, (9) cycloalkylalkyl,
(10) cyanoalkyl,
(11) loweralkyl substituted by -CO2R3 wherein R3 (i) hydrogen, (ii) loweralkyl, (iii) cycloalkyl, (iv) aryl or (v) arylalkyl,
(12) loweralkyl substituted by -C(O)N(Rs)~R6) wherein R5 and R6 are independently selected from (i) hydrogen, (ii) loweralkyl, .. . , . . , . .. . ,- . . . .
WO9l/00725 PCT/US9D/03630 .. ..
Z~ . 55 (iii) cycloalkyl, (iv) alkoxyalkyl, (v) alkenyl, (vi) aryl and (vii) arylalkyl,
WO9l/00725 PCT/US9D/03630 .. ..
Z~ . 55 (iii) cycloalkyl, (iv) alkoxyalkyl, (v) alkenyl, (vi) aryl and (vii) arylalkyl,
(13) -W-CO2R3 wherein R3 is defined as above and W is (i) cycloalkylalkylene, (ii) arylalkylene or (iii) heteroarylalkylene,
(14) adamantyl,
(15) indanyl and
(16) -CH(aryl)-X wherein X is arylalkyl;
with the proviso that R1 and R2 are not both hydrogen.
Substituted amino also includes ~ H~R8 --N /J
(CH2)r wherein n is 1 to 3, r is 1 to 3 and J is (1) --S--, (2) -S(O)-, (3) -S(O)2-~
(4) -O-, (5) -CH2-r ~6) -N~Rs)- wherein RS is defined as above or (7) -N (C (O) R4) wherein R4 is defined as above and R8 represents one, two or three substituents independently .
2~
selected from (1) hydrogen, ~2) loweralkyl, (3) haloalkyl, ~4) aryl, (5) -C~O)R4 wherein R4 is independently defined as above, (6) -C(O)N(RS)(R6) wherein Rs and R6 are independently defined as above, (7) -0Rl6 wherein R16 is (i) hydrogen or (ii) hydroxyl protecting group, (8) hydroxyalkyl, (9) alkoxyalkyl, (10) -NH~R1s) wherein Rls is (i) hydrogen or (ii) an N-protecting group, (11) cyano and (12) halo.
The term "alkylamino" as used herein refers to -NHR40 wherein R40 is a loweralkyl group.
The term "dialkylamino" as used herein refers to -NR4lR42 wherein R4l and R42 are independently selected from loweralkyl.
The term "aminocarbonyl" as used herein refers to --C (O) NH2 -The term "alkylaminocarbonyl" as used herein refers to -C(0)Rso wherein Rso is an alkylamino group.
The term "dialkylaminocarbonyl" as used herein refers to -C(O)Rs1 wherein Rs1 is a dialkylami.o group.
.
, . ,, . . . . . . . -. : , ; -The term "alkenylaminocarbonyl" as used herein refers to -C(O)NHRs2 wherein Rs2 is an alkenyl group.
The term "halogen" or "halo" as used herein refers to F, Cl, Br, I.
The terms "alkoxy" and "thioalkoxy" as used herein refer to R13O- and R13S- respectively, wherein R13 is a loweralkyl group.
The term "alkoxycarbonyl" as used herein refers to -C(O)OR43 wherein R43 is loweralkyl.
The term "aryl" or "aryl group" as used herein refers to a monocyclic, bicyclic or tricyclic carbocyclic ring system containing one or more aromatic carbocyclic rings including, but not limited to, phenyl, naphthyl, indanyl, fluorenyl, ~1,2,3,4)-tetrahydronaphthyl, indenyl, isoindenyl and the like. Aryl groups can be unsubstituted or substituted with one, two, or three substituents independently selected from loweralkyl, alkoxy, thioalkoxy, carboxy, alkoxycarbonyl, arylcarbonyloxy, arylalkylcarbonyloxy, heterocycliccarbonyloxy, heterocyclicalkylcarbonyloxy, arylalkoxy, heterocylicalkoxy, -OSO3H, cyano, nitro, haloalkyl, hydroxy, amino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkenylaminocarbonyl, alkylamino and dialkylamino.
The term "arylalkyl" as used herein refers to an aryl group appended to a loweralkyl radical.
The term "arylalkylene" as used herein refers to an aryl group appended to an alkylene radical.
The term "arylcarbonyloxy" as used herein refers to Rs4C(O)O- wherein Rs4 is an aryl group.
.
'''' 2~ - ?q55 .
The term "arylalkylcarbonyloxy" as used herein refers to RssC~O)O- wherein Rss is an arylalkyl group.
The term "arylalkoxy" as used herein refers to R56O-wherein Rs6 is an arylalkyl group.
The term "heteroaryl" as used herein refers to a monocyclic or bicyclic aromatic ring system, each ring having 5 or 6 atoms, one to four of which are independently selected from oxygen, sulfur and nitrogen.
Heteroaryl groups also include a heteroaryl ring as defined above fused to a benzene ring. Heteroaryl groups can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, halo, hydroxy, cyano, nitro, haloalkyl, alkoxy, thioalkoxy, amino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkenylaminocarbonyl, alkylamino, dialkylamino, N-protected amino, protected hydroxyl, carboxylic acid, carboxamide, arylcarbonyloxy, arylalkylcarbonyloxy, heterocycliccarbonyloxy, heterocyclicalkylcarbonyloxy, arylalkoxy, heterocylicalkoxy, -OSO3H, carbamyl and aryl.
The term "heteroarylalkyl" as used herein refers to a heteroaryl group appended to a loweralkyl radical.
The term 'Iheteroarylalkylene'' as used herein refers to a heteroaryl group appended to an alkylene radical.
The term "heterocyclic ring" or "heterocyclic" as used herein refers to any 3- or 4-membered ring containing a heteroatom selected from oxygen, nitrogen and sulfur; or a 5- or 6-membered ring containing one, two or three nitrogen atoms; one nitrogen and one sulfur atom; or one nitrogen and one oxygen atom. The 5-membered ring has 0-2 ~. ; ' -, W091t0072~ P~T/US90/03630 ~.
z~755 double bonds and the 6-me~bered ring has 0-3 double bonds.
The nitrogen and sulfur heteroatoms can be optionally oxidized. The nitrogen heteroatoms can be optionally quaternized. The term "heterocyclic" includes any bicyclic or tricyclic group wherein the heterocyclic ring is fused to one or two benzene rings or one or two heterocyclic groups independently defined as above.
Heterocyclics include thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, tetrahydrofuranyl, pyranyl, pyronyl, pyridyl, pyrazinyl pyridazinyl, piperidyl, piperazinyl, morpholinyl, thionaphthyl, benzofuranyl, isobenzofuryl, indolyl, oxyindolyl, isoindolyl, indazolyl, indolinyl, 7-azaindolyl, isoindazolyl, benzopyranyl, coumarinyl, isocoumarinyl, quinolyl, isoquinolyl, naphthridinyl, cinnolinyl, quinazolinyl, pyridopyridyl, benzoxazinyl, quinoxadinyl, chromenyl, chromanyl, isochromanyl, carbolinyl, and the like. Heterocyclic groups can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, haloalkyl, oxo, hydroxy, protected hydroxyl, alkoxy, thioalkoxy, amino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkenylaminocarbonyl, alkylamino, dialkylamino, N-protected amino, cyano, nitro, carboxylic acid, carboxamide, arylcarbonyloxy, arylalkylcarbonyloxy, heterocycliccarbonyloxy, heterocyclicalkylcarbonyloxy, arylalkoxy, heterocylicalkoxy, -OSO3H, carbamyl and aryl.
The term "heterocyclicalkyl" as used herein refers to a heterocyclic group appended to a loweralkyl group.
: . , .: ~ -,~ . .
:: .- , . ~ :. -W09t~00725 PCT/US9Q/03630 "
2~ ~55
with the proviso that R1 and R2 are not both hydrogen.
Substituted amino also includes ~ H~R8 --N /J
(CH2)r wherein n is 1 to 3, r is 1 to 3 and J is (1) --S--, (2) -S(O)-, (3) -S(O)2-~
(4) -O-, (5) -CH2-r ~6) -N~Rs)- wherein RS is defined as above or (7) -N (C (O) R4) wherein R4 is defined as above and R8 represents one, two or three substituents independently .
2~
selected from (1) hydrogen, ~2) loweralkyl, (3) haloalkyl, ~4) aryl, (5) -C~O)R4 wherein R4 is independently defined as above, (6) -C(O)N(RS)(R6) wherein Rs and R6 are independently defined as above, (7) -0Rl6 wherein R16 is (i) hydrogen or (ii) hydroxyl protecting group, (8) hydroxyalkyl, (9) alkoxyalkyl, (10) -NH~R1s) wherein Rls is (i) hydrogen or (ii) an N-protecting group, (11) cyano and (12) halo.
The term "alkylamino" as used herein refers to -NHR40 wherein R40 is a loweralkyl group.
The term "dialkylamino" as used herein refers to -NR4lR42 wherein R4l and R42 are independently selected from loweralkyl.
The term "aminocarbonyl" as used herein refers to --C (O) NH2 -The term "alkylaminocarbonyl" as used herein refers to -C(0)Rso wherein Rso is an alkylamino group.
The term "dialkylaminocarbonyl" as used herein refers to -C(O)Rs1 wherein Rs1 is a dialkylami.o group.
.
, . ,, . . . . . . . -. : , ; -The term "alkenylaminocarbonyl" as used herein refers to -C(O)NHRs2 wherein Rs2 is an alkenyl group.
The term "halogen" or "halo" as used herein refers to F, Cl, Br, I.
The terms "alkoxy" and "thioalkoxy" as used herein refer to R13O- and R13S- respectively, wherein R13 is a loweralkyl group.
The term "alkoxycarbonyl" as used herein refers to -C(O)OR43 wherein R43 is loweralkyl.
The term "aryl" or "aryl group" as used herein refers to a monocyclic, bicyclic or tricyclic carbocyclic ring system containing one or more aromatic carbocyclic rings including, but not limited to, phenyl, naphthyl, indanyl, fluorenyl, ~1,2,3,4)-tetrahydronaphthyl, indenyl, isoindenyl and the like. Aryl groups can be unsubstituted or substituted with one, two, or three substituents independently selected from loweralkyl, alkoxy, thioalkoxy, carboxy, alkoxycarbonyl, arylcarbonyloxy, arylalkylcarbonyloxy, heterocycliccarbonyloxy, heterocyclicalkylcarbonyloxy, arylalkoxy, heterocylicalkoxy, -OSO3H, cyano, nitro, haloalkyl, hydroxy, amino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkenylaminocarbonyl, alkylamino and dialkylamino.
The term "arylalkyl" as used herein refers to an aryl group appended to a loweralkyl radical.
The term "arylalkylene" as used herein refers to an aryl group appended to an alkylene radical.
The term "arylcarbonyloxy" as used herein refers to Rs4C(O)O- wherein Rs4 is an aryl group.
.
'''' 2~ - ?q55 .
The term "arylalkylcarbonyloxy" as used herein refers to RssC~O)O- wherein Rss is an arylalkyl group.
The term "arylalkoxy" as used herein refers to R56O-wherein Rs6 is an arylalkyl group.
The term "heteroaryl" as used herein refers to a monocyclic or bicyclic aromatic ring system, each ring having 5 or 6 atoms, one to four of which are independently selected from oxygen, sulfur and nitrogen.
Heteroaryl groups also include a heteroaryl ring as defined above fused to a benzene ring. Heteroaryl groups can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, halo, hydroxy, cyano, nitro, haloalkyl, alkoxy, thioalkoxy, amino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkenylaminocarbonyl, alkylamino, dialkylamino, N-protected amino, protected hydroxyl, carboxylic acid, carboxamide, arylcarbonyloxy, arylalkylcarbonyloxy, heterocycliccarbonyloxy, heterocyclicalkylcarbonyloxy, arylalkoxy, heterocylicalkoxy, -OSO3H, carbamyl and aryl.
The term "heteroarylalkyl" as used herein refers to a heteroaryl group appended to a loweralkyl radical.
The term 'Iheteroarylalkylene'' as used herein refers to a heteroaryl group appended to an alkylene radical.
The term "heterocyclic ring" or "heterocyclic" as used herein refers to any 3- or 4-membered ring containing a heteroatom selected from oxygen, nitrogen and sulfur; or a 5- or 6-membered ring containing one, two or three nitrogen atoms; one nitrogen and one sulfur atom; or one nitrogen and one oxygen atom. The 5-membered ring has 0-2 ~. ; ' -, W091t0072~ P~T/US90/03630 ~.
z~755 double bonds and the 6-me~bered ring has 0-3 double bonds.
The nitrogen and sulfur heteroatoms can be optionally oxidized. The nitrogen heteroatoms can be optionally quaternized. The term "heterocyclic" includes any bicyclic or tricyclic group wherein the heterocyclic ring is fused to one or two benzene rings or one or two heterocyclic groups independently defined as above.
Heterocyclics include thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, tetrahydrofuranyl, pyranyl, pyronyl, pyridyl, pyrazinyl pyridazinyl, piperidyl, piperazinyl, morpholinyl, thionaphthyl, benzofuranyl, isobenzofuryl, indolyl, oxyindolyl, isoindolyl, indazolyl, indolinyl, 7-azaindolyl, isoindazolyl, benzopyranyl, coumarinyl, isocoumarinyl, quinolyl, isoquinolyl, naphthridinyl, cinnolinyl, quinazolinyl, pyridopyridyl, benzoxazinyl, quinoxadinyl, chromenyl, chromanyl, isochromanyl, carbolinyl, and the like. Heterocyclic groups can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, haloalkyl, oxo, hydroxy, protected hydroxyl, alkoxy, thioalkoxy, amino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkenylaminocarbonyl, alkylamino, dialkylamino, N-protected amino, cyano, nitro, carboxylic acid, carboxamide, arylcarbonyloxy, arylalkylcarbonyloxy, heterocycliccarbonyloxy, heterocyclicalkylcarbonyloxy, arylalkoxy, heterocylicalkoxy, -OSO3H, carbamyl and aryl.
The term "heterocyclicalkyl" as used herein refers to a heterocyclic group appended to a loweralkyl group.
: . , .: ~ -,~ . .
:: .- , . ~ :. -W09t~00725 PCT/US9Q/03630 "
2~ ~55
-17-The term "heterocycliccarbonyloxy" as used herein refers to Rs7C(O)O- wherein R57 is a heterocyclic group.
The term "heterocyclicalkylcarbonyloxy" as used herein refers to RsgC~O)O- wherein R5g is a heterocyclicalkyl group.
The term "heterocyclicalkylene" as used herein refers to a heterocyclic group appended to an alkylene radical.
The term "heterocyclicalkoxy" as used herein refers to RsgO- wherein Rsg is a heterocyclicalkyl group.
The term "N-protecting group" or "N-protected" as used herein refers to those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undesirable reactions during synthetic procedures or to prevent the attack of exopeptidases on the compounds or to increase the solubility of the compounds and includes, but is not limited to, sulfonyl, acyl, acetyl, pivaloyl, t-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz), benzoyl or an a-aminoacyl residue, which may itself be N-protected similarly.
The term "hydroxyl protecting group" as used herein refers to a substituent which protects hydroxyl groups against undesirable reactions during synthetic procedures and includes, but is not limited to, substituted methyl ethers, for example methoxymethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzyl, and triphenylmethyl; terahydropyranyl ethers;
substituted ethyl ethers, for example, 2,2,2-trichloroethyl and t-butyl; silyl ethers, for example, trimethylsilyl, t-butyldimethylsilyl and -:
;
. .
2~?5~755 t-butyldiphenylsilyl; cyclic acetals and ketals, for example, methylene acetal, acetonide and benzylidene acetal; cyclic ortho esters, for example, methoxymethylene; cyclic carbonates; cyclic boronates; and esters, for example acetates or benzoates.
Exemplary compounds of the present invention include:
N-(3'-Quinolylcarbonyl)-R-Valine-di-n-pentylamide;
N-(2'-Indolylcarbonyl)-R-Valine-di-n-pentylamide;
N-(4',8'-Dihydroxy-2'-quinolylcarbonyl)-R-Valine-di-n-pentylamide;
N-(2'-Naphthoyl)-R-Valine-di-n-pentylamide;
N-~3'-Quinolylcarbonyl)-R-Norleucine-di-n-pentylamide;
N-(2'-Indolylcarbonyl)-R-Norleucine-di-n-pentylamide;
N-(3'-Quinolylcarbonyl-R-(O-benzyl)Serine-di-n-pentylamide;
N-(3'-Quinolylcarbonyl)-(2R,3S)-(O-benzyl)Threonine-di-n-pentylamide;
N-(3'-Quinolylcarbonyl)-(2R,3S)-Threonine-di-n-pentylamide;
N-(3'-Quinolylcarbonyl)-(2R,3S)-(O-acetyl)Threonine-di-n-pentylamide;
N-(3'-Quinolylcarbonyl)-(2R,3S)-(O-methyl)Threonine-di-n-pentylamide;
N-(3'-Quinolylcarbonyl)-3-(2'-thienyl)-R-Alanine-di-n-pentylamide;
N-(2l-Indolylcarbonyl)-R-Histidine-di-n-pentylamide;
N-(3'-Quinolylcarbonyl)-R-Histidine-di-n-pentylamide;
N -(3'-Quinolylcarbonyl)-N -(benzyloxycarbonyl)-R-Lysine-di-n-pen~ylamide;
:,,' '- , :. , .: ,: . : .
, , , - , : :
. . , , :.
29~ 55 N-~3'-Quinolylcarbonyl)-R-Phenylalanine-di-n-pentylamide;
Na-(3'-Quinolylcarbonyl)-N-(2'-chlorobenzyloxycarbonyl)-R-Lysine-di-n-pentylamide;
N-(3'-Quinolylcarbonyl)-R-(4'-hydroxyphenyl)glycine-di-n-pentylamide;
Na-(3'-Quinolylcarbonyl)-NE-(acetyl)-R-Lysine-di-n-pentylamide;
N-(2'-Indolylcarbonyl)-R-Tyrosine-di-n-pentylamide;
N-(3',4'-Dichlorobenzoyl)-R-Tyrosine-di-n-pentylamide;
N-(2'-Naphthoyl)-R-Tyrosine-di-n-pentylamide;
N-(3'-Quinolylcarbonyl)-R-Tyrosine-di-n-pentylamide;
Methyl N-(3'-Quinolylcarbonyl)-R-Tyrosyl-S-phenylglycinate;
N-(2'-Indolylcarbonyl)-R,S-Homoserine-di-n-pentylamidei N-~3'-Quinolylcarbonyl)-R,S-Homoserine-di-n-pentylamide;
N-(2'-Indolylcarbonyl)-R-MethioninesulfGxide-di-n-pentylamide;
N-(3'-Quinolylcarbonyl)-R-Methionine-di-n-pentylamide;
N-(3'-Quinolylcarbonyl)-R-Methioninesulfoxide-di-n-pentylamide;
- Na-(3'-Quinolylcarbonyl)-N~-phenylthiolcarbonyl-R-Lysine-di-n-pentylamide;
N-(3'-Quinolylcarbonyl)-R-Tyrosine-di-n-pentylamide hydrochloride;
N-~3'-Quinolylcarbonyl)-R-Histidine-di-n-pentylamide dihydrochloride;
N-(2'-Indolylcarbonyl)-glycine-di-n-pentylamide;
N-(3'-Quinolylcarbonyl)glycine-di-n-pentylamide;
N-(3'Quinolylcarbonyl)-R-phenylglycine-di-n-pentylamide;
' ~
-, ,- , ~' -i WO91/00725 PCT/US9OtO3630 ., 21~
N-(4',8'-Dihydroxy-2'-quinolylcarbonyl)-R-Phenylglycine-di-n-pentylamide;
N-~5'-Fluoroindolylcarbonyl)-R-phenylglycine-di-n-pentylamide;
N-(4',8'-Dihydroxy-2'-quinolylcarbonyl)glycine-di-n-pentylamide;
N-(2'-Naphthoyl)glycine-di-n-pentylamide;
N-(3'-Methylphenylaminocarbonyl)glycine-di-n-pentylamide;
N-(4',8'-Dihydroxy-2'-quinolylcarbonyl)-R-(4'-hydroxyphenyl)-glycine-di-n-pentylamide;
N-(q',8'-Dihydroxy-2'-quinolylcarbonyl)-(2R,3S)-(O-benzyl)-Threonine-di-n-pentylamide;
Methyl N-(3'-Quinolylcarbonyl)-R-Methionine-S-(p-hydroxy)-phenylglycinate;
N-(3'-Quinolylcarbonyl)-R-Serine-di-n-pentylamide;
N-~8'-Hydroxy-2-quinolylcarbonyl)-glycine-di-n-pentylamide;
N-Methyl-N-~3'Quinolylcarbonyl)-glycine-di-n-pentylamide;
N-(3'-Iodo-2'-indolylcarbonyl)-glycine-di-n-pentylamide; and N-(2'-Indolylcarbonyl)-R-Alanine-di-n-pentylamide.
The compounds of the invention may be made as shown in the following scheme(s). The compounds of the invention having one asymmetric center can exist as separate enantiomers or as mixtures or enantiomers. The compounds of the invention which contain two or more asymmetric carbon atoms can exist as pure diastereomers, mixtures of distereomers, dias~ereomeric racemates or mixtures of diastereomeric racemates. The present ., ~ , , . ~ - ~ . - . .. . .. . ..
: : :. - . . : . .. ... .
.:
..
- ... . . :
WO9l/00725 PCT/US90~03630 2(~
.`:` . ~`.
invention includes within its scope all of the isomeric forms A number of synthetic pathways exist for the production of a-amino acids and their derivatives. The invention is not limited to those methods discussed here -for the synthesis of a-amino acids but is meant to include those variations and methods encompassed by ~he prior art as discussed in the chemical literature in its entirety.
a-Amino acids ~refer to Scheme 1) can be produced directly by the displacement of a-halogenated esters (1, x is halo) and the like or other a-situated leaving sroups by ammonia and or other substituted amines (Rg is hydrogen, loweralkyl, carboxyester-substituted alkyl) and/or their analogs ~e.g., carbamates, hydrazines, azides) (e.g., Marvel nL~ ~YUL;h ~Q, 81, 1940; 106, 1940; ~1, 60, 1941;
79, l9ql; Birnbaum, ~ h8m, 333, 1953). The amino group is then unmasked, for example by reduction, and the ester group (amide, etc.) is saponified to the acid in a standard fashion.
A second method involves the condensation of an a-ketoester (amide, etc) with an amine or amine equivalent (e.g., hydroxylamine, hydrazine, carbamate, etc.) and the subsequent reduction of this product (2) to the a-aminoester (amide, acid, etc. (e.g., Can ~ Chem, 29, 427, 1951; J Ora hem, 38, 822, 1973; J Q~ ~h~m, ~, 878, 1941~). Alternatively, an organometalic reagent can be added to the oxime 2 ~imine, etc.) to provide as final products either monosubstituted a-amino acids in the case where D is hydrogen, or disubstituted amino acids in the .
, : .
Z~755 case where D is other than hydrogen (e.g., Tetrahedron L~S~ 2), 4973, 1987).
A third method is the alkylation of a carbanion resulting from compound (3) with an electrophilic nitrogen source ~eg. diethylazodicarboxylate). The intermediate product can subsequently be unmasked to provide the desired a-amino acid. A similar method involves alkylation of the carbanion derived from compound (4) with an appropriate alkylating agent. This method also allows for the possibility of disubstitution of the a center.
A fifth route involves the Strecker reaction and its modifications. Reaction of cyanide and ammonium on aldehydes and ketones (S) provides the amino acid.
A last method involves the direct reduction of unsaturated heterocyclic carboxylic acids (6) to directly provide the cyclic amino acids (7), (wherein D and R9 are encompassed in a ring).
With suitably available a - amino acids (8) (Scheme 2) the amino group is protected with an N protecting group (most frequently Boc or Cbz) and, if the carboxylic acid has not been unmasked, it is saponified with base to provide the parent carboxylic acid (9). The N-protected intermediate is then coupled with the amine HNR1R2 using any of a number of standard coupling techniques (carbodiimide, BOPCl, chloroformates, oxalylchloride, etc.). Preferred secondary amines are of the type where R
and R2 are alkyl, arylalkyl, aryl, or represent another amino acid. The resulting product (10) is then N-deprotected using HCl or trifluoroacetic acid to remove a Boc group and hydrogenolysis or HBr to remove a Cbz group.
.. .
: ~ ' ' , , . ~ , . . '' , . .
WO91/00~25 PCT/US90/03630 2 ~ 5 5 The resultant amine ~11) is then coupled with aromatic carboxylic acids, aromatic acid halides, heteroaromatic carboxylic acids, aromatic isocyanates, aromatic sulfonic acids, aromatic sulfonyl chlorides, and the like using standard coupling techniques to provide the desired products ~12), (13), (14), and (15). Preferred acyl coupling partners groups include: quinoline carboxylic acids, indole carboxylic acids, substituted benzoic acids and benzoyl chlorides, arylisocyanates and arylisothiocyanates, naphthoic acids, benzothiofuranyl carboxylic acids and the like.
WO 9l/00725 PCI`/USgO/03630 21?~755 Scheme 1 O H2~R9 1 D I D
o H2/cDtDlyst (Rlo=H) H O
R g _ N~l~ o ~ R r R ~ ~ o R
D 2 Rlo~ R10 D
0 1. bDse IH O
~O R R ~N ~I~O ~R
D 3 2. ":~H2 ' D
1. bDse/DX ,H O
`1/~ ~o.R , R ~N~I~ R
2. H D
o Strecker l O
RgJ~D Rlo D
C~ U, ... : ' .
~ . . ~ . . ..
WO gl/00~25 PCI'/US90/03630 Z~755 : i . . .
, ,. . . .. ~
Scheme 2 ~N3~ `H D~o Rg Rg 0 9 coupling agent D R10 R1 D R10 ~R1 R2 deprotect P N~ R2 \\ \
~rCOz~ I \ \ArSO3H/coupllng agent or \ ArS02CI
coupllng¦ \ \ArNCO
agent ~
0~ N ~ N `R \ Ar r3~ R2 Rg O O D R10 ,R1 14 12 ~N~N.R D R10 , Ar Rg O NH ~N~ 'R2 1~ Alr R g O
.. ~ . . . . ,, , . -. , , ~ . .
. . .
.
2~ S5 Intermediates for the preparation of the compounds of formula I include compounds of the formula:
D R1o P~- N
Rg O
whereln G is (l) NH2 or ~2) substituted amino;
Rg is ~l) hydrogen, ~2) loweralkyl, ~3) carboxy-substituted alkyl or ~4) carboxyester-substituted alkyl;
Rlo is (l) hydrogen, (2) loweralkyl, (3) functionalized alkyl or (4) cycloalkyl;
D is (l) hydrogen, (2) loweralkyl, (3) functionalized alkyl, (4) cycloalkyl, (5) aryl, (6) functionalized oxyalkyl or ~ 7) heterocyclic;
or Rlo t~ken together with D is ~l) C4 to C6 alkylene, , :;: . '' : '~
ZC?5-77~55 . `. .: `
(2) - (CH2) q~V~ (CH2) r~ wherein q is 1 to 3, r is 1 to 3 and V is (i) --o--, ( i i ) --S--, (iii) -CH2- or ~iv) -N(R25)- wherein R2s is hydrogen, loweralkyl, haloalkyl, alkoxyalkyl, arylalkyl, aryl or an N-protecting group;
or Rg taken together with D is (1) C3 to C5 alkylene or (2) -(CH2)p-V-(CH2)t- wherein p is 1 to 3, t is 1 to 3 and V is defined as above; and P1 is hydrogen or an N-protecting group.
Other intermediates for the preparation of compounds of the formula I include compounds of ~he formula:
~ B ~ Z
wherein Z is (1) --C (O)--, (2) -C(S)- or (3) -S(0)2-;
B is (1) absent, (2) alkylene, (3) alkenylene, (4) substituted alkenylene, ~5~ -R2Ç-R27- wherein R2ç is absent, or -C~2- and R27 is -O-, -S-, -NH- or -N(lo~-eralkyl)- or ', . .- !' . .
., ` . . . .
' ' . '".,. '' ' ', ' , WO9l/0072~ PCT/US90/03630 ,~
2~ ? ~ S 5 ~6) -R27-CH2- wherein R27 is defined as above;
Ar is (1) aryl or ~2) a heterocyclic group; and Z' is an activating group; or B-Z-Z' taken together represent -N=C=O, -N=C=S, -CH2-N=C=O or -CH2-N=C=S.
Activating groups are those functional groups which activate a carboxylic acid or sulfonic acid group toward coupling with an amine to form an amide or sulfonamide bond. Activating groups Z' include, but are not limited to, -OH, -SH, alkoxy, thioalkoxy, halogen, formic and acetic acid derived anhydrides, anhydrides derived from alkoxycarbonyl halides such as isobutyloxycarbonylchloride and the like, N-hydroxysuccinimide derived esters, N-hydroxyphthalimide derived esters, N-hydroxybenzotriazole derived esters, N-hydroxy-5-norbornene-2,3-dicarboxamide derived esters, 4-nitrophenol derived esters, 2,4,5-trichlorophenol derived esters and the like.
The following examples will serve to further illustrate preparation of the novel compounds of this invention.
Example 1 N-(t-Butvlo~ycarbonyl)-R-Valine-di-n-pentylamide N-t-Butyloxycarbonyl-R-Valine (2.5 g, ll.S mmol) was stirred at 0 C in 30 mL of methylene chloride ~CH2Cl2) with bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOPC1, 3.5 g, 13.8 mmol) and 1.5 mL (11.5 mmol) of triethylamine (TEA). To this reaction mixture was added dl-n-pentylamine (11.6 mL, 58 mmol). The mi:cture was stirred overnight and allowed to warm to room temperature.
. . . .
~'' ` . .
WO9l/00725 PCT/US90/03630 2~ 55 r An additional equivalent of BOPCl was added after 18 hrs and the reaction mixture was stirred an additional day at ambient temperature. The solvents were evaporated in vacuo and the residue taken up in ethylacetate ~EtOAc) and washed with water, 1 N hydrochloric acid (HCl) solution, saturated sodium bicarbonate solution (NaHCO3), water.
The organic solution was dried over magnesium sulfate (MgSO4). After filtration and concentration of the filtrate in vacuo, the residue was chromatographed using ethyl acetate-hexane as the solvent system in the ratio (1:4). The product was isolated as an oil 79% yield (3.25 g). ~a]D= +21.2 (c=1.5, MeOH). MS~CI) m/e 357(m+H) .
1H NMR(CDCl3,300MHz) ~ 0.85-1.0(m,12H), 1.32(m,8H), 1.4-1 5(m,4H), 1.5(s,9H), 1.84(m,lH), 3.05(m,lH), 3.2(m,lH), 3.35(m,lH), 3.55(m,lH), 4.42(m,lH), 5.25(d,J-7Hz,lH).
R-Valine-di-n-pentylamide hydrochloride The product of example 1 (0.2 g, 0.6 mmol) was dissolved in 4 N HCl in dioxane (10 mL) and stirred under inert atmosphere (N2) for an hour. When the reaction was complete by tlc the solvents were evaporated in vacuo and hexane and diethylether were added. The residue was triturated with these two solvents and the solvents again evaporated in vacuo. This procedure was repeated several times until product was obtained as a glass in quantitative yield. MS(CI) m/e 293(m+H) .
-- . ~: . , : :
.: .,, , ., :: ~,- ~ : . . .
WO 91/00725 PCI`/US90/03~30 .. ;: .
z~ 755 Example 3 N-(3'-Ouinolylcarbonyl)-R-Valine-di-n-~entvlamide The hydrochloride of example 2 (150 mg, 0.5 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI, 100 mg), HOst (135 mg) and quinoline-3-carboxylic acid (88 mg) were stirred at 0C under nitrogen in 5 mL of anhydrous CH2C12. To this mixture was added 120 IlL of N-methylmorpholine (NMM) and the mixture was stirred overnight (warming to ambient temperature). The reaction mixture was poured into ethyl acetate and water and the organic extract was washed successively with water, 10g~
citric acid solution, and saturated aqueous NaHCO3. The solution was dried over MgSO4, filtered and concentrated.
The residue was chromatographed using ethylacetate ~EtOAc) and hexane as the elutant mixture to provide 110 mg of an oil (54~ yield) after removal of the volatiles. [a]D= -14.8 ~cz0.5, MeOH). MS(CI) m/e 412(m+H) . lH
NMR(CDC13,300MHz) ~ O.92(m,6H), 1.05(m,6H), 1.35 (m,8H), 1.5-1.7(m,4H), 2.15(m,lH), 3.05(m,lH), 3.3-3.4(m,lH), 3.5(m,lH), 3.65(m,lH), 5.08(dd,J=3, 9Hz,lH), 7.25(d,J=9Hz,lH), 7.62 (t,J=7Hz,lH), 7.8(t,J=7Hz,lH), 7.91(d,J=lOHz,lH), 8.16(d,J=lOHz,lH), 8.6(d,J=3Hz,lH), 9.35(d,J=3Hz,lH). Analysis calculated for C25H37N3O2: C
72.95, H 9.06, N 10.21; found: C 72.61, H 9.21, N 9.97.
Example 4 N-(2'-Indolylcarbonyl)-~ aline-~ -pentylamide The hydrochloride of example 2 ~130 mg, 0.45 mmol), EDCI (90 mg), HOBt (120 mg) and indole-2-carboxylic ac d , - . :
W09lt00725 PCT/US90tO3630 2~ SS
~,,.. ...:,...
(75 mg) were stirred at 0C under nitrogen in 5 mL of anhydrous CH2Cl2. To this mixture was added 100 ~L of NMM
and the mixture was stirred overnight (warming to ambient temperature). The reaction mixture was poured into ethylacetate and water and the organic extract was washed successively with water, 10% citric acid solution, and saturated aqueous NaHCO3. The solution was dried over MgSO4, filtered and concentrated. The residue was chromatographed using ethylacetate and hexane as the elutant mixture to provide 36 mg of product (75% yield) after evaporation of the volatiles. mp= 132-4C. [a~D= -9.2 (c=0.5, MeOH). MS(CI) m/e 400(m+H) . lH
NMR~CDCl3,300MHz) ~ 0.9(t,J=7Hz,6H), 1.0(m,6H), 1.2-1.4(m,8H), 1.5-1.6(m,4H), 2.12(m,lH), 3.05(m,lH), 3 3(m,lH), 3.42(m,lH), 3.63(m,lH), 5 0(q,J=3,6Hz,lH), 7.0(m,1H), 7.1(d,J=9Hz,lH), 7.25~t,J=7.5Hz,lH), 7.3(t,J-7.5Hz,lH), 7.41(d,J=7Hz,lH), 7.65(d,J=7Hz,lH), 9.3(bs,1H). C,H,N analysis calculated for C2qH37N3O2 C
72.14, H 9.34, N 10.52; found: C 72.52, H 9.25, N 10.49.
Example ~
N-(2'-Ouinolylcarbonvl)-R-Valine-di-n-pentylamide The reaction was performed in a similar manner to that in example 3 utilizing 0.2 g of the hydrochloride salt of example 2, quinoline-2-carboxylic acid (0.12 g), EDCI (0.15 g), HOBt (0.1 g), and NMM (0.18 mL). The product was isolated in 80% yield (0.225 g). mp= 78-79C.
[a)Dc -13.1 (c=l.l, MeOH). MS(CI) m/e 412(m+H) . lH
NMR(CDC13,300MHz) ~ 0.9(m,6H), 1.05(m,6H), 1.2-1.4(m,8H), 1.55(m,4H), 2.22(m,lH), 3.08(m,lH), 3.4(m,2H), 3.64(m,lH), .
' W09l/00725 PCT~US90/~3630 21?~55 5.0~dd,J=3,7Hz,lH), 7.62~t,J=7Hz,lH), 7.78~t,J=7Hz,lH), 7.85~d,J=9Hz,lH), 8.15(d,J=9Hz,lH), 8.35(m,2H), 8.85(d,J=10Hz,lH). C,H,N analysis calculated for C25H37N3O2, H2O: C 72.17, H 8.96, N 10.10; found: C
72.36, H 8.93, N 10.03.
Example 6 N-~E-2'-Cyano-3'-~4''-hydro~yphenyl)prop-2'-enoyll-R-Valine-di-n-pentylamide The hydrochloride of example 2 (300 mg, 1.03 mmol)~
EDCI (200 mg), HOBt (280 mg) and a-cyano-q-hydroxycinnamic acid (195 mg) were stirred at 0C under nitrogen in 15 mL
of anhydrous CH2Cl2. To this mixture was added 250 ~L of NMM and the mixture was stirred overnight (warming to ambient temperature). The reaction mixture was poured into ethylacetate and water and the organic extract was washed successively with water, 10% citric acid solution, and saturated aqueous NaHCO3. The solution was dried over magnesium sulfate, filtered and concentrated. The residue was chromatographed using ethylacetate and hexane as the elutant mixture to provide 225 mg of an oily product (57 yield) after evaporation of the volatiles. [~]D= -9.8 (c=1.15, MeOH) MS(CI) m/e 428(m+H) . H
NMR(CDCl3,300MHz) ~ O.92(m,6H), 1.08(m,6H), 1.35(m,8H), 1.56-1.75(m,9H), 2.15(m,lH), 3.1(m,lH), 3.3-3.5(m,2H), 3.7(m,lH), 4.65(m,lH), 6.73(d,J=9Hz,lH), 6.85(d,J=9Hz,2H), 7.65(d,J=9Hz,2H), 7.72(s,1H), 9.28(s,1H). C,H,N analysis calculated for C25H37N3O3: C 70.22, H 8.72, N 9.83, found:
C 69.88, H 8.39, N 9.60.
- - . . - . - . - - - . - -: : , ~
W091t00725 PCT/US90/03630 Z~ SS
Example 7 N-(2'-Benzothiofuranylcarbonyl)-R-Valine-di-n-p~ntylamide The reaction was performed in a similar manner to that in example 3 utilizing 0.3 g of the hydrochloride salt of example 2, benzothiofuran-2-carboxylic acid (0.205 g), EDCI (0.22 g) HOBt (0.28 g), and NMM (0.22 mL). The oily product was isolated in 58% yield, 0.28 g [a]D= ~
5.85 (c=2.0, MeOH). MS(CI) m/e 417(m+H) , 158. H
NMR(CDCl3,300MHz) ~ 0.g-l.l(m,12H), 1.2-1.3(m,8H), 1.5-1.6(m,4H), 2.15(m,lH), 3.05(m,lH), 3.3(m,lH), 3.42(m,lH), 3.65(m,lH), 5.0(q,J=3,6Hz,lH), 7.00(d,J=9Hz,lH), 7.41(m,2H), 7.80(s,lH), 7.86(m,2H). C,H,N analysis calculated for C24H36N22S' 0-25 H2O
6.65; found: C 68.73, H 8.48, N 6.71.
~m~l~ 8 N- (4 ' . 8 ' -Dihydroxy-2'-quinolylcarbonyl)-~-Valine-di-n-pentylamide The hydrochloride salt of example 2 (0.95 g, 3.22 mmol) was stirred in 25 mL of CH2C12 with NMM (0.7 mL) under nitrogen at 0 C. EDCI (0.7 g) and HOBt (0.11 g) were added followed by the addition of 4,8-dihydroxyquinoline-2-carboxylic acid (0.66 g, 3.22 mmol).
The reaction mixture was stirred overnight (warming to ambient temperature). The solvents were evaporated in vacuo and the residue taken up in ethylacetate and washed successively with water, 0.1 N solution of HCl, water and brine. The organic solution was dried over MgSO4 and then filtered. Solvents were evaporated in vacuo and the crude product subjected to flash chromatography using , . -- ~:: , . , . : .
- ::
~`
. , , ' . ' ';
Zc`~-~'55 ethylacetate, hexane and methanol as the elutant mixture.
The product was crystallized from methanol-water to provide 0.82 g ~56%). mp= 233-235C. ~a]D = -15.6 (c=0.5, MeOH). MS(CI) m/e 444(m+H) . lH .
NMR(DMSOd6,300MHz) ~ 0.84(m,6H), 0.92(m,6H), 1.1-1.35(m,8H), 1.4-1.6(m,4H), 2.33(m,lH), 3.1-3.45(m,2H), 3.55(m,2H), 4.67(m,1H), 7.1(d,J=9Hz,lH), 7.42(t,J=7Hz,lH), 7.55(m,2H), 9.62(d,J=9Hz,lH), 10.3(s,lH), 11.75(s,lH).
C,H,N calculated for C25H37N3O4: C 67.69 H 8.41, N 9.47;
found: C 67.47 H 8.45, N 9.39.
Examp~e ~
N-(2l-Benzofuranvlcarbonvl)-R-Valine-di-n-~entvlamide The reaction was performed in a similar manner to that in example 8 utilizing 0.3 g of the hydrochloride salt of example 2, benzofuran-2-carboxylic acid (0.19 g), EDCI (0.22 g~, HOBt (0.28 g), and NMM (0.22 mL). Product was isolated in 56% yield (0.225 g). [a]D= -29.2 (c=l.l, MeOH). MS(CI) m/e 401(m+H) . H NMR(CDC13,300MHz) ~
0.9-1.0(m,6H), 1.05(m,6H), 1.25-1.4(m,8H), 1.5-1.68(m,4H), 2.15(m,lH), 3.1(m,lH), 3.28-3.5(m,2H), 3.62(m,lH), 5.0(dd,J=3,6Hz,lH), 7.28(t,J=8Hz,lH), 7.4(t,J=8Hz,2H), 7.45(s,lH), 7.52(d,J=9Hz,lH), 7.65(d,J=9Hz,lH). C,H,N
analysis calculated for C24H36N2O3: C 71.96, H 9.06, N
6.99; found: C 72.09, H 9.08, N 6.99.
: ~ . . :
W09t/00725 PCT/US90/03630 .
Z ~ ~ ? 7 5 5 ..
~xam~le lQ
~-r4'-Hydroxy-2'-phenyl-3'-quinolylcarbonyll-R-Valine- ~
~ '.
The reaction was performed in a similar manner to that in example 8 utilizing 0.2 g of the hydrochloride salt of example 2, 4-hydroxy-2-phenyl-quinoline-3-carboxylic acid (0.18 g), EDCI (0.16 g), HOBt (0.19 g), and NMM (0.16 mL). Product was isolated in 64% yield (0.22 g). mp= 154-155C. [a]D = -30.0 (c=0.4, MeOH).
MS(CI) m/e 504(m+H) . H NMR(DMSOd6~300MHz) 0.82(m,14H), 1.2(m,8H), 1.38(m,4H), 1.94(m,lH), 3.02tm,2H), 3.2~m,lH), 3.4(m,lH), 4.55(m,lH), 7.43(m,5H), 7.7(m,2H), 8 2 ~d,J=7Hz,lH), 12.02(s,lH). C,H,N analysis calculated for C31H41N3O3: , , found: C 73.73, H 8.18, N 8.34.
Example 11 ~-(4'-Hydroxy-7'-~-ifluoro-3'-quinolylcarbonyl~
Valine-di-n-pentvlamide The reaction was performed in a similar manner to that in example 8 utilizing 0.21 g of the hydrochloride salt of example 2, 4-hydroxy-7-trifluoro-quinoline-3-carboxylic acid (0.185 g), EDCI (0.15 g), HOBt (0.2 g), and NMM (0.16 mL). Product was isolated in 37~ yield, 0.16 g. mp= 194-195C. [a]D = -79.2 (c=0.5, MeOH).
MS~CI) m/e 497(m+H) . lH NMR(DMSOd6,300MHz) ~
0.88(m,12H), 1.35(m,8H), 1.45(m,2H), 1.6(m,2H), 2.05(m,lH) 3.0(m,2H), 3.25-3.4(m,2H), 3.48(m,lH), 4.85(dd,J-3,9Hz,lH), 7.8(d,J=7Hz,lH), 8.1(s,lH), 8.45(d,J=7Hz,lH), 8.9(s,1HJ, 10.2(d,J=7Hz,lH), 12.9(bs,1H) . . .:, ~ : . .
:-: . . : . - . : .
. , .; :
.
Z ~ ~ ? 7 5 5 C,H,N analysis calculated for C26H26F3N3O3, 0.2 H2O: C
62.56, H 7.35, N 8.41; found: C 62.57, H 7.17, N 8.38.
Example 1~-(7'-Chloro-4'-~ydroxy-3'-auinolylcarbonyl~-R-Valine-di-n-pentylamide The reaction was performed in a similar manner to that in example 8 utilizinq 5.0 g of the hydrochloride salt of example 2, 4-hydroxy-7-chloro-quinoline-3-carboxylic acid (3.8 g), EDCI (3.5 g), HOBt (4.6 g), and NMM (3.8 mL) and 10 mL DMF. Product was isolated in 54%
yield, 4.25 g. mp= 205-206 C. ~a]D = -93.8 (c=0.5, MeOH). MS~CI) m/e 463~m+H) . H NMR~DMSOd6,300MHz) 0.95(m,6H), 1.15(d,J=8Hz,3H), 1.26(d,J-8Hz,3H), 1.38(m,8H), 1 65(m,2H), 1.8(m,lH), 2.0(m,lH), 2.23(m,lH), 3.15(m,lH), 3.35(m,lH), 3.48(m,lH), 3.72(m,lH), 4.6(t,J=6Hz,lH), 7.2(dd,J=3,9Hz,lH), 7.6(d,J=9Hz,lH) 7.68(d,J=2Hz,lH), 8.26(d,J=7Hz,lH), 10.25(d,J=6Hz,lH), 12.25(d,J=9Hz,lH). C,H,N analysis calculated for C25H36ClN3O3: C 64.98, H 7.85, N 9.09, Cl 7.67; found: C
65.16, H 8.04, N 8.94, Cl 7.91.
Example 13 N-(9'-Hydroxy-2'-quinolylcarbonyl)-~-Valine-di-n-pentylamide The reaction was performed in a similar manner to that in example 8 utilizing 0.2 g of the hydrochloride salt of example 2, 4-hydroxyquinoline-2-carboxylic acid ~0.13 g) EDCI (0.14 g), HOBt ~0.19 g), and NMM /0.15 mL).
Product was isolated in 71~ yield (0.207 g). mp= 70-, ..
' ~ " ' ' ' ' WO9l/00725 PCT/US90/03630 2~ 7S5 ~'.' '`.''':,;
71C [~]D = -13.3 (c=0.6, MeOH). MS(CI~ m/e 428(m+H) .
H NMR~DMSOd6,300MHz) ~ 0.85-l.l(m,12H), 1.2-1.4(m,8H), 1.5-1.7(m,4H~, 2.15(m,lH), 3.02(m,1H), 3.25(m,lH), 3.45(m,lH), 3.64(m,lH), 4.95(dd,J=3,6Hz,lH), 6.7(bs,lH), 7.35-7.5(m,2H), 7.6~(t,J=7Hz,2H), 8.35(d,J=8Hz,lH), 10.4(bs,1H). C,H,N analysis calculated for C25H37N3O3: C
70.22, H 8.72, N 9.83; found: C 69.91, H 8.71, N 9.68.
Example 1N-r5'-(N-Allylcarbamyl)pyridyl-3'-carbonyll-R-Valine-di-n-pentylamide The hydrochloride salt of example 2 (0.20 g, 0.69 mmol) was stirred in 15 mL of CH2C12 with NMM, (0.15 mL, 1.4 mmol) under nitrogen at 0C. EDCI (0.135 g, 0.69 mmol) and HOBt (0.19 g, 0.14 mmol) were added followed by the addition of 5-allylcarbamylnicotinic acid (0.142 g, 0.69 mmol). The reaction mixture was stirred overnight (warming to ambient temperature). The solvents were evaporated in vacuo and the residue taken up in ethylacetate and washed successively with water, saturated NaHCO3, a saturated solution of citric acid, water, and brine. The organic solution was dried over MgSO4 and then filtered. Solvents were evaporated in vacuo and the crude product subjected to flash chromatography using ethylacetate and hexane as the elutant mixture. The oily product was isolated in 56% yield (0.17 g). MS(CI) m/e 445 (m+H) . H NMR(CDC13,300MHz) ~ 0.85-l.l(m,12H), 1.2-1.4(m,8H), 1.5-1.6(m,4H), 2.1(m,lH), 3.05(m,lH), 3.3(m,lH), 3.48(m,lH), 3.65(m,lH), 4.15(m,2H), 5.0(dd,J=3,6Hz,lH), 5.25(m,2H), 5.95(m,lH), 6.95(m,lH), ' ,' ," . : ':, "~ ', "' ' : ' , ,' . ' ', ''. ., ' ' " , ~ . ' WOgl/0072~ PCT/US90/03630 .
~' . . ;'' Zc~ 5S
7.15~d,J=9Hz,lH), 8.98(s,1H), 9.15(s,2H). C,H,N analysis calculated for C25HgoN403 C 67.53, H 9.07, N 12.60;
found: C 67.27, H 8.97, N 12.53.
~
N-(l'-Ethyl-7'-methvl-4'-oxo-1',8'-na~hthyridinyl-3'-carbonyl)-R-Valine-di-n-pentvlam~de The hydrochloride salt of example 2 (0.2 g, 0.69 mmol) was stirred in 15 m~ of CH2Cl2 with NMM (0.15 mL, 1.4 mmol) under nitrogen at 0 C. EDCI (0.135 g, 0.69 mmol) and HOBt (0.190 g, 1.38 mmol) were added followed by the addition of nalidixic acid (0.160 g, 0.69 mmol). The reaction mixture was stirred overnight (warming to ambient temperature). The solvents were evaporated in vacuo and the residue was taken up in ethylacetate and washed successively with water, saturated NaHCO3, a saturated solution of citric acid, water and brine. The organic solution was dried over MgSO4 and then filtered.
Solvents were evaporated in vacuo and the crude product subjected to flash chromatography using ethylacetate and hexane as the elutant mixture. The purification provided 0.19 g (59%) of an oil. MS(CI) m/e 471(m+H) . lH
NMR(CDC13,300MHz) ~ 0.9(m,6H) 1.05(m,3H), 1.20-1.4(m,10H), 1.48-1.8(m,8H), 2.1(m,lH), 2.65(s,3H), 3.05(m,lH), 3.4(m,2H), 3.6(m,lH), 4.5(dd,J=3,9Hz,lH), 4.6(m,lH), 4.95(dd,J=3,6Hz,lH), 7.25(m,2H), 8.68(m,lH), 8.85(m,lH).
C,H,N analysis calculated for C27H42O3N4, 0.25 H2O: C
68.34, H 9.03, N 11.82; found: C 68.12, H 8.83, N 12.07.
~. . .
.
WO91/0072~ PCT/US90/03630 ~?~ 55``-~ ~ .
N-~Z-2'-Fluoro-3'-Dhenyl~ro~-2'-enoyll-R-Valine-di-n-~ntylamide The reaction was performed in a similar manner to that in example 3 utilizing 0.27 g of the hydrochloride salt of example 2, a-fluorocinnamic acid (0.16 g~, EDCI
~0.19 g), HOBt (0.25 g), and NMM (0.21 mL). The oily product was isolated in an 68% yield, 0.25 g [a] D= +7.1 (c=l.1, MeOH). MS(CI) m/e 405(m+H) . H
NMR(CDCl3,300MHz) ~ O.82-1.0(m,12H), 1.2-1.5(m,8H), 1.5-1.7(m,4H), 2.1(m,lH), 3.05(m,lH), 3.25(m,lH), 3.4(m,lH), 3.6(m,lH), 4.85(m,lH), 7.05~d,J=42Hz,lH), 7.1(d,J=laHz,lH), 7.3-7.45~m,3H), 7.62(d,J=9Hz,2H). C,H,N
analysis calculated for C24H37FO2N2: C 71.25, H 9.22, N
6.93; found: 70.99, H 9.14, N 6.95.
E~mRle 17 N-(2' Naphthoyl)-R-Valine-di-n-~entvlamide The reaction was performed in a similar manner to that in example 3 utilizing 0.2 g of the hydrochloride salt of example 2, 2-naphthoic acid (0.12 g), EDCI (0.13 g), HOBt (0.18 g), and NMM ~0.16 mL). The product was isolated as an oil in 72% yield, 0.2 g. [a]D= -13.0 ~c=1.0, MeOH). MS~CI) m/e 411(m+H) . H
NMR(CDCl3,300MHz) ~ 0.8-0.9(m,6H), l.l(m,6H), 1.2-1.4(m,8H), 1.55-1.67(m,4H), 2.13(m,lH), 3.0-3.1(m,lH), 3.25-3.3(m,lH), 3.5lm,lH), 3.65(m,lH), 5.08(dd,J=3,6Hz,lH), 7.11(d,J=9Hz,lH), 7.52(m,2H), 7.9(m,4H), 8.33(s,lH). C,H,N analysis calculated for ~::.. : . .- . . . , : . ~:
WO9l/00725 PCTtUS90/03630 C26H38N2O2: C 76.05, H 9.33, N 6.82; found: C 76.20, H
9.32, N 6.98.
~xample 1~
N-r3'-(3''-Pyridyl)prop-2'- noyll-R-Valine-di-n-pentyl~mide The reaction was performed in a similar manner to that in example 3 utilizing 0.3 g of the hydrochloride salt of example 2, 3-(3'-pyridyl)acrylic acid (0.17 g), EDCI (0.22 g), HOBt ~0.28 g), and NMM (0.22 mL). An oil was isolated in 76~ yield, 0-3 g [a~D = +10.0 (c=0.85, MeOH). MS(CI) m/e 388(m+H) . lH NMR(CDCl3,300MHz) 0.8-1.05(m,12H), 1.2-1.4(m,8H), 1.45-1.72(m,4H), 2.06(m,lH), 3.1(m,lH), 3.2-3.5(m,2H), 3.5-3.65(m,lH), 4.92(dd,J=2,6Hz,lH), 6.6(d,~z15Hz,lH), 7.28(d,J=9Hz,lH), 7.3(m,lH), 7.6(d,J=15Hz,lH), 7.8(d,J-9Hz,lH), 8.58(d,J=6Hz,lH), 8.74(d,J=2Hz,lH). C,H,N analysis calculated for C23H37N3O2, 0.75 H2O Ç
10.48; found: C 68.74, H 9.31, N 10.21.
Example 1~
N-(1',2'.(3'S) 4'-Tetrahvdrocarbolinyl-3'-carbonvl)-R-Valine-di-n-~entylamide The reaction was performed in a similar manner to that in example 3 utilizing 250 mg of the hydrochloride salt of example 2, N-L-1,2,3,4-tetrahydroharman-3-carboxylic acid ~270 mg), EDCI (160 mg), HOBt (235 mg), and NI~M (190 mL). The oily product was isolated in 38%
yield (148 mg). [a]D= -5.5 (c=0.2, MeOH). MS(CI) m/e 455(m+H) . H NMR(CDC13,300MHz) ~ 0.8-1.0(m,12H), 1.2-., .
. ~
~ ' ' ,~ ' ' - , WO91/~0725 PCT/US90/03630 ~ ~ 5 ? ~ 5 S
1.35~m,8H), 1.5(m,4H), 1.6(m,lH), 2.05(m,lH), 2.55-2.82(m,lH), 3.1-3.4(m,4H), 3.55(m,2H), 4.1(m,lH), 4.75(m,lH), 7.0-7.15(m,2H), 7.25(d,J=9Hz,lH), 7.45(d,J=9Hz,lH), 7.8(bs,1H), 7.85(bs,1H), 8.26(s,1H).
C,H,N analysis calculated for C27H42N4O2, 0.75 H2O: C
69.27, H 9.36, N 11.97; found: C 69.58, H 9.16, N 11.91.
Example 20 N-(l'-Hydroxy-2'-naphthoyl)-R-Valine-di-n-pentylamide The reaction was performed in a similar manner to that in example 3 utilizing 250 mg of the hydrochloride salt of example 2, 1-hydroxy-2-naphthoic acid (160 mg), EDCI (180 mg), ~OBt ~240 mg), and NMM ~200 ~L). Product was isolated in 85~ yield ~310 mg). mp= 85-86C. ta]D=
+90.5 ~c=0.6, MeOH). MS(CI) m/e 427(m~H) . H
NMR(CDCl3,300MHz) ~ O.9(m,6H), 1.05(m,6H), 1.25-1.4(m,8H), 1.5-1.7(m,4H), 2.15(m,lH), 3.05(m,lH), 3.25(m,lH), 3.5(m,lH), 3.65(m,lH), 5.06(dd,J=3,9Hz,lH), 7.2(d,J=9Hz,lH), 7.35~d,J=lOHz,lH), 7.45~d,J=lOHz,lH), 7.5(dd,J=3,6Hz,lH), 7.6(dd,J=3,6Hz,lH), 7.75(d,J=7Hz,lH), 8.4(d,J=9Hz,lH), 10.6(bs,lH). C,H,N analysis calculated for C26H38N2O3: C 73.20, H 8.98, N 6.57; found: C 73.24, H 9.02, N 6.55.
Example 21 ~ -(t-Butyloxycarbonyl)-R-Norleucine-di-n-pentylamide N-(t-Butyloxycarbonyl)-R-Norleucine (1.2 g, 5.2 mmol) was sti.red at 0 C in 40 mL of CH2Cl2 with BOPCl (1.5 g, 5.9 mmol?, and TEA (0.7 mL, 5.2 mmol). To this reaction mixture was added di-n-pentylamine (2.5 mL, 10.5 mmol).
.
WO ~l/00725 PCT/US90/03630 The mixture was stirred overnight and allowed to warm to room temperature. An additional equivalent of BOPCl was added after 18 hrs and the reaction stirred an additional day at ambient temperature. The solvents were evaporated in vacuo and the residue taken up in ethylacetate and washed with water, 1 N HCl, saturated NaHCO3 solution, water and then the organic solution was dried over MgSO4.
After filtra~ion and concentration of the filtrate in vacuo, the residue was chromatographed using ethylacetate-hexane as the solvent system in the ratio (1:4). The product was isolated as an oil in 75% yield (1.45 g).
MS(CI) m/e 371(m+H) , lH NMR(CDC13,300MHz) ~ 0.9-1 2~m,9H), 1.24-1 35~m,12H), 1.5~s,9H), 1.55-1.6~m,4H), 1.88~m,2H), 3.1~m,lH), 3.32~m,lH), 3.92~m,lH), 3.6~m,lH), 5.15(m,lH), 6.9~d,J=lOHz,lH).
ExampLe ~
R-Norleucine-di-n-pentylamide hydrochloride The product of example 21 (1.4g, 3.8 mmol) was dissolved in 4 N HCl in dioxane (25 mL) and stirred at room temperature for an hour. When the reaction was complete by tlc the solvents were evaporated in vacuo and hexane and diethylether were added. The residue was triturated with these solvents and the solid product was filtered away in quantitative yield. [a]D= -1.4 ~c=0.6, MeOH). MS(CI) m/e 271(m+H) . H NMR(DMSOd6,300MHz) 0.87(m,9H), 1.2-1.4(m,12H), 1.42-1.6(m,4H), 1.7(m,2H), 3.0(m,lH~, 3.1-3.3(m,2H), 3.53(m,lH), 4.14(bs,lH), 8.25(bs, 2r;, .
:
:, . . . . - , ~:
. " .. . ..
W09l/00725 PCTtUS90/03630 .:
2~ 55`
Example 23 N-(3'-Ouinolylcarbonyl~-R-Norleucine-di-n-pentylamide The hydrochloride of example 22 (240 mg, 0.87 mmol), EDCI (170 mg), HOBt (240 mg) and quinoline-3-carboxylic acid (150 mg) were stirred at 0C under nitrogen in 20 mL
anhydrous CH2C12. To this mixture was added 200 ~L of NMM
and the mixture was stirred overnight (warming to ambient temperature). The reaction mixture was poured into ethylacetate and water and the organic extract was washed successively with water, 10% citric acid solution, and saturated aqueous NaHCO3. The solution was dried over MgSO4, filtered and concentrated. The residue was purified by chromatography using ethylacetate and hexane as the elutant mixture to provide 200 mg of the glassy product (54% yield) after evaporation of the volatiles.
[a]Ds -10.5 (c=1.0, MeOH). MS(CI) m/e 426(m+H) . 1H
NMR(CDCl3,300MHz) ~ 0.9(m,9H), 1.35(m,12H), 1.55(m,2H), 1.65-1.80(m,4H), 3.10(m,lH), 3.25-3.35(m,lH), 3.4(m,lH), 3.55-3.6(m,lH), 5.15(m,lH), 7.4(d,J=9Hz,lH), -7.6(dd,J=3,7Hz,lH), 7.8(dd,J=3,7Hz,lH), 7.9(d,J=9Hz,lH), 8.15(d,J=9Hz,lH), 8.6(d,J=2Hz,lH), 9.35(d,J=3Hz,lH).
C,H,N analysis calculated for C26H39N3O2, 0.3 EtOAc: C
72.27, H 9.23, N 9.27; found: C 72.26, H 9.01, N 9.54.
Example 24 N-(2'-Indolylcarbonyl)-R-Norleucine-di-n-pentylamide The hydrochloride salt of example 22 (0.30 g, 1.0 mmol) was stirred in 10 mL of CH2C12 with NMM (0.2 mL, 2.0 mmol) under nitrogen at 0 C. EDCI (0.2 g, 1.1 mmol) and HOBt (0.27 g, 2.0 mmol) were added followed by the .. . . , .. . ( ,, - . . - .
.
:. , -: : . : . --;: :. -' .: :
5~
addition of indole-2-carboxylic acid (0.162 g, 1.0 mmol).
The reaction mixture was stirred overnight (warming to ambient temperature). The solvents were evaporated in vacuo and the residue taken up in ethylacetate and washed successively with water, saturated NaHCO3, a saturated solution of citric acid, water and brine. The organic solution was dried over MgSO4 and then filtered. Solvents were evaporated in vacuo and the crude product subjected to flash chromatography using ethylacetate and hexane as the elutant mixture. The product was crystallized from ethylacetate and hexane to provide a glass 0.285 g (69~).
[a]D= -10.6 (c=0.8, MeOH). MS(CI) m/e 414(m+H) . lH
NMR(CDC13,300MHz) ~ 0.9(m,9H), 1.2-1.4(m,10H), 1.5-1.7~m,6H), 1.86(m~2H), 3.15(m,1H), 3.3-3.4(m,2H), 3.58(m,lH), 5.1(m,lH), 7.0(d,J=2Hz,lH), 7.15(dd,J=3,7Hz,lH), 7.3(m,2H), 7.4(d,J=9Hz,lH), 7.67(d,J=9Hz,lH), 9.4(s,1H). C,H,N analysis calculated for C25H39N3O2, 0.75 H2O: C 70.30, H 9.55, N 9.84; found:
C 70.38, H 9.20, N 9.85.
Example 25 N-(t-Butyloxycarbonyll-R-(O-benzvl)Serine-di-n-pentylamide N-(t-Buiyloxycarbonyl)-R-(O-benzyl)serine (3.0 g, 10.15 mmol) was stirred at 0C in 50 mL of CH2C12 with BOPCl (2.8 g, 11 mmol) and 2.0 mL (1.5 mmol) of TEA. To this reaction mixture was added di-n-pentylamine (7 mL, 35 mmol). The mixture was stirred overnight and allowed to warm to room temperature. An additional equivalent of BOPCl was added after 18 hrs and the reaction stirred an , - :
.. .
' , 55 ~ . ..
additional day at ambient temperature. The solvents were evaporated in vacuo and the residue taken up in ethylacetate and washed with water, 1 N HCl solution, saturated NaHCO3, water and then the organic solution was dried over MgSO4. After filtration and concentration of the filtrate in vacuo, the residue was purified by chromatography using ethylacetate-hexane as the elutant system in the ratio (1:9). The product was isolated as an oil in 44% yield (1.9 g). MS(CI) m/e 435(m+H) . H
NMR(CDCl3,300MHz) ~ 0.89(m,6H), 1.28(m,8H), 1.4(s,9H), 1.55(m,4H), 3.05-3.2(m,2H), 3.4-3.65(m,4H), 4.5(m,2H), 4.85(m,lH), 5.35(d,J=7Hz,lH), 7.31(m,5H).
~L~ ~ '.
R-(O-Ben ~ drochloride The product of example 25 (0.43 g, 1.0 mmol) was dissolved in 4 N HCl in dioxane (10 mL) and stirred under inert atmosphere (N2) for a~ hour. When the reaction was complete by tlc the solvents were evaporated in vacuo and hexane and diethylether were added. The residue was triturated with these two solvents and the solvents again removed in vacuo. This procedure was repeated several times until the product was obtained as a glassy solid in 93% yield (0 35 g). [a]D= +1.6 (c=0.5, MeOH). MS(CI) m/e 335(m+H) .
::
-. . , ~(~ ? ~ 5 5 ~mL1~ 27 N-(3'~Ouinolylcarbonyl-R-(O-benzyl)Serine-di-~-pentylamide The hydrochloride salt of example 26 (0.35 g, 0.95 mmol) was stirred in 25 mL of CH2C12 with NMM, (0.22 mL, 2 mmol) under N2 at 0C. EDCI (0.19 g, 1.0 mmol) and HOBt (0.27, 2 mmol) were added followed by the addition of quinoline-3-carboxylic acid (0.165 g, 0.95 mmol). The reaction mixture was stirred overnight (warming to ambient temperature). The solvents were evaporated in vacuo and the residue taken up in ethylacetate and washed successively with water, saturated NaHCO3, a saturated solution of citric acid, water and brine. The organic solution was dried over MgSO4 and then filtered. Solvents were evaporated in vacuo and the crude product subjected to flash chromatography using ethylacetate and hexane as the elutant mixture. The product was crystallized from ethylacetate and hexane to provide a semisolid, 0.44 g (94%). [a]D= -4.0 (c=0.45, MeOH). MS(CI) mte 490~m+H) . H NMR~CDC13,300MHz) ~ 0.9(m,6H), 1.2-1.4~m,8H), 1.5-1.6~m,4H), 3.05-3.28~m,2H), 3.5-3.7~m,2H), 3.8(m,2H), 4.57(m,2H), 5.4(m,lH), 7.3(m,5H), 7.4(d,J=9Hz,lH), 7.62(dd,J=2,7Hz,lH), 7.81(dd,J=2,7Hz,lH), 7.9(d,J=8Hz,lHj, 8.15(d,J=9Hz,lH), 8.58(d,J=3Hz,lH), 9.3(d,J=3Hz,lH). C,H,N analysis calculated for C30H39N3O3, 0.75 H2O: C 71.61, H 8.11, N 8.35; found: C
71.73, H 8.01, N 8.21.
.
.: .
2 ~ ~ ? ~ 5 5; ;
Exam~le 28 N-(t-Butyloxycarbonyl)-R-Phenvlalanine-di-n-pentylamide The reaction was performed in a similar manner to that in example 2 utilizing N-(t-Butyloxycarbonyl)-R-Phenylalanine (0.8 g, 3.1 mmol), BOPCl (1.2, 4.06 mmol), dipentylamine (3.1 mL, 15 mmol), and TEA (0.4 mL, 3.1 mmol). The oily product was isolated in 65.5% yield (0.87 g). [a]D= +7.0 (c=1.0, MeOH). MS(CI) m/e 405(m+H) .
H NMR(CDC13,300MHz) ~ 0.85(m,6H), 1.15-1.45(m,8H), 1.5(s,9H), 1.55-1.6(m,4H), 2.9-3.1(m,5H), 3.5(m,lH), 4.25(m,lH), 5.3~d,J=9Hz,lH), 7.25~m,SH).
Exam~le 22 N-(t-Butyloxycarbonyl)-(2R 3S)-(O-benzyl)Threonine-di-n-Dentylamide The reaction was performed in a similar manner to that in example 1 utilizing N-~t-Butyloxycarbonyl)-D-(O-benzyl)- threonine ~5 g, 16.2 mmol), BOPCl ~8.2 g, 16.2 mmol), dipentylamine (16 mL, 78.5 mmol), and TEA (2.1 mL, 16.2 mmol). The product was isolated in 58% yield (4.15 g). MS(CI) 449(m+H) . H NMR(CDCl3,300MHz) ~
0.85(t,J=6Hz,6H), 1.18(d,J=6Hz,3H), 1.2-1.35(m,8H), 1.45(s,9H), 1.5-1.6(m,4H), 3.0-3.18(m,2H), 3.41-3.63(m,2H), 3.75~m,lH), 4.57(dd,J=12,18Hz,2H), 4.65(m,lH), 5.5(d,J=9Hz,lH), 7.30(m,SH).
.. . ..... ... . ~. , . ': .. :. ' : .
. .- , ....
WO91/00725 PCT/US9OtO3~30 r~_, ,'755 Example 30 (2R 3S~-(O-Benzyl)Threonine-di-n-~entylamide hydrochloride The product of example 29 (1 g, 2.22 mmol) was deprotected and isolated in a similar manner to that in example 2. The product was isolated as an oil. [a] D =
+13.3 (c=l.l, MeOH). MS(CI) m/e 359(m+H) . H
NMR(DMSOd6,300MHz) ~ 0.86(m,6H), 1.08-1.32(m,11H), 1.48(m,4H), 3.03(m,2H), 3.42~m,2H), 3.88(m,lH), g.2(d,J-6Hz,lH), 4.56(m,2H), 7.35(m,5H), 8.35(bs,2H).
~ ~ .
N-~3'-Ouinolvlcarbonyl)-(2R.3S)-lO-ben~yl)Threonine-di-n-pentylamide The hydrochloride salt of example 30 (0.25 g, 0.65 mmol) was stirred in 15 mL of CH2C12 with NMM (0.175 mL, 1.3 mmol) under nitrogen at 0C. EDCI (0.15 g, 0.8 mmol) and HOBt (0.18 g, 1.3 mmol) were added followed by the addition of quinoline-3-carboxylic acid (0.115 g, 0.65 mmol). The reaction mixture was stirred overnight (warming to ambient temperature). The solvents were evaporated in vacuo and the residue taken up in ethylacetate and washed successively with water, saturated NaHC03, a saturated solution of citric acid, water and brine. The organic solution was dried over MgS04 and then filtered. Solvents were evaporated in vacuo and the crude product subjected to flash chromatography using ethylacetate and hexane as the elutant mixture. The oily product was isolated in 62% yield (0.2g). [a~D= -4.1 - . - , . , :
.
: , . ~ . , WO9l/~0725 PCT/US90tO363~
, . .
2~ 55 .- ,, lc-1.0, MeOH). MS(CI) m/e 504(m+H) . H
NMR(CDCl3,300MHz) ~ 0.9(m,6H), 1.2-1.45~m,11H), 1.5-1.7~m,4H), 3.0-3.25~m,2H), 3.56-3.7~m,2H), 3.9~m,lH), 4.5~m,2H), 5.3~apparent q,J=4.5Hz,lH), 7.2-7.3~m,5H), 7.56~d,J=6Hz,lH), 7.65~t,J=7Hz,lH), 7.8~t,J=7Hz,lH), 7.92~d,J=9Hz,lH) 8.15~d,J=9Hz,lH), 8.63~d,J=2Hz,lH), 9.35~d,J=3Hz,lH). C,H,N analysis calculated for C31H41N3O3, 1.6 H2O: C 69.92, H 7.89, N 8.37; found: C
69.81, H 7.78, N 8.08.
E~m~l~ 32 N-(3'-Ouinolvlcarbonyl)-(2R 3S)-Threonine-di-n-pentylam;de The product of example 31 (1 g, 2 mmol) was stirred in 20 mL of CH2C12 and 7 mL of borontristrifluoroacetate ~1.0 M solution in trifluoroacetic acid) was added at 0C.
The mixture was stirred approximately 1 hour The tlc revealed some starting material therefore ano~her 5 mL of borontristrifluoroacetate and 5 mL trifluoroacetic acid were added. The reaction proceeded overnight to completion by tlc analysis. The reaction mixture was diluted with MeOH and then concentrated in vacuo. The residue was purified by chromatography using ethylacetate and hexane as the elutant mixture. The pure fractions were pooled together and the desired product characterized as the di-trifluoroacetic acid salt. mp= 84-6 C. [~]D= -11.6 ~c=0.55, MeOH). MS~CI) m/e 414~m+H) . 1H
NMR~CDC13,300MHz) ~ 0.85~m,6H), 1.13~d,J=7Hz,3H), 1.15-1.38~m,8H), 1.48~m,2H), 1.6~m,2H), 3.1~m,1H), 3.32-3.53(m,4H), 4.05~m,1H), 4.9~t,J=6Hz,lH), 7.7~t,J=6Hz,lH), ! . . , , ~
' , ~, , ` ' ' ` : ' ' ' :
WO91/0072~ PCT/US90/03630 ~5 ~75~5 7 88~t,J-7Hz,lH), 8.1~d,J=9Hz,lH), 8.8~d,J=9Hz,lH), 8.93~bs,lH), 9.31~bs,lH), 10.02~bs,lH). C,H,N analysis calculated for C24H35N33~ 2 CF3C2 6.55; found: C 52.31, H 5.62, N 6.66.
Example ~
N-(3'-Ouinolylcarbonyl)-(2R 3S)-(O-acet-~l)Threonine-di-n-pentylamide Pyridine ~20 ~L) and acetic anhydride ~60 ~L) were added to the product of example 32 ~51 mg, 0.125 mmol) which was dissolved in acetonitrile ~2 mL). The reaction mixture w~s stirred overnight at room temperature.
Ethylacetate was added and this solution was washed ~uccessively with water and brine. The organic solution was dried over MgSO4. After filtration and concentration of the filtrate in vacuo, the residue was purified by chromatography using ethylacetate and hexane as the elutant system in the ratio ~9:1). The product was isolated as a glass in 44% yield (25 mg). MS~CI) m/e 456(m+H) . H NMR~CDC13,300MHz) ~ 0.9~m,6H), 1.25-1.45~m,11H), 1.52~m,2H), 1.7~m,2H), 2.05~s,3H), 3.1(m,2H), 3.3-3.6 (m,3H), 5.28(m,lH), 5.44(m,lH), 7.35~d,J=9Hz,lH), 7.65~t,J=7Hz,lH), 7.82~t,J=7Hz,lH), 7.95~d,J=7Hz,lH), 8.18~d,J=9Hz,lH), 8.6~d,J=3Hz,lH), 9.35~d,J=3Hz,lH).
C,H,N analysis calculated for C26H37N3O4, 0.4 H2O: C
67.48, H 8.23, N 9.08; found: C 67.69, H 8.20, N 8.60.
.. . , . . - . : .~
: .- ~ . : ., - .
. : '', . . .
WO91/00725 PCT/US90/0363~
. .
2a~?~ss~ ~;;, ~--' ~xamDle N-(3'-Ouinolvlcarbonyl)-~2R.3S)-~O-methyl)Threonine-di-n-pentylamide Lithium bis(trimethylsilyl)amide in THF ~0.15 mL of 1.0 M solution in THF) was added to a cooled ~-10C) solution of the product of example 32 ~55 mg, 0.14 mmol) in 2 mL tetrahydrofuran (THF) and then methyl iodide ~0.015 mL) was added. The reaction mixture was stirred approximately 1 hour and slowly wa-med to room temperature. Tlc revealed some starting material therefore another equivalent of methyl iodide t0.01 mL) was added. The reaction then proceeded to completion by tlc. The reaction mixture was concentrated in vacuo.
Ethylacetate was added to the residue, which was then washed with water and brine. The ethylacetate extract was dried over MgSO4. Filtration and concentration of the filtra~e in vacuo, provided a residue which was purified by chromatography using ethylacetate and hexane as the elutant mixture. An oil was isolated in 47% yield (28 mg).
MS(CI) m/e 428(m+H) . H NMR(CDCl3,~00MHz) ~ 0.92(m,6H), 1.25(d,J=6Hz,3H), 1.25-1.4(m,8H)j 1.55-1.6(m,4H), 3.05(m,lH), 3.2-3.3(m,2H), 3.35(s,3H), 3.58-3.82(m,2H), 5.25(m,lH), 7.45(d,J=9Hz,lH), 7.65(t,J=6Hz,lH), 7.8(t,J=6Hz,lH), 7.9(d,J=9Hz,lH), 8.18~d,J=9Hz,lH), 8.6(d,J=3Hz,lH), 9.35(d,J=3Hz,lH).
. :., ' ~ : .
; : -WO9l/00725 PCT/US90/0363 ~, :
2~ 5~
N-(t-Butyloxycarbonyl)-3-(2'-thienyl)-R-Alanine-di-n-~ ,.
N-~t-Butyloxycarbonyl)-R-3-~2'-thienyl)-Alanine ~0.78 g, 3.25 mmol) was stirred at 0C in 25 mL of CH2Cl2 with BOPCl ~0.44 g, 3.25 mmol) and 0.5 mL, (3.25 mmol) of TEA.
To this reaction mixture was added di-n-pentylamine ~2 mL, 10 mmol). The mixture was stirred overnight and allowed to warm to room temperature. An additional equivalent of BOPCl was added after 18 hrs and the reactions stirred an additional day at ambient temperature. The solvents were evaporated in vacuo and the residue taken up in ethylacetate and washed with water, 1 N HCl solution, saturated NaHCO3 solution, water and then the organic soluti~n was drièd over magnesium sulfate. After filtration and concentration of the filtrate in vacuo, the residue was purified by chromatography using ethylacetate-hexane as the solvent system in the ratio (1:4). The product was isolated as an oil in 57~ yield ~0.76 g).
[a~D= -2.27 (c=0.66, MeOH). MS(CI) m/e 411(m+H) , 355, 311. lH NMR(CDCl3,300MHz) ~ 0.85(m,6H), 1.15-1.38(m,10H), 1.45(s,9H), 1.51(m,2H), 3.1(m,4H), 3.22(m,lH), 3.4(m,lH), 4.75(apparent q,J=lOHz,lH), 5.45(d,J=9Hz,lH), 6.83(d,J=6Hz,lH), 6.9(t,J=4Hz,lH), 7.15(d,J=6Hz,lH).
- : .
: - ~
. ~ ',, - .:
..
.
WO 91~00725 PCT/US90/0363 :' 2~755 -, .,~
~xample R-3-(2'-Thienyl)-Alanine-di-n-pentylamide hydrochlorid~
The product of example 35 (0.22 g, 0.59 mmol) was deprotected and isolated in the same manner as that in example 2 in quantitative yield. MS(CI) m/e 327~M+H) .
Example 37 N-(3'-Ouinolylcarbonyl)-3-(2'-thienyl)-R-Alanine-di-n-pentylamide The reaction was performed in a similar manner to that in example 3 utilizing ~80 mg, 0.23 mmol) of the hydrochloride salt of example 36, quinoline-3-carboxylic acid ~40 mg), EDCI ~50 mg), HOBt (62 mg), and NMM (51 ~L).
An oil was isolated in 45% yield, ~48 mg). MS~CI) m/e 466~m+H) . H NMR~CDC13,300MHz) ~ 0.9~m,6H), 1.2-1.4(m,8H), 1.45-1.65~m,4H), 3.05-3.4(m,4X), 3.45-3.6~m,2H), 5.35~dd,J=6,7Hz,lH), 6.87~d,J=3Hz,lH), 6.99~m,lH), 7.18~d,J=6Hz,lH), 7.4~d,J=9Hz,lH), 7.63~dd,J=3,7Hz,lH), 7.8(dd,J=3,7Hz,lH), 7.9(d,J=8Hz,lH), 8.15(d,J=8Hz,lH), 8.6~d,J=3Hz,lH), 9.32~d,J=3Hz,lH).
C,H,N analysis calculated for C27H35N3O2S, 0.9 H2O: C
67.29, H 7.70, N 8.72; found: C 67.60, H 7.47, N 8.98.
E~ample 38 N-(t-Butyloxycarbonyl)-S-Valir.~-di-n-pentylamide The reaction and product isolation were performed in a similar manner to that in example 1 utilizing N-~t-Butyloxycarbonyl)- S-Valine (2.5 g, 11.5 mmol), BOPCl (3.5 g, 13.8 mmol) and dipentylamine (11.6 mL, 58 mmol), and ' -WO91/0072~ PCT/US90/~3630 ~': '' ` ' ,' , ;~?~755 TEA (1.6 mL, 12 mmol). The oily product was isolated in 55% yield (2.25 g). [a]D= -21.1 (c=1.0, MeOH). MS(CI) m/e 357~m+H) . H NMR(CDC13,300MHz) ~ O.9(m,6H), 1.05(m,6H), 1.25-1.35(m,8H), 1.95(s,9H), 1.5-1.55(m,4H), 1.95(m,lH), 3.0(m,lH), 3.2(m,lH), 3.36(m,lH), 3.6(m,lH), 4.4(dt,J=3,7Hz,lH), 5.24(d,J=9Hz,lH).
Example 39 S-Valine-di-n-pentylamide hydrochloride The product of example 38 (0.2 g, 0.57 mmol) was deprotected and the product isolated as in example 2 in quantitative yield. MS(CI) m/e 257(m+H) .
~xample ~Q
N-(3'-Ouinolylcarbonyl)-S-Valine-di-n-pent~lamide The reaction sequence was performed in a similar manner to that in example 3 utilizing 175 mg of the hydrochloride salt of example 39, quinoline-3-carboxylic acid (110 mg), EDCI (125 mg), HO~t (165 mg), and NMM (75 ~L). The glassy product was isolated in 80% yield, (198 mg)- [a]D= +12.95 (c=0.8, MeOH). MS(CI) m/e 412(m+H) .
H NMR(CDCl3,300MHz) ~ 0.8-1.05(m,12H), 1.2-1.44(m,8H), 1.55(m,4H), 2.15(m,lH), 3.1(m,lH), 3.3(m,lH), 3.5(m,lH), 3.65(m,1H), 5.1(dd,J=3,6Hz,lH), 7.25(d,J=7Hz,lH), 7.62(t,J=7Hz,lH), 7.8(t,J=7Hz,lH), 7.9(d,J=8Hz,lH), 8.15(d,J=9Hz,lH), 8.61(d,J=3Hz,lH), 9.35(d,J=3Hz,lH).
C,H,N analysis calculated for C25H37N3O2, 0.25 H2O: C
72.16, H 9.09, N 10.10; found: C 72.41, H 9.21, N 9.97.
, : , , : -. . .. .: , WO91/00725 PCT/US9OtO3630 2C?5~5S
.. ...
. ....
N-tt-Butyloxycarbonyl)-~im-tosyl)-R-Histidine-di-n-pentylamide N-(t-Butyloxycarbonyl)-R-(Nim-tosyl)-histidine, (4.95 g, 12.6 mmol) was stirred at 0C in 50 mL of CH2C12 with BOPCl (3.2 g, 12.6 mmol) and 1.65 mL (12.6 mmol) TEA. To this reaction mixture was added di-n-pentylamine (7.7 mL, 38 rnmol). The mixture was stirred overnight and allowed to warm to room temperature. An additional equivalent of BOPCl was added after 18 hrs and the reaction stirred an additional day at ambient temperature. The solvents were evaporated in vacuo and the residue was taken up in ethylacetate and washed with water, 1 N HCl solution, saturation NaHC03, water. The organic solution was dried over MgS04. After filtration and concentration of the filtrate in vacuo, the residue was purified by chromatography using ethylacetate-hexane as the solvent system in the ratio (1:4). The product was isolated as an oil in 75% yield (5.1 g). [a]D= +8.8 (c=1.0, MeOH).
MS(CI) m/e 549(m+H) . H NMR(DMSOd6,300MHz) ~ 0.85(m,6H), 1.05-1.46(m,21H), 2.42(s,3H), 2.67(m,2H), 3.03-3.15(m,4H), 4.52(m,1H), 7.0(s,1H), 7.28(d,J=7Hz,lH), 7.49(d,J=7Hz,2H), 7.9(d,J=7Hz,2H), 8.28(s,lH). C,H,N analysis calculated for C28H44N405S: C 61.28, H 8.08, N 10.21; found: C 61.04, H 8.05, N 10.10.
~ '' ' .
.... . . .
WO91/0072~ PCT/US90/0363~
~' E~ample~ 42 (Nim-Tosyl)-R-Histidine-di-n-pentylamide To a solution of the product of example 41 (6.7 g, 12.21 mmol) in CH2C12 (100 mL) was added trifluoroacetic acid (TFA, 40-50 mL). The reaction mixture was stirred at room temperature 60 minutes. When reaction was complete by tlc, the solvents were evaporated several times in vacuo and CH2C12 was added with a saturated solution of NaHCO3. The reaction mixture was stirred vigorously another 1 hr and after separation of layers, the organic layer was washed several times with water and brine. The - -CH2C12 layers and washings were dried over magnesium sulfate. The product was then concentrated in vacuo. The semisolid product was isolated and dried in a vacuum oven over P2O5 at room temperature, 5.1 g (93% yield).
[a]D= -9.4 (c=1.0, MeOH). MS~CI) m/e 449(m+H) , 264, 295. lH NMR(CDCl3,300MHz) ~ O.85(m,6H), 1.1-1.35(m,8H), 1.47-1.6(m,4H), 2.45(s,3H), 2.9-3.2(m,6H), 3.4-3.55(m,2H), 4.5(m,lH), 7.18(s,lH), 7.35(d,J=8Hz,2H), 7.82(d,J=8Hz,2H), 7.95(s,lH).
Example 43 N-(2l-Indolylcarbonyl)-R-~istidine-di-n-pentylamide The compound of example 42 (170 mg, 0.5 mmol), EDCI
(105 mg), HOBt (135 mg) and indole-2-carboxylic acid (85 mg) were stirred at 0 C under nitrogen in 10 mL of anhydrous CH2C12. To this mi:cture was added 110 ~L of NMM
and the mlxture was stirred overnight (warming to ambient temperature). The reaction mixtu e was poured into ' .. : ' .'.. . . -- :- .. , , . ' :. , . ~: .. . . .. . . -: ~
:-, . - . : ,. :- . - : -- : .. : . . . .
WO 9l/00725 PCTtUS90/03630 ethylacetate and water and the organic extract was washed successively with water, 10% citric acid solution, and saturated aqueous NaHCO3. The soiution was dried over MgSO4, filtered and concentrated. The residue was purified by chromatography using chloroform/methanol/
ammonia as the elutant mixture to provide 98 mg of the semisolid product (45% yield) after evaporation of the ~olatiles. [a]D= +9.8 (c=0.46, MeOH). MS(CI) m/e 438(m+H) , 253, 281. H NMR(CDCl3,300MHz) ~ O.75-0.95(m,6H), 1.2(m,8H), 1.5(m,4H), 3.13(m,4H), 3.3(m,lH), 3.4(m,lH), 3.5(m,2H), S.32(m,lH), 6.8(s,lH), 6.9(s,lH), 7.1(t,J=7Hz,2H), 7.2(t,J=7Hz,2H), 7.35(d,J=9Hz,lH), 7.59(d~J=9Hz,lH)~ 9.8(s,lH). C,H,N analysis calculated for C25H35N5O2, 0.5 H2O: C 67.23, H 8.13, N 15.68; found:
C 67.24 H 8.06, N 15.24.
~am~le 44 -(t-Butyloxycar~on~ N -(benzyloxycarbonyl)-R-Lysine-di-n-pentylamide The reaction was performed in a similar manner to that in example 1 utilizing N -t-Butyloxycarbonyl-R-(N -benzyloxycarbonyl)Lysine (S g, 13.1S mmol), BOPCl (6.7 g, 26.3 mmol), di-n-pentylamine (26 mL, 131 mmol) and TEA
(1.8 mL, 13.S mmol) in CH2Cl2 (25 mL). The oily product was isolated in 64.5% yield (4.4 g). [a]~= +65.3 (c=0.15, MeOH). MS(CI) m/e 520(m+H) . H
NMR(CDCl3,300MHz) ~ 0.9(m,6H), 1.2-1.35(m,12H), 1.41(s,9H), l.S-1.66(m,4H), 3.05-3.25(m,9H), 3.3(m,2H), 3.5(m,2H), 9.53(m,lH), 4.9~m,lH), 5.1(s,2H), 5.38(d,J=9Hz,lH), 7.3(m,SH).
:: . , . -: : - --: "
::
z~755 ~ample q5 N-(t-Butyloxycarbonyl)-3-(1'-naphthvl)~R-~lanine-di-n-pentylamine N-(t-Butyloxycarbonyl)-3-~1'-naphthyl)-R-Alanine (0.35 g, 1.1 mmol) was stirred at 0C in 25 mL of CH2C12 with BOPCl, (0.3 g, 1.2 mmol), and 0.15 mL of TEA (1.2 mmol). To this reaction mixture was added di-n-pentylamine (0.8 mL, 4 mmol). The mixture was stirred overnight and allowed to warm to room temperature. An additional equivalent of BOPC1 was added after 18 hrs and the reaction stirred an additional day at ambient temperature. The solvents were evaporated in vacuo and the residue taken up in ethylacetate and washed with water, 1 N HC1 solution, saturated NaHCO3, water and then the organic solution was dried over MgSO4. After filtration and concentration of the filtrate in vacuo, the residue was purified by chromatography using ethylacetate-hexane as the solvent system in the ratio (1:4). The product was isolated as an oil in 65% yield (0.25 g).
MS(CI) m/e 455(m+H) . H NMR(CDC13,300MHz) ~ 0.7-0.8(m,6H), 0.9(m,8H), 1.2-1.3(s,4H), 1.35(s,9H), 3.0(m,2H), 3.35(m,2H), 3.5-3.6(m,2H), 4.3(m,lH), 7.4(m,lH), 7.45-7.55(m,2H), 7.6(m,lH), 7.8 (d,J-9Hz,lH), 7.85(d,J=9Hz,lH), 8.35(d,J=9Hz,lH), 8.9(bs,lH).
Ex~mple 46 3-(l~-Naphthy~ lanine-di-n-pent~lamide hydrochloride The product of example 45 (0.32 g, 0.72 mmol) was dissolved in 4 N HCl in dioxane ~10 mL) and stirred under . .
. - : . : , , : ::: -: : .
W09l/00725 PCr/US90/03630 .
inert atmosphere (N2) for an hour. When the reaction was complete by tlc the solvents were evaporated in vacuo and hexane and diethylether added. The residue was triturated with these two solvents until the product was obtained as a glassy solid in quantitative yield.
MS(CI) m/e 391(m+H) . lH NMR(CDC13,300MHzl: ~ 0.63(m,3H), 0.85(m,3H), l.OS-1.45(m,10H), 1.5-1.72(m,2H), 2.62(m,lH), 2.85(m,lH), 3.6-3.92(m,4H), 4.85(m,lH), 9.73(m,2H), 7.36(m,lH), 7.5(m,lH), 7.7(d,J=6Hz,lH), 7.75(d,J=6Hz,lH), 8.35(d,Jz8Hz,lH), 8.92(bs,2H), 9.9(s,lH).
E~mple 47 N-~3'-Ouinolylcarbonyl)-3-(l'-Naphthyl)-R-Alanin~-di-n-pentylamide The hydrochloride of example 96 (200 mg, 0.52 mmol), EDCI, HO~t (70 mg) and quinoline-3-carboxylic acid (90 mg) were stirred at 0C under N2 in 5 mL of anhydrous CH2Cl2.
To this mixture was added lO~L of NMM and the mixture was stirred overnight (warming to ambient temperature). The reaction mixture was poured into ethylacetate and water and then the separated organic extract was washed successively with water, 10% citric acid solution, and saturated aqueous NaHC03. The solution was dried over MgS04, filtered and concentrated. The residue was purified by chromatography using ethylacetate and hexane as the elutant mixture to provide 180 mg of the oily product (68% yield) after removal of the volatiles.
MS(CI) m/e 510(m+H) , 280. lH NMR(CDC13,300MHz) ~
0.72(m,3H), O.9(m,3H), 1.1-1.45(m,10H), 1.5.1-6(m,2H), 2.38-2.6(m,2H), 2.85(m,lH), 3.47(m,2H), 3.9(m,lH), .. ~.... ...
.. : . , ,.. ;., - ' ~ ~ . . :
: .
Z~ ,, S5 5.6(m,lH), 7.35(d,J=6Hz,2H), 7.52(t,J=7Hz,2H), 7.6-7.7(m,3H), 7.72-7.93(m,3H), 8.15(d,J=9Hz,lH) 8.55(d,J=9Hz,lH), 8.6(d,J=3Hz,lH), 9.4(d,J=3Hz,lH).
ExamDle ~
N-(t-Butyloxycarbonyl)-3-~2'-naphthyl)-R-Alanine-di-n-pentylamide N-(t-Butyloxycarbonyl)-3-(2'-naphthyl)-R-Alanine (0.31 g, 1.0 mmol) was stirred at 0C in 25 mL of CH2Cl2 with BOPCl, (0.38 g, 1.5 mmol) and 0.2 mL of TEA (1.5 mmol). To this reaction mixture was added di-n-pentylamine (0.7 mL, 3.5 mmol). The mixture was stirred overnight and allowed to warm to room temperature. An additional equivalent of BOPCl was added after 18 hrs and the reaction stirred an additional day at ambient temperature. The solvents were evaporated in vacuo and the residue taken up in ethylacetate and washed with water, 1 N HCl solution, saturated NaHCO3, and water.
The organic solution was dried over MgSO9. After filtration and concentration of the filtrate in vacuo, the residue was purified by chromatography using ethylacetate-hexane as the solvent system in the r~tio (1:4). The product was isolated as an oil in 62% yield (0.28 g).
MS(CI) m/e 455(m+H) , 355.
Ex~-m-pl~ 49 3-(2'-Naphthvl~-R-Alanine-di-n-~entylamide h~drochloride The product of example 48 (0.28 g, 0.6 mmol) was dissolved in 4 N HCl in dioxane ~10 mL) and stirred under N2 for an hour. When the reaction was complete by tlc the ,,. , . ~ -~: ., .. - ....................... . .
,: . : : . ~ . . .
, .
2~ 5S
solvents were evaporated in vacuo and then hexane and diethylether were added. The residue was triturated with these two solvents until the product was obtained as a glassy solid in 93% yield. MS(CI) m/e 355(m+H) .
Example 50 N-(3'-Ouinolylcarbonyl)-R-Histidine-di-~-pentylamide The free base of example 42 ~3.7 g, 9.26 mmol), EDCI, (1.7 g, 9 mmol), HOBt (3.65 g) and 1.5 g quinoline-3-carboxylic acid were stirred at 0C in 50 mL of anhydrous ~imethylformamide (DMF) and CH2Cl2 in 1:1 ratio. After reaction was complete by tlc, solvents were evaporated under vacuum and the residue dissolved in large excess of ethylacetate (300 mL). Water was added and the organic extract was washed with 10% citric acid solution, and saturated NaHCO3. The solution was dried over MgSO4, filtered and concentrated. The residue was purified by chromatography using chloroform-methanol and ammonium hydroxide as the elutant mixture to provide 1.98 g (68.3~) product. [~]D= -6.9 (c=0.25, MeOH). MS(CI) m/e 450(m+H) , 156. H NMR(CDC13,300MHz) ~ 0.9(m,6H), 1.29(m,8H), 1.45-1.6(m,4H), 3.08-3.2(m,3H), 3.23-3.4(m,2H), 3.5-3.6(m,lH), 5.3(apparent q,J=9Hz,lH), 6.85(s,lH), 7.6(m,3H), 7.(t,J=6H,lH), 7.88(d,J=8Hz,lH), 7.97(d,J=8Hz,lH), 8.15(d,J=8Hz,lH), 8.6(d,J=3Hz,l~), 9.3(d,J=3Hz,lH). N-(3'-Quinolylcarbonyl)-(Nim-tosyl)-R-histidine-di-n-pentylamide ~0.2 g) also was isolated refer to example 51.
. . -: . - - .:
~, , ' , . ' .
' . ', . .
WO91~00725 PCT/US90/03630 ~
',~
i ~1?~ 55 Exam~le ~1 N-3'-Ouinolylcarbonyl-(Nlm-tosyl)-R-Histidine-di-n-pentylamide The title compound of example 51 was isolated as a side product in the procedure in example 50. la]D= +13.3 (c=1.05, MeOH). MS(CI) m/e 604~m+H) , 450. H
NMR(CDC13,300MHz) ~ 0.9~m,6H), 1.3(m,8H), 1.45-1.7(m,4H), 2.25~s,3H), 3.0-3.13(m,3H), 3.25(m,1H), 3.35(m,1H), 3.5(m,1H), 5.36(apparent q,J=6Hz,lH), 7.15(m,3H), 7.6(t,J=7Hz,2H), 7.7(d,J=9Hz,2H), 7.8-7.9(m,2H), 7.95(d,Jz2Hz,lH), 8.13(d,J=7Hz,lH), 8.45(d,J=3Hz" H), 9.18(d,J=3Hz,lH). C,H,N analysis calculated for C33H41N5O9S: C 65.64, H 6.85, N 11.60; found: C 65.58, H
6.84, N 11.50. ?
Example 52 ~_(Benzyloxycarbony~ -R-Lvsin~-di-n-oentylamide hydroc~1o~;~e The compound was prepared in similar manner to example 2 via deprotection of the product of example 44 using 4 N HCl in dioxane. The product was isolated in quantitative yield. MS(CI) m/e 420(m+H) .
~xample 53 Na-(3'-Ouinolylcarbonyl)-N -(benzyloxycarbonyl)-~-Lysine di-n-oentyl2mide The reaction was performed in the similar manner to that in example 3 utilizing 1.0 g of hydrochloride salt of example 52 quinoline-3-carboxylic acid (0.38 g), EDCI
(0.95 g), HOBT (0.6 g), and NMM (0.48 mL). The oily : ,:: ' -. .: -, , .. . . . . .
r -2(~ ~jr?~s5 , product was isolated in 72~ yield. [~D= +2.7 (c=0.7, MeOH). MS(CI) m/e 575(m+H) . lH NMR(C~Cl3,300MHz) 0.9(m,6H), 1.3-1.62(m,8H), 1.53(m,6H), 1.65(m,2H), 1.85(m,2H), 3.05-3.55(m,lH), 5.05(m,lH), 5.15(m,2H), 7.28(m,SH), 7.55(t,J=8Hz,lH), 7.8(m,3H), 8.18(d,J=9Hz,lH), 8.58~d,J=2Hz,lH), 9.32~d,J=2Hz,lH). C,H,N calculated for C34H96N4O4: C 71.05, H 8.07, N 9.75; found: C 71.00, H
8.18, N 9.68.
Ex~mRle 54 N-(3'-Ouinolylcarbonyl~-R-~ysine-di-n-pentylamide To a suspension of 0.5 g 10~ Pd/C in methanol ~MeOH, 25 mL) and cyclohexadiene (3 mL) under N2 was added a solution of the product of example 53 (0.51 g, 0.89 mmol) in methanol via cannula. The reaction mixture was stirred overnight at ambient temperature. Cyclohexadiene (2 mL) was added and the reaction was continued overnight. The mixture was filtered through celite and washed several times with methanol. The filtrate and washings were combined and concentrated in vacuo. The residue was subjected to flash chromatography using chloroform-methanol and ammonium hydroxide 90:10:1 as the elutant mixture. Lyophilization provided product in 64% yield (0.25 g). MS(CI) m/e 441(m+H) . H NMR(DMSOd6,300MHz) 0.85(m,6H), 1.15-1.35(m,8H), 1.4-1.65(m,4H), 1.7(m,2H), 1.75(m,2H), 2.7(m,2H), 3.1-3.5(m,8H), 4.9(m,lH), 7.7~t,J=6Hz,lH), 7.88(t,J=6Hz,lH), 8.1(d,J=8Hz,2H), 8.9(d,J=3Hz,lH), 9.0(d,J=3Hz,lH), 9.3(d,J=3Hz,lH). C,H,N
analysis calculated for C26H40N402, H2O: C 69.45, H 8.97, N 12.46; found: C 69.98, H 8.76, N 12.03.
: - ,, . :: . , ,: . ~' . ' ~ ' ' WO~1/00725 PCT/US90/03630 ~' 2~5~755 ExampleN-(t-Butyloxycarbonyl)-R-(4'-Hydroxy~henyl)~lycine-di-n-pentylamide The reaction was performed in a similar manner to that in example 1 utilizing N-~t-Butyloxycarbonyl)-R-4'-hydroxy phenylglycine (5 g, 18.7 mmol), BOPCl (5.1 g, 20 mmol), dipentylamine (8 mL, 37 mmol), and TEA (2.6 mL).
The product was isolated in 78% yield (5.9 g). MS(CI) m/e 407(m+H) . H NMR(CDC13,300MHz) ~ 0.85(m,6H), 1.1-1.35~m,8H), 1.3(s,9H), 1.45-1.58(m,9H), 3.0(m,lH~, 3.15(m,2H), 3.45~m,lH), 5.42~d,J=9Hz,lH), 6.02~d,J=9Hz,lH), 6.5~s,lH), 6.75~d,J=9Hz,2H), 7 18~d,J-gHz,2H).
FxampleN-(8'-~ydroxy-2'-~uino~lcz hony~ al;~-d;-n-pe~tylamide The title compound was prepared in a similar fashion to that in example 3. mp= 143-4 C. MS~CI) m/e 428~m+H) , 293, 158. lH NMR~CDC13,300MHz) ~ 8.58~d,J=lOHz,lH), 8.31(s,2H), 8.09(s,lH), 7.54(m,lH), 7.39(dd,J=1,8Hz,lH), 7.24(m,lH), 5.01(dd,J=7,10Hz,lH), 3.65(dt,J=7,16Hz,lH), 3.28-3.55(m,2H), 3.06(dt,J=7,14Hz,lH), 2.22(septet,J=7Hz,lH), 1.50-1.75(m,9H), 1.25-1.42(m,8H), 1.06(d,J=7Hz,3H), 1.03(d,J=7Hz,3H), 0.92(t,J=7Hz,3H), 0.89~t,J=7Hz,3H). C,H,N analysis calculated for C25H37N3O3, 0.1 H2O: C 69 93, H 8.73, N 9.79; found: C
69.78, H-8.51, N 9.61.
' ' ~ . ' ! : ~ , WO91/0072~ PCT~US90/03630 2~'5~5S
., ;, , E~a~le 57 R-Phenylalanine-di-n-pentylamide hydrochloride The compound was prepared in similar manner to example 2 via deprotection of N-t-Butyloxycarbonyl-R-Phenylalanine- di-n-pentylamide, the product of example 28, using 4 N HCl in dioxane. The product was isolated in quantitative yield. MS(CI) m/e 305(m+H) .
Example ~
N-(3'-Ouinolylcarbonyl)-R-Phenylalanine-di-n-pentylamide The hydrochloride of example 57 (870 mg, 2.46 mmol), EDCI (550 mg), HOBt ~300 mg), and quinoline-3-carboxylic acid (430 mg) were stirred at 0C under N2 in 25 mL of anhydrous CH2CL2. To this mixture was added 550 ~L of NMM
and the mixture was stirred overnight (warming to ambient temperature). The reaction mixture was poured into ethylacetate and water and the organic solution was separated. The organic extract was washed sùccessively with water, 10% citric acid solution, and saturated aqueous NaHCO3. The solution was dried over MgSO4, filtered and concentrated. The residue was purified by chromatography using ethylacetate and hexane as the elutant mixture to yield 870 mg of product (77%) after removal of the volatiles. [a]D= +12.9 (c=1.05, MeOH).
MS(CI) m/e 460~m+H) . lH NMR(CDC13,300MHz) ~ 0.9(m,6H), 1.15-1.4(m,8H), 1.5-1.55~m,4H), 2.9-3.12tm,3H), 3.2(m,2H), 3.48-3.6(m,lH), 5.35(m,lH), 7.27~m,5H), 7.48(d,J=10Hz,lH), 7.62(t,J=8Hz,lH), 7.8(t,J=8Hz,lH), 7.9(d,J=9Hz,lH), 8.15(d,J=9Hz,lH), 8.55(d,J=3Hz,lH), 9.38(d,J~3Hz,lH).
- .
~,:
.
~ .
SS
C,H,N analysis calculated for C29H37N3O2, 0.5 H2O: C
74.32, H 8.39, N 8.97; found: C 73.92, H 8.05, N 8.83.
~L~ ~
N-(2'-MethylDhenylaminocarbonyl)~R-Valine-di-n-~entylamide A solution of hydrochloride of example 2 (0.15 g, 0.52 mmol), 2-methyl-phenylisocyanate ~0.1 g) and triethylamine (0.1 mL) was allowed to react at ambient temperature. The solvent was removed in vacuo and the residue dissolved in ethylacetate. Water was added and the mixture extracted several times with EtOAc. The combined ethylasetate extracts were washed with brine and dried over MgS04. The volatiles were removed in vacuo and the residue purified by chromatography. The oily product was isolated in 80% yield. [a~D= +1.5 (c=0.4, MeOH).
MS(CI) m/e 390~m+H) . H NMR~CDCl3,300MHz) ~ 0.8-1.0(m,12H), 1.12-1.41(m,8H), 1.42-1.78~m,4H), 2.01~m,lH), 2.22~s,3H), 3.25~m,lH), 3.35~m,2H), 3.51(m,lH), 4.7~m,lH), 6.5~m,lH), 6.7~s,lH), 7.04~t,J=6Hz,lH), 7.16~m,2H), 7.53~d,J=9Hz,lH). C,H,N analysis calculated for C23H39N3O2: C 70.91, H 10.09, N 10.79; found: C 70.57, H
9.46, N 10.57.
Example 60 Na-(t-Butyloxycarbor.yl)-N (2'-chlorobenzyloxycarbonyl)-R-L~sine-di-n-pentylamide N -~t-Butyloxycarbonyl)-N -~2'-chlorobenzyloxyCarbonyl)-R-Lysine ~1.0 g, 2.4 mmol) was stirred at 0 C in 25 mL of CH2Cl2 with BOPCl, ~0.65 g, 2.6 ~ ., . . ,, , .. - - . , . . , : .
. . , ~ , , ,, . : , .~ : -,. , ,: . ~ .; , . - :
.
wo 9l/00725 PCrtVS90/03630 f:- ;
2~ 55 ~ . ! ', ' '. .
mmol), and TEA (0.35 mL, 2.4 mmol). To this reaction mixture was added di-n-pentylamine (2.5 mL, 12 mmol). The mixture was stirred overnight and allowed to warm to room temperature. An additional equivalent of BOPCl was added after 18 hrs and the reaction stirred an additional day at ambient temperature. The solvents were evaporated in vacuo and the residue taken up in ethylacetate and washed with water, 1 N HCl solutionj saturated NaHCO3, and water.
The organic solution was dried over MgSO4. After filtration and concentration of the filtrate in vacuo, the residue was purified by chromatography using ethylacetate-hexane as the solvent system in the ratio ~1:4). The product was isolated as an oil in 53~ yield ~0.7 g).
MS~CI) m/e 554~m+H) , 326. 1H NM~CDC13,300MHz) ~
0.g(m,6H), 1.2-1.38~m,12H), 1.42~s,9H), 1.5-1.7~m,4H), 3.02-3.45~m,4H), 3.48~m,4H), 4.5~m,lH), S.01~m,lH), 5.2~s,2H), 5.4~d,J=9Hz,lH), 7.25~m,2H), 7.3-7.45~m,2H).
Example 61 _(2'-Chlorobenzyloxycarbonyl)-R-Lysine-di-n-pentylamide hydrochloride The compound was prepared in similar manner to example 2 via deprotection of the product of example 60, using 4 N HCl in dioxane. The product was isolated in quantitative yield. MS(CI) m/e 454(m+H) , free base.
.. . .. . .
. . .
~ '55 -68-Exam~le ~2 ~ -(3'-Ouinalylcarbonyl~-N -(2'-chlorobenzyloxycarbonyl)-R-Lysine-di-n-pentylamide The hydrochloride salt of example 61 (0.5 g, 1.02 mmol) was stirred in 15 mL of CH2C12 with NMM (0.29 mL, 2.2 mmol) under N2 at 0C. EDCI (0.25 g, 1.3 mmol) and HOBt (0.3 g, 2.2 mmol) were added followed by the addition of quinoline-3-carboxylic acid (0.1 g, 1.1 mmol). The reaction mixture was stirred overnight and allowed to slowly warm to ambient temperature. The solvents were evaporated in vacuo and the residue taken up in ethylacetate and washed successively with water, saturated NaHCO~, a saturated solution of citric acid, water and brine. The organic solution was dried over MgSO4 and then filtered. Solvents were evaporated in vacuo and the crude product subjected to flash chromatography using ethylacetate and hexane as the elutant mixture. The product was isolated as an oil, 0.46 g (74~). MS(CI) m/e 609(m+H) . H NMR(CDCl3,300MHz) ~ 0.8-0.96(m,6H) 1.16-1.42(m,12H), 1.45-1.6(m,2H), 1.8-2.0(m,2H), 2.7(m,2H), 3.07-3.45(m,4H), 3.5-3.65(m,2H), 5.15(m,3H), 6.85(d,J=12Hz,lH), 7.2(d,J=9Hz,2H), 7.4(d,J=9Hz,2H), 7.6(m,2H), 7.8(t,J=7Hz,lH), 7.9(t,J=7Hz,lH), 8.15(d,J=9Hz,lH), 8.6(s,1H), 9.35(d,J=3:-.7,1H). C,H,N
analysis calculated for C34H45ClN404, 0.6 H2O: C 65.86, H
7.41, N 9.04; found: C 65.63, H 7.29, N 9.92.
... .... ~ . . , -. . .: . - , . . .
. . , ~, . . .
.~ . . .
WO 9l/00725 PCT/US90/03630 !
S~
~1m~l~ 63 N-(3'-Ouinolylcarbonyl)-3-(2'-Naph~hyl)-R-Alanine-di-n-dipentylamide The reaction was performed in a similar manner to that in example 3 utilizing 75 mg of hydrochloride salt of example 49, quinoline-3-carboxylic acid (34 mg), EDCI (q0 mg), HOBt (50 mg), and NMM (22 ~L). The oily product was isolated in 31% yield, (32 mg). MS(CI) m/e 510(m+H) .
lH NMR(CDC13,300MHz) ~ 0.85(m,6H), 1.06-1.35(m,12H), 2.85(m,lH), 3.0(m,2H), 3.35(m,2H), 3.55(m,lH), 5.45(apparent q,J=7Hz,lH), 7.32-7.5(m,4H), 7.62(t,J=6Hz,lH), 7.68-7.82(m,5H), 7.88(d,J=7Hz,lH), 8.15(d,J=7z,lH), 8.52~d,J=2Hz,lH).
E~ample 64 R-~4'-Hydroxyphenyl)-glycine-di-n-pe~ L~mide hydrochloride The compound was prepared in similar manner to example 2 via deprotection of the product of example 55, using 4 N HCl in dioxane. The oily product was isolated in 90% yield. []D= -87.0 (c=0.2, MeOH). MS(CI) m/e 307(m+H) H NMR(DMSOd6,300MHz) ~ 0.82(m,6H), 1.02-1.2(m,8H), 1.3-l.S(m,4H), 3.05-3.3(m,2H), 3.32-3.4(m,2H), 5.22(bs,lH), 6.83(d,J=9Hz,2H), 7.25(d,J=9Hz,2H), 8.4(bs,3H).
"' ' ;. .
-, . .
WO91/0072~ PCT/US90/03630 ~' Z~?si~755 Fxample 65 N-~3 -Ouinolylcarbonyl)-R-(4 -hydroxyphenyl~alycine-di-n-pentylamide The reaction was performed in a similar manner to that in example 3 utilizing (300 mg, 2.6 mmol) of hydrochloride salt of example 64, quinoline-3-carboxylic acid ~450 mg), EDCI (550 mg), HOBt (380 mg), and NMM (0.62 mL). Product was isolated in 53% yield (0.78 g). mp= 79-80 C. (a]D= -99.6 (c=1.0, MeOH). MS(CI) m/e 462(m+H) .
lH NMR(CDC13,300MHz) ~ 0.85(t,J=7Hz,6H), 1.1-1.3(m,10H), 1.4-1.5(m,2H), 3.1-3.2(m,2H), 3.25-3.5(m,2H), 5 9(d,J=9Hz,lH), 6.6(d,J=9Hz,2H), 7.25(d,J=9Hz,2H), 7 7(t,J=7Hz,lH), 7.85(t,J-7Hz,lH), 8.08(d,J=9Hz,2H), 3.9(d,J=3Hz,lH), 9.1(d,J=6Hz,lH), 9.25(d,J=3Hz,lH), 9.53(s,1H). C,H,N analysis calculated ~or C28H35N3O3: C
72.85, H 7.64, N 9.10; found: C 72.65, H 7.65, N 9.08.
Example 66 N -~3 -Ouinolylcarbonyl~-N -(acetyl)-R-~ysine-di-n-pentylamide The reaction was performed in a si~ilar manner to that in example 33 utilizing 60 mg of t:~e product of example 54 and pyridine with acetic anhydride. The oily product was purified by standard chroma=ography and isolated in 33% yield (22 mg). [a]D= -1.3 (c=0.5, MeOH).
MS(CI) m/e 483(m~H) . H NMR (CDC13,30~MHz) ~ 0.92(m,6H), 1.23-1.4(m,8H), 1.45-1.7(m,8H), 1.8~m,2:-), 1.98~s,3H), 3.1~m,lH), 3.25(m,2H), 3.32(m,lH), 3.6~.~,2H), 5.15(m,lH), 5.85(bs,lH), 7.5(d,J=8Hz,lH), 7.65(t,J=-.Hz,lH), .
~, .. . . . . . . . .
-, ., ~ . - : -' - ~
.
, .. .. .
WO9l/00725 PCT/US90/03630 z~'?7S5 7.82~t,J=6Hz,lH), 7.94~d,J=8Hz,lH), 8.18~d,J=8Hz,lH), 8.62~d,J=2Hz,lH), 9.36~d,2Hz,lH).
~
N-(5'-Hydroxyindolyl-2'-carbonyl)-R-Valine-di-n-pentylamide The 5-hydroxyindole-2-carboxylic acid ~95 mg), hydrochloride of example 2 (150 mg), NMM (0.12 mL), HOBt (70 mg), and EDCI (105 mg) reacted under similar conditions to those described in example 3. The product was isolated in 74~ yield. MS(CI) m/e 916(m+H) . 1H
NMR~CDCl3,300MHz) ~ 0.9~m,6H), 1.0(apparent q,J=7Hz,6H), 1.32~m,8H), 1.62(m,4H), 2.11(m,lH), 3.15(m,lH), 3.2(m,lH), 3.43~m,lH), 3.62~m,lH), 4.95~m, lH), 5 . 6 ~ s, lH), 6 . 78~m,lH), 6.88~dd,J=2,9Hz,lH), 6.98~d,J=9Hz,lH), 7.02~d,J=2Hz,lH), 7.25~d,J-9Hz,lH), 9.3~s,lH).
Example 68 N-(4'-Chlorobenzenesulfonyl)-~-Valine-di-n-pentylamide The hydrochloride of example 2 (60 mg, 0.22 mmol), NMM (25 ~L), was dissolved in 10 mL of CH2C12 and 4-chlorophenylsulfonyl chloride (46 mg) was added to this reaction mixture and stirred overnight (warming to ambient temperature). The solvent was evaporated in vacuo and ethylacetate and water both in large ~xcess were added to the residue. The organic extrac~s were successively washed with saturated aqueous NaHCO3, 0.1 HC1 solution and brine. The combined extracts were dried over MgSO9, .. ~ :.' ' ' ':, Zl?~75~
filtered and concentrated. The product was purified by chromatography using ethylacetate and hexane as elutants.
The pure product was isolated in 75% yield (59 mg). mp=
89-90 C. [~]D= -61.8 (c=0.5, MeOH). MS(CI) m/e 431(m+H) . H NMR(CDC13,300MHz): ~ 0.9(m,12H), 1.15(m,8H), 1.3~m,4H), 1.85(m,lH), 2.9(m,2H), 3.02(m,lH), 3.22(m,lH), 3.8(m,lH), 5.75(d,J=9Hz,lH), 7.43(m,2H), 7.75(m,2H). C,H,N analysis calculated for C21H35ClN2O3S:
C 58.52, H 8.18, N 6.50; found: C 58.56, H 8.22, N 6.48.
Exam~le 69 4-Chlorocinnamic acid N-hydroxysuccinimide ester To a solution of 4-chlorocinnamic acid (0.8g, 4.38 mmol) in CH2C12 was added N-hydroxysuccinimide (0.55 g, 4.8 mmol) and EDCI and the reaction mixture was stirred at ambient temperature overnight. The solvents were removed in vacuo and the residue dissolved in ethylacetate and water. Combined EtOAc extracts were dried over MgSO4 and the solution concentrated in vacuo. The residue was crystallized from a mixture of ethylace-ate and hexane.
The product was isolated in 72% yield (0.88g). mp= 192-193 C. MS(CI) m/e 297(m+NH4 ). H NMR(DMSOd6,300MHz) 2.87(s,4H), 7.05(d,J=17Hz,lH), 7.56(d,J=9Hz,2H), 7.92(d,J=9Hz,2H), 7.99(d,J=17Hz,lH).
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. .
.~
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Exam~le 70 -(3'-Oui~lylcarbonyJIL-N-rE-3'-(4''-chlorophenyl)prop-2'-enoyll-R-Lysine-di-n-pentylamide To a solution of example 54 (60 mg, 0.14 mmol) in dimethylformamide (8 mL) cooled to 0C were added NMM (35 ~L) and the active ester of example 69 (40 mg,0.14 mmol).
The mixture was stirred overnight with warming to ambient temperature. The DMF was removed in vacuo and the residue was chromatographed on silica using ethylacetate-hexane as the elutant mixture. The oily product was isolated in 40%
yield (35 mg). MS(CI) m/e 605(m+H) . H NMR(CDCl3,300MHz) ~ 0.92(m,~H), 1.3(m,8H), 1.62(m,8H), 1.83(m,2H), 3.14~m,lH), 3.35(m,4H), 3.58(m,lH), 5.15(m,lH), 6.18~m,lH), 6.35(d,J-17Hz,lH), 7.25~m,6H), 7.48(d,~=17Hz,lH), 7.62(t,J=8Hz,lH), 7.83(t,J=8Hz,lH), 8.15(d,J=9Hz,lH), 8.62(d,J=2Hz,lH), 9.37(d,J=2Hz,lH).
Example 71 N-(t-Butyloxycarbonyl)-R-Tyrosine-di-n-pentylami~
N-t-Butyloxycarbonyl-R-Tyrosine (4.5 g, 15.4 mmol) was stirred with BOPCl (3.92 g, 15.4 mmol) and dipentylamine (7.9 mL, 39 mmol) in 100 mL of tetrahydrofuran (THF) at 4C and allowed to warm to room temperature overnight. After one day, additional BOPCl (800 mg) was added and, after two days, the volatiles were evaporated. The residue, dissolved in EtOAc, was extracted with 0.1 M citric acid solution, 0.1 M sodium carbonate (Na2CO3) solution, and water; then dried over magnesium sulfate (MgSO4), filtered and concentrated in ,: . . .
:; ~ ' ' . , : ' ,: , ' . . . .
: . . -~.;
vacuo to yield an oil, 5.67 g, 13.4 mmol ~87.4%). Rf=
0.45 (2:1 hexanes-EtOAc). la]D = +2.8 (c=0.76, MeOH).
MS(CI) m/e 421(m+H) . lH NMR(CDC13,300MHz) ~
0.88(apparent q,J=7Hz,6H), 1.15-1.32(m,10H), 1.36-1.47(m,11H), 2.80-3.07(m,5H), 3.38-3.48(m,1H), 4.72(apparent q,J=6Hz,lH), 5.41(d,J=8Hz,lH), 6.70(d,J=8Hz,2H), 7.02(d,J=8Hz,2H).
Example 72 R-Tyrosine-di-n-pentylamide hydrochloride The product of example 71 (2.0 g, 4.75 mmol) was dissolved in 4 N HCl in dioxane (20 mL, 80 mmol) that was precooled to 4C. After 3 hours, the excess reagent was evaporated and the oily residue was placed under high vacuum overnight to yield a glass, 1.5 g, 4.2 mmol (87%).
[a~D = -42.8 (c=1.2, MeOH). MS(CI) m/e 321(m+H) . lH
NMR(DMSOd6,300MHz) 8 0.82-0.89(m,6H), 1.1-1.4(m,12H), 2.70-3.04(m,5H), 3.37-3.50(m,lH), 4.22(dd,J=5,7Hz,lH), 6.70(d,J=8Hz,2H), 6.99~d,J=8Hz,2H), 8.37(bs,3H), 9.48(s,lH).
E~m~L~ 73 N~O-Di-(3'-Ouinolylcarbonyl)-R-Tyrosine-di-n-pentylamide The product of example 72 (357 mg, 1 mmol), quinoline-3-carboxylic acid (173 mg, 1 mmol), HOBt (13 mg, 0.1 mmol), and TEA (279 ~L, 2 mmol) were dissolved in 10 mL methylene chloride and EDCI (191 mg, 1 mmol) was then added in one portion. After 3 days, the volatiles were evaporated and the residue, in EtOAc, was e:~tracted as in example 71. The residue was then purifie~ by . ~, . . . .
:'~ : ; ', ' '' ',, : ' , , " : ~
: . -/
chromatography on silica gel eluted with 1% ethanol in chloroform to provide first the mono-acylated material (19 mg, see example 80) followed by an oily product, (108 mg, 0.17 mmol, 17% yield). Rf= 0.36 (18:1 chloroform-ethanol). []D = +5.8 (c=0.5, CHC13). [a]D = +53.2 (c=0.73, MeOH). MS(CI) m/e 631(m+H) , 518, 458, 446, 368.
lH NMR(CDCl3,300MHz) ~ 0.88-0.94(m,6H), 1.22-1.91(m,10H), 1.50-1.59(m,2H), 2.96-3.30(m,5H), 3.52-3.62(m,lH), 5.33-5.92(m,lH), 7.22(d,J=8Hz,lH), 7.30(d,J=8Hz,lH), 7.37(d,J=8Hz,2H), 7.63(dt,J=1,7Hz,lH), 7.68(dt,J=1,7Hz,lH), 7.79-7.93(m,3H), 8.0(dd,J=1,8Hz,lH), 8.16(d,J=3Hz,lH), 8.22(d,J=8Hz,lH), 8.56~d,J=2Hz,lH), 9.02(d,J=2Hz,lH), 9.32(d,J=2Hz,lH), 9.54(d,J=2Hz,lH).
C,H,N analysis calculated for C39H42N4O4, H2O: C 72-20, H
6.84, N 8.64; found: C 72.38, H 6.62, N 8.50.
Exam~le 74 N-(2'-In~olyl~carbonyl)-R-Tyrosine-d~-n-pentylamide The product of example 72 (200 mg, 0.56 mmol), indole-2-carboxylic acid (97 mg, 0.6 mmol) and TEA (84 ~L, 0.6 mmol) were dissolved in 5 mL methylene chloride and treated with EDCI (115 mg, 0.6 mmol) at room temperature.
After 3 days, the solvent was evaporated and the residue was extracted as in example 71. Column chromatography on silica gel eluted with 1% ethanol in methylene chloride provided product. Rf= 0.38 (18:1 methylene chloride-ethanol). mp= 124-7 C.l [~]D = +21.4 (c=1.17, MeOH).
MS(CI) m/e 964(m+H) . H NMR(CDCl3,300MHz) ~
0.88(apparent q,J=8Hz,6H), 1.15-1.56(m,12H), 2.46-3.22~m,5H~, 3.48-3.54(m,lH), 5.23-5.32(m,lH), 6.12(s,lH), : :, -.
WO 91tO0725 PCTtUS90/03630 SS
6.70(d,J=8Hz,2H), 6.95(d,J=lHz,lH), 7.05(d,J=8Hz,2H), 7.13(dt,J=1,7Hz,lH), 7.18(d,J=8Hz,lH), 7.27(dt,J=1,7Hz,lH), 7.90(d,J=8Hz,lH), 7.64(d,J=8Hz,lH), 9~22(s,lH). C,H,N analysis calculated for C28H37N3O3: C
72.54, H 8.05, N 9.06; found: C 72.37, H 8.10, N 8.80.
Example 75 N-(3',4'-Dichlorobenzoyl)-R-Tyrosine-di-n-pentylamide The product of example 72 (103 mg, 0.29 mmol) was dissolved in 5 mL methylene chloride and treated with 3,4-dichlorobenzoylchloride (126 mg, 0.6 mmol) and TEA (84 ~L, 0.6 mmol) at room temperature. After 2 hours, additional acid chloride (13 mg) and TEA (8 ~L) were added and the reaction was stirred overnight. The volatiles were evaporated and the residue, in EtOAc, was extracted with 0.1% citric acid, H2O; then dried over MgSO4, filtered and concentrated in vacuo. The resulting diacylated product residue was dissolved in 10 mL of 1:1 THF-methanol and treated with 1 N NaOH (290 mL, 0.29 mmol). After 1 hour, tlc revealed complete reaction and the solvent was evaporated in vacuo. The residue was dissolved in EtOAc and acidified with 0.1 M citric acid. The EtOAc layer was then washed until neutral, dried over MgSO4, filtered and concentrated in vacuo. The residue was warmed with 80%
aqueous ethanol and cooled overnight to provide a solid, 64 mg, 0.13 mmol (45% yield). mp= 148-52 C. [a]D =
+15.6 (c=1.0, MeOH). MS(CI) m/e 493(m+H) . H
NMRtCDCl3,300MHZ) ~ 0.88-0.92~m,6H), 1.2-1.6(m,12H), 2.93-3.22(m,5H), 3.50-3.60(m,lH), 5.21-5.28(m,lH), 6.29(s,lH), 6.68(d,J=8Hz,2H), 7.02(d,J=8Hz,2H), 7.15(d,J=8Hz,lH), - .
- , . .
'' ~ ., - -, .
W091/00725 PCT~US90/03630 2~ 55 7.47(d,J=8Hz,lH), 7.59(dd,J=2,8Hz,lH), 7.91(d,J=2Hz,lH).
C,H,N analysis calculated ~or C26H34Cl2N2O3: C 63.28, H
6. 94, N 5.68; found: C 63.39, H 7.00, N 5.54.
Example 76 N-(2'-Naphthoyl)-R-Tyrosine-di-n-pentylamide The product of example 72 (100 mg, 0.28 mmol) was acylated with 2-naphthoic acid (52 mg, 0.30 mmol) in the presence of TEA (39 ~L, 0.28 mmol) and EDCI ~57 mg, 0.30 mmol) in 5 mL methylene chloride. The reaction and extractive workup were performed as in example 71 to yield 120 mg, 0.25 mmol (89%). mp= 128-133C. [a]D = +11.8 (c=0.68, MeOH). MS(CI) m/e 975(m+H) , 303, 290. H
NMR(CD30D,300MHz) ~ 0.88-0.93(m,6H), 1.19-1.38(m,9H), 1.44-1 62(m,3H), 2.99(dd,J=7,13Hz,lH), 3.08-3.29(m,4H), 3.37-3.47(m,lH), 5.22(dd,J=7,9Hz,lH), 6.72(d,J=8Hz,2H), 7.13(d,J=8Hz,2H), 7.53-7.62(m,2H), 7.84(dd,J=2,9Hz,lH), 7.90-7.99(m,3H), 8.37(s,lH). C,H,N analysis calculated for C30H38N2O3: C 75.91, H 8.07, N 5.90; ound: C 75.57, H 7.97, N 5.83.
Example N-t-Butyloxycarbonyl-(O-benzyl)-R-Tyrosine-di-n-pentylamide N-t-Butyloxycarbonyl-(O-benzyl)-R-Tyrosine (3.71 g, 10 mmol) was stirred with di-n-pentylamine (5.1 mL, 25 mmol), HOBt (1.4 g, 10 mmol) and TEA (1.4 mL, 10 mmol) in 150 mL methylene chloride at 4C and then BOPCl (2.6 g, 10 mmol) was added. The reaction was allowed to reach room temperature overnight. After one day, additional BOPCl ,~
~: : `: . : - -WO91~00725 PCT/US90/03630 _~, 1' ~` .
;~?~ S5 (260 mg) and TEA (140 ~L) were added. After 2 days, the volatiles were evaporated and the residue (in EtOAc) was extracted with 0.1 M H3PO4, 0.1 M Na2CO3, H2O; then dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluted with 2:1 hexanes-EtOAc to yield an oil, 1.3 g, 2.55 mmol (25%).
[a]D = +5.8 (c=1.5, MeOH). MS(CI) m/e 511(m+H) , 456, 393. H NMR~CDC13,300MHz) ~ 0.84-0.93(m,6H), 1.1-1.35(m,12H), 1.41(s,9H), 2.81-3.04(m,5H), 3.36-3.46(m,1H), 4.15-4.23(m,1H), 5.03(s,2H), 5.32(d,J=8Hz,lH), 6.87(d,J=8Hz,2H), 7.11(d,J=8Hz,2H), 7.32-7.43(m,5H).
~xam~ 78 (O-Benzyl)-R-Tyr~sine-di-n-pentylamide hydrochloride The product of example 77 (1.3 g, 2.55 mmol) was treated with 5 mL of 4 N HCl in dioxane, precooled to 4C.
The reaction mixture was then allowed to reach room temperature. After 1 hour tlc revealed complete reaction and the excess reagent was evaporate. The residue was placed under high vacuum overnight to yield an oil, 1.2 g.
Rf= 0.59 (80:20:1 chloroform-methanol-ammonium hydroxide).
[~]D = -32.5 (c=2.2, MeOH). MS(CI) m/e 411(m+H) . H
NMR(DMSOd6,300MHz) ~ 0.85(apparent q,J=7Hz,6H), 1.07-1.38(m,12H), 2.68-2.97(m,4H), 3.05(dd,J=5,13Hz,lH), 3.32-3.92(m,2H), 4.27(dd,J=5,8Hz,lH), 5.09(s,2H), 6.93(d,J=8Hz,2H), 7.12(d,J=8Hz,2H), 7.32-7.43(m,5H), 8.37~s,3H).
... . .
WO91/00725 PCT/US90/0363~
, 21?~755 E~m~l~ 79-(3'-Ouinolylcarbonyl;-(O-benzyl)-R-Tyrosine-di-n-pentylamide EDCI (290 mg, 1.5 mmol) was added to a cooled (4C) solution of quinoline-3-carboxylic acid (260 mg, 1.5 mmol), the product of example 78 (650 mg, 1.35 mmol), and TEA (418 ~L, 3.0 mmol) in 5 mL methylene chloride. The stirred reaction mixture was allowed to warm to room temperature overnight. After evaporation of the volatiles, the residue was dissolved in EtOAc and extracted with 0.1 M H3PO9 (3x), 0.1 M Na2CO3 (3x), brine (3x); then dried over MgSO4, filtered and concentrated in vacuo to yield an oil, 650 mg, 1 15 mmol ~85%). Rf- 0.77 ~18:1 chloroform-ethanol), 0.40 ~1:1 hexanes-EtOAc). [~]D
~0.21 ~c=0.47, CHC13). MS~FAB) m/e 566(m+H) , 393, 381. H NMR(CDC13,300MHz) ~ 0.91(apparent q,J=7Hz,6H), 1.17-1.38(m,10H), 1.43-1.6(m,2H), 2.86-3.17(m,SH), 3.49-3.59(m,lH), 5.03(s,2H), 5.26-5.33~m,lH), 6.90(d,J-8Hz,2H), 7.16~d,J=8Hz,2H), 7.28-7.43(m,6H), 7.62(dt,J=1,7Hz,lH), 7.82(dt,J=1,8Hz,lH), 7.90(d,J=8Hz,lH), 8.18(d,J=8Hz,lH), 8.54(d,J=2Hz,lH), 9.32(d,J=2Hz,lH). C,H,N analysis calculated for C36H43N3O3: C 76.55, H 7.88, N 7.29;
found: C 76.43, H 7.66, N 7.43.
Example 80 N-(3~-ouinolylcarbonyl)-p-T~rosin~-c~-n-~entylamide The product of example 79 (614 mg, .09 mmol) was dissolved in 30 mL methanol and treated ~Jith 10% Pd/C (200 mg, pre-wetted with solvent under nitroa~n) under 1 : : , - ~ 1, ' . . ..
: . ~
: . - , , . :
:, , .' ' ~ :,. ~ ... . .
,. . . ... .. . . .. . . . .. .. . . . .. .
atmosphere hydrogen gas. Another 200 mg of catalyst was added after 4 hours and the reaction mixture was stirred overnight. The mixture was then filtered and the filtrate concentrated in vacuo. Silica gel column chromatography of the residue (eluted with a 2:1 to 1:1 hexane-EtOAc step gradient) provided 270 mg, 0.57 mmol (52% yield). mp=
135-37 C. [~]D = +12.6 (c=0.5, MeOH). MS(CI) m/e 476(m+H) , 347, 321, 291. H NMR(CDC13,300MHz) ~
0.91(t,J-7Hz,6H), 1.29-1.38(m,8H), 1.48-1.62(m,9H), 3.0-3.28(m,5H), 3.51-3.61(m,lH), 5.30-5.38(m,lH), 6.72(d,J=8Hz,2H), 6.78(s,lH), 7.06(d,J=8Hz,2H), 7.38(d,Jz8Hz,lH), 7.60(t,J=7Hz,lH), 7 80(dt,J=1,7Hz,lH), 7.88(d,J=8Hz,lH), 8 15~d,J-9Hz,lH), 8.58(d,J=2Hz,lH), 9.27(d,J=2Hz,lH). C,H,N analysis calculated for C29H37N3O3: C 73.23, H 7.84, N 8.83; found: C 73.23, H
7.89, N 8.76.
Example ~1 N-(3'-Ouinolylcarbonyl)-(O-bisulfat~l)-R-Tyrosine di-n-pentylamide ammonium salt The product of example 80 (59 mg, 0.12 mmol) was dissolved in 2 mL DMF and treated with rreshly prepared pyridine-sulfur trioxide complex (H.C.Reitz et al J. Amer.
Chem. ~QÇ~ 68, 1031-5, 1946) overnight at room temperature. The pyridine was evaporated in vacuo and the DMF solution was poured into water and t:~e pH adjusted to 7 with 1 N NaOH. The homogeneous solution was then frozen and lyophilized. Preparative C-18 chrom~tography of the residue eluted with a gradient from 100~ aqueous buffer (0.05 M ammonium acetate, pH 6.2) to 50~
.
W09t/00725 PCT/US90/03630 I
2~ SS
.', , ~ "5 acetonitrile/aqueous buffer over 10 minutes provided product fractions which were pooled, frozen and lyophilized to yield 48 mg, 0.08 mmol (67%). mp= 113-6C.
[a]D = +12.2 ~c=0.88, MeOH). MS(FAB) m/e 559~m-H) , 368, 302, 298. H NMR(D20,300MHz) ~ 0.68-0.75(m,6H), 0.98-1.43(m,12H), 2.98-3.28(m,6H), 5.22(t,J=7Hz,lH), 7.24~d,J=8Hz,2H), 7.30(d,J=8Hz,2H), 7.44(t,J=8Hz,lH), 7.62(d,J=8Hz,lH), 7.69(t,J=8Hz,lH), 7.82(d,J=8Hz,lH), 8.36(s,1H), 8.78(s,lH). C,H,N analysis calculated for C29H40N4O6S, 0.50 H2O: C 59.88, H 7.10, N 9.63; found:
C 59.77, H 6.82, N 9.11.
~xample ~L
3~5-Di-iodo-N-(3'-quinolylcarbonyl)-R-Tvr-di-n-pentylamide (b) 3-Iodo-N-(3'-quinolylcarbonyl)-R-T~r-di-n-pentylamide Iodine (27 mg, 0.11 mmol) was mixed with morpholine (40 ~L, 0.46 mmol) in 5 mL methanol and added to the product of example 80 (50 mg, 0.11 mmol) in 15 mL methanol at room temperature. The reaction was stirred until tlc indicated complete reaction. After evaporation of the solvent, chromatography of the residue on silica gel eluted with a step gradient of chloroform to 1~ ethanol in chloroform provided first the diiodo product followed by the monoiodo compound. Diiodo product (a): [a~ D = +18 (c=0.11, MeOH). MS~CI) m/e 728(m+H) , 602. H
NMR(CDCl3,300MHz) ~ 0.92(apparent q,J=7Hz,6H), 1.2-1.45(m,12H), 2.92-3.13~m,SH), 3.53-3.67(m,lH), 5.22-.
:: .: -: , .. . . .. . .. ....
.
WO91/00725 PCT/US90~3630 ~ ....
, Z~
5.28(m,1H), 5.72(s,1H), 7.27(d,J=7Hz,lH), 7.56(s,2H), 7.63(dt,J=1,8Hz,lH), 7.83(dt,J=1,8Hz,lH), 7.93(d,J=8Hz,lH), 8.18(d,J=8Hz,lH), 8.55(d,J=2Hz,lH), 9.33(d,J=2Hz,lH). C,H,N analysis calculated for C29H35I2N3O3, 0.4 EtOAc: C 48.19, H 5.05, N 5.51; found:
C 48.43, H 5.03, N 5.79. Monoiodo product (b): mp= 75-85 C. MS(CI) m/e 602(m~H) . H NMR(CDCl3,500MHz) 0.84(apparent q,J=7Hz,6H), 1.13-1.35(m,9H), 1.37-l.S3(m,3H), 2.90-2.98(m,3H), 3.02-3.08(m,2H), 3.48-3.5S(m,lH), 5.18-S.23(m,lH), 6.83(d,J=8Hz,lH), 7.05(dd,J=1,8Hz,lH), 7.22(d,J=8Hz,lH), 7.46(d,J=2Hz,lH), 7.57(dt,J=1,8Hz,lH), 7.76(dt,J=1,8Hz,lH), 7 84(d,J=8Hz,lH), 8.10~d,J=8Hz,lH), 8.98~d,J=2Hz,lH), 9.24~d,J~2Hz,lH). C,H,N analysis calculated for C29H36IN3O3, 1.5 H20: C 55.42, H 6.25, N 6.69; found: C
55.19, H 5.95, N ~.17.
Example 83 N-(3'-Ouinolylcarbonyl)-(O-methyll-R-T~roslne-di-n-pentylamide The product of example 80 (25 mg, 0.053 mmol) was dissolved in 1 mL acetone and K2CO3 ~8 mg, 0.058 mmol) and methyl iodide (5 ~L, 0.08 mmol) were added. After 3 hours at reflux, additional methyl iodide (5 mL) and acetone (2 mL) were added. After 2 days, the volatiles were evaporated and the residue, in EtOAc, was extracted with 0.1% aqueous citric acid, water; then dried over MgSO4, filtered and concentrated in vacuo. MS~CI) m/e 490~m+H) , 476, 361, 347, 317. H NMR~CDC13,300MHz) ~ 0.86-0.93(m,6H), 1.2-1.56~m,12H), 2.42-3.15(m,5H), 3.49-, .. .. .
, - : . ~: . . .
.. - . . - :
WO91/00725 PCT/USgO/03~30 ;~'5~7S5 .. V
3.59(m,1H), 3.78(s,3H), 5.27-5.39(m,1H), 6.77(d,J=8Hz,lH), 6.82(d,J=8Hz,lH), 7.08(d,J=8Hz,lH), 7.16(d,J=8Hz,lH), 7.41-7.46(m,1H), 7.56-7.63(m,1H), 7.76-7.82(m,1H), 7.83-7.88(m,lH), 8.14(d,J=8Hz,lH), 8.53(d,J=2Y.z,lH), 9.29(t,J=2Hz,lH).
Example 8Methyl N-t-Butyloxycarbonyl-(O-benzyl)-R-Tyrosyl-S-phenylglycinate N-t-Butyloxycarbonyl-(O-benzyl)-R-Tyrosine (1.0 g, 2.7 mmol), methyl S-phenylglycinate hydrochloride (540 mg, 2.7 mmol), HOBt (362 mg, 2.7 mmol) and TEA (374 ~L, 2.7 mmol) were dissolved in 20 mL THF and treated with BOPCl (682 mg, 2.7 mmol). The reaction was followed by tlc (18:1 chloroform-ethanol) and additional BOPCl ~200 mg) and TEA (374 ~L) were added after 1,2 and 4 days.
Methylene chloride (20 mL) also was added after 2 days.
After 1 week, the volatiles were evaporated in vacuo and the residue, in EtOAc, was extracted as in example 71.
Chromatography of the residue on silica gel eluted with a step gradient from 9:1 to 2:1 hexanes-EtOAc yielded 485 mg, 1.13 mmol (42%). mp= 138-39C. [a]D = +48.7 (c=1.0, MeOH). MS(CI) m/e 519(m+H) , 463, 419. lH
NMR~CDC13,300MHz) ~ 1.41(s,9H), 2.92-3.04~m,2H), 3.71(s,3H), 4.35~bs,lH), 5.01(s,3H), 5.43-5.46(m,lH), 6.78(d,J=7Hz,lH), 6.82(d,J=8Hz,2H), 7.02(d,J=8Hz,2H), 7.19-7.23(m,lH), 7.30-7.45(m,10H).
:
- .: - ~ .. .~.. ..
.~
W091~00725 PCT/US9OJ03630 ~, ;~(?~i~755 ExamDle ~ethyl (O-Benzyl)-R-Tyrosyl-S-phenylglycinate hydrochloride The product of example 84 (450 mg, 1.05 mmol) was dissolved in 4 N HCl in dioxane (5 mL, 20 mmol) precooled to 4C. After 1 hour, the excess reagent was evaporated in vacuo and the product used directly in the next step.
mp= 153-6C. [a]D = +43-7 (c=0.76, MeOH). MS(FAB) m/e 419~m+H) , 403, 226. H NMR(DMSOd6,300MHZ) ~ 2-86-3.00(m,2H), 3.67(s,3H), 4.13(bt,J=5Hz,lH), 5.03(s,2H), 5.45(d,J=7Hz,lH), 6.88(d,J=8Hz,2H), 7.05(d,J=8Hz,2H), 7.22-7.25(m,2H), 7.33-7.46(m,8H), 8.28~s,3H), 9.35(d,J=7Hz,lH).
Example 86 Methyl N-t3'-Ouinolvl~arbonyl~-(O-benzyl)R-Tyrosyl-S-phenylalycinate Quinoline-3-carboxylic acid (182 mg, 1.05 mmol), TEA
(146 ~L, 1.05 mmol) and the product of example 85 (1.05 mmol) were dissolved in 20 mL methylene chloride and EDCI
(201 mg, 1.05 mmol) was added at ambient temperature.
After 4 days, the volatiles were evaporated and the residue was extracted as in example 71. The solvents were evaporated in vacuo to provide 407 mg, 0.71 mmol (68%
yield). mp= 153-8 C. [a]D = +73.0 (c=1.2, CHC13-MeOH/l:l). MS(FAB) m/e 574(m+H) , 419, 381. H
NMR(CDC13,300MHz) ~ 3.06(dd,J=8,14Hz,lH), 3.20(dd,J-5,14Hz,lH), 3.70(s,3H), 4.94-5.02(m,3H), 5.53(d,J=7Hz,lH), 6.78(d,J=8Hz,2H), 6.83(d,J=7Hz,lH), -' -: :
: .. .': '. : : ~ :
W O 91/00725 PC~rtUS90/03630.`
2(?5i~55 ~;
7.01(d,J=8Hz,2~), 7.14~d,J=7Hz,lH), 7.20-7.23(m,2H), 7.33-7.36~m,4H), 7.39-7.49(m,4H), 7.62(dt,J=1,7Hz,lH), 7.82(dt,J=1,7Hz,lH), 7.88(d,J=8Hz,lH), 8.15(d,J=8Hz,lH), 8.54(d,J=2Hz,lH), 9.28(d,J=2Hz,lH). C,H,N analysis calculated for C35H3lN3Os~ 0-5 H2O C 72.15~ H 5-54~ N
7.21; found: C 72.05, H 5.63, N 6.88.
Exa~L~ 87 Methyl N-(3'-OuinolylcarbQnyl)-R-Tyrosyl-S-phenylglycinate The product of example 86 (200 mg, 0.35 mmol) was dissolved in 10 mL methylene chloride and treated with trimethylsilyliodide (TMSI, 198 ~L, 1.39 mmol) at room temperature. Additional TMSI (198 ~L) was added after 1 day After 3 days, the reaction was quenched with methanol for 5 minutes and then poured into 0.1 M citric acid and extracted with ethylacetate (3x). The combined ethylacetate solution was washed with water; then dried over MgSO4, filtered and concentrated in vacuo. The crude solid was purified by chromatography on silica gel eluted with a s~ep gradient of 1 to 5% ethanol in methylene chloride and then crystallized from EtOAc and hexane to yield 51 mg (30%). mp= 238-40 C. [a~D = +72.6 (c=0.23, MeOH). MS(CI) m/e 484(m+H) , 319. H NMR(CDCl3-CD3OD,300MXz) ~ 3.0-3.16~m,2H), 3.72(s,3H), 4.92-5.01(m,lH), 5.50(d,J=7Hz,lH), 6.67(d,J=8Hz,2H), 6.99(d,J=8Hz,2H), 7.21-7.24(m,2H), 7.35-7.38(m,3H), 7.40(s,1H), 7.68(dt,J=1,7Hz,lH), 7.86(dt,J=1,7Hz,lH), 7.98(d,J=8Hz,lH), 8.12(d,J=8Hz,lH), 8.14(d,J=6Hz,lH), 8.22~d,J=8Hz,lH), 8.68(d,J=2Hz,lH), 9.21(d,J=2Hz,lH).
:. : ..
, , , , -.: . . . . .
.- , . - . . ~ ., .
: . . .: : .. . , ~ ~ , ~ : . , . . ~ , ~ , . , . -W091/0072~ PCT/US90/03630 2~ ' . 55 C,H,N analysis calculated for C28H25N3O5: C 69.55, H 5.21, N 8.69; found: C 69.20, H 5.29, N 8.60.
.Example 88 N'-Benzyloxycarbonyl-(2 R)-aminobutyrolactone N-Benzyloxycarbonyl-R-methionine (283 mg, 1.0 mmol) and a-iodo acetamide (555 mg, 3.0 mmol) were dissolved in 6 mL of 50% aqueous ethanol and warmed to 4C for 4 days.
Citric acid was added (3 mL of a 0.1 M solution) and the mixture was refluxed for 4 hours. After evaporation of the volatiles, the residue was poured into water and extracted with ethyl acetate (3x). The combined ethylacetate solution was extracted with 0.5 N HCl, water;
then dried and concentrated in vacuo. The resulting residue was chromatographed on silica gel eluted with 1:1 hexanes-ethylacetate to yield 106 mg, 0.52 mmol (52%).
(cf: Ozinskas, A.J., Rosenthal, G.A., ~. Oraanic Chem. 51, 5047, 1986). mp= 124-5 C. [a]D z +31.3 (c=1.2, MeOH).
H NMR(CDC13,300MHz) ~ 2.16-2.28(m,lH), 2.76~2.86(m,lH), 4.2-9.31(m,1H), 4.37-4.50(m,2H), 5.13(s,2H), 5.32(bs,1H), 7.32-7.38(m,5H).
.
Example 89 N-Benzyloxycarbonyl-Homoserine-di-n-pentylamide The product of example 88 (620 mg, 2.8 mmol) and dipentylamine (1.4 mL, 7 mmol) were dissolved in 60 mL
acetonitrile and then heated to reflux overnight. After evaporation of the volatiles, the residue was chromato~raphed on silica gel eluted with a step gradient from chloroform to 1% ethanol in chloroform to yield an , . . . - .
:
. . . . ... . . .
: :
, .
oil, 580 mg, 1.6 mmol (56~). [a]D = +0.31 (c=0-96, MeOH). MS(CI) m/e 393(m+H) , 253, 236, 192. lH
NMR(CDC13,300MHz) ~ 0.87-0.93(m,6H), 1.22-1.38(m,8H), 1.47-1.63(m,4H), 1.86-1.97(m,lH), 3.01-3.20(m,2H), 3.34-3.43(m,2H), 3.52-3.72(m,4H), 4.76(dt,J=3,11Hz,lH), 5.1(d,J=12Hz,lH), 5.13(d,J=12Hz,lH), 5.93(d,J=8Hz,lH), 7.31-7.38(m,5H).
Example 90 N'-(2'-Indolylcarbonyl)-(2,RS)-aminobutyrolactone EDCI (191 mg, 1.0 mmol) was added to a solution of indole-2-carboxylic acid (161 mg, 1.0 mmol), a-aminobutyrolactone hydrobromide (182 mg, 1.0 mmol), HOBt ~135 mg, 1.0 mmol), and TEA (279 ~L, 2.0 mmol) irl 15 mL
methylene chloride at room temperature. Additional EDCI
(120 mg) and TEA (56 ~L) were added after 1 day. After 5 days, the volatiles were evaporated and the residue, in EtOAc, was extracted with 1 M H3PO4, 0.1 M Na2CO3, and brine. The solution was dried over MgSO4, filtered and concentrated in vacuo. The product was crystallized from EtOAc to yield 147 mg, 0.6 mmol, 60%. Rf= 0.17 (1:1 hexanes-EtOAc). mp= 235-6C. MS(CI) m/e 245(m+H) , 144.
H NMR(CDC13-CD3OD,300MHZ) ~ 1.86-2.51(m,lH), 2-19-2.79(m,lH), 4.32-4.42(m,lH), 4.56(dt,J=2,11Hz,lH), 4.82(dd,J=8,11Hz,lH), 7.1-7.15(m,2H), 7.28(dt,J=1,8Hz,lH), 7.40(s,0.5 H), 7.46(d,J=8Hz,lH), 7.66(d,J=8Hz,lH).
.
. . :- . . . ~ :
- . . ; ., . : , ' ~ ' , ., :: .
:.
--.
WO91/0072~ PCT/US90103630 . .
Z ~
E~ample ~1 ~-~2'-Indolylcarbonyl)-R,S-Homoserine-di-n-pentylamide The product of example 90 (25 mg, 0.1 mmol) and dipentylamine ~50 ~L, 0.25 mmol) were dissolved in 2 mL
THF and warmed to 50C. Additional dipentylamine (250 ~L) was added after several hours. After 4 days, the volatiles were evaporated and the residue was chromatographed on silica eluted with 2:1 hexanes-EtOAc.
Yield: 26 mg, 0.06 mmol, 60%. mp= 128-139 C. MS(CI) m/e 402(m+H) , 158. H NMR(CDCl3,300MHz) ~ 0.92(t,J=7Hz,6H), 1.26-1.42(m,10H), 1.52-1.72(m,3H), 1.98-2.11(m,lH), 2.69~t,J=8Hz,lH), 3.06-3.26(m,2H), 3.42-3.52(m,lH), 3.60-3.77(m,3H), 5.12-5.20(m,lH)~ 7.03~d,J=lHz,lH), 7.16(dt,J-1,8Hz,lH), 7.31~dt,J=1,7Hz,lH), 7.42(dd,J=1,8Hz,lH), 7.48~d,J=8Hz,lH), 7.67(d,J=8Hz,lH), 9.13(s,1H). C,H,N analysis calculated for C23H35N3O3, 0.5 H2O: C 67.28, H 8.84, N 10.24; found: C 67.42, H 8.64, N
10 . 10 .
E~mple 92 N'-(3'-Ouinolylcarbonyl)-(2,RS)-aminobutyrolactone Quinoline-3-carboxylic acid (5.2 g, 30 mmol) was coupled to a-aminobutyrolactone (5.5 g, 30 mmol) in a manner similar to that in example 90 to provide 2.62 g, 10.2 mmol (34~ yield). Additional extraction of the aqueous layer with EtOAc yielded another 820 mg, 3.2 mmol (10.7~). R~= 0.26 (18:1 chloroform-ethanol). mp= 160-63 C. MS(CI) m/e 257(m+H) . H ~MR(CDC13,300MHz) ~ 2.32-2.46(m,lH~, 2.91-3.01(m,lH), 4.35-4.43(m,lH), ,, :: :: : . : ~. :
.. . . .
.
, :. . ': ~ ~, ' WO91/0072S PCT/US90~03630 , ?5-'755 4.56~dt,J=2,10Hz,lH), 4.83-4.92(m,lH), 7.36(d,J=6Hz,lH), 7.60(dt,J=1,8Hz,lH), 7.81(dt,J=2,8Hz,lH), 7.86(d,Js8Hz,lH), 8.12(dd,J=1,8Hz,lH), 8.59(dd,J=1,2Hz,lH), 9.28(d,J=2Hz,lH). C,H,N analysis found: C 65.42, H 4.82, N 10.82.
Example N-(3'-Ouinolylcarbonyl)-R.S-Homoserlne-di-n-pentylamid~
The product of example 92 (500 mg, 2.0 mmol) was treated with dipentylamine (1.5 mL, 7.4 mmol) in 25 mL of toluene and refluxed. After 2 days, an additional 1 mL of dipentylamine was added and the heating was continued.
After 1 week, the volatiles wer~ evaporated in vacuo and the excess amine was removed by Kugelrohr distillation.
The residue was then chromatographed on silica gel eluted with a step gradient of chloroform to 4% ethanol in chloroform to yield an oil, 611 mg, 1.48 mmol (79%).
MS(CI) m/e 419(m+H) . 1H NMR(CDCl3,300MHz) ~ 0.88-0.95(m,6H), 1.25-1.42(m,7H), 1.52-1.75(m,5H), 2.04-2.15(m,lH), 3.06-3.28(m,2H), 3.46-3.57(m,2H), 3.62-3.81(m,3H), 4.01(dd,J=5,9Hz,lH), 5.21-5.28(m,lH), 7.63(dt,J=1,8Hz,lH), 7.72(d,J=7Hz,lH), 7.83(dt,J=1,8Hz,lH), 7.93(dd,J=1,7Hz,lH), 8.18(d,J=8Hz,lH), 8.62(d,J=2Hz,lH), 9.37(d,J=3Hz,lH).
C,H,N analysis calculated for C24H35N3O3, 0.25 H2O: C
68.95, H 8.56, N 10.05; found: C 69.26, H 8.45, N 10.06.
:~ . , , . ...... ,.,:,,.. : : .: : ,. -;, . ,. . , , :
WO91/0072~ PCT/US90/~3630 . ~ ~
2~C > ~ 55 --so--Example 94 N-(3'-Ouinolvlcarbonyl)-R,S-Ho~oserine-n-pentylamide The product of example 92 ~200 mg, 0.8 mmol) and n-pentylamine (232 ~L, 2.0 mmol) were dissolved in 20 mL of 1:1 THF-acetonitrile and stirred at room temperature until starting material was consumed (tlc: Rf= 0.15, 18:1 chloroform-ethanol). The volatiles were evaporated in vacuo. The residue was mixed with hexanes and the product filtered away to yield 273 mg, 0.79 mmol (99%). mp= 181-3 C. MS(CI) m/e 344(m+H) . H NMR~CDC13,300MHz) ~
0.91(t,J-7Hz,3H), 1.30-1.38(m,4H), 1.51-1.58(m,2H), 1.95-2.04(m,1H), 2.12-2.21(m,1H), 3.25-3.36(m,2H), 3.80(bs,2H), 4.26(bs,lH), ~.83-4.90(m,lH), 7.37(bt,J=3Hz,lH), 7.69(dt,J-1,5Hz,lH), 7.83(dt,J=1,6Hz,lH), 7.93(d,J=6Hz,lH), 8.10(d,J-6Hz,lH), 8.15(d,J-7Hz,lH), 8.68(d,J-2Hz,lH), 9.37(d,J-lHz,lH)~ C,H,N analysis calculated for ClgH25N3O3, 0.25 CHC13: C 61.13, H 6.82, N
11.26; found: C 60.82, H 6.88, N 11.16.
Example 95 N-t-Butyloxycarbonyl-R-Methionine-di-n-~entylamide BOPCl (5.1 g, 20 mmol) was added to a cooled solution (4 C) of N-t-Butyloxycarbonyl-R-Methionine (5.0 g, 20 mmol), dipentylamine (8.0 mL, 40 mmol), in 60 mL of dry THF and the stirred reaction was allowed to attain room temperature overnight. The volatiles were evaporated in vacuo. The residue was dissolved in EtOAc and extracted successively with 1 M H3PO9 (3x), 1 M Na2CO3 (3x), brine (3~.); then dried over MgSO4, filtered and concentrated in ~. . , : : .
~ , .
, xr~7ss vacuo to yield an oil: 4.6 g, 11.7 mmol ~59%). Rf= 0.81 (1:1 hexanes-EtOAc). [a]D = +27.5 (c=2.7, MeOH). MS(CI) m/e 389(m+H) , 333, 311, 258, 219, 202, 158. H
NMR(CDC13,300MHz) ~ O.86-0.93~m,6H), 1.21-1.37~m,9H), 1.42~s,9H), 1.43-1.66~m,3H), 1.76-1.96~m,2H), 2.11(s,3H), 2.54(t,J=7Hz,2H), 3.06-3.15~m,lH), 3.19-3.29~m,lH), 3.32-3.42~m,lH), 3.46-3.56~m,lH), 4.68-4.75~m,lH), 5.37~d,J=9Hz,lH).
E~mple 96 N-(3'-Ouinolylcarbonyl)-tO-methyl)-R,S-Homoserine-di-n-pentylamide The product of example 93 was methylated in a similar manner to that in example 34 to provide the title compound after purification by chromatography.
Example 97 N-(3'-Ouinolylcarbonyl!-(O-benzyl)-R,S-Homoserine-di-n-~entylamide The product of example 93 was benzylated in a manner similar to that in example 34 utilizing benzyl bromide as the alkylating agent. The title compound was provided after purification by chromatography.
Example 98 R-M~thionine-di-n-~entylamide trifluoroacetate sal~
The product of example 95 ~4 g, 10.3 mmol) was dissolved in 30 mL trifluoroacetic acid precooled to 4C.
After 2 hours, the excess reagent was evaporated and the residue was placed under high vacuum overnight. [a]D =
. . - : , . -. ,, :
.: . . . . :
' " - ~' ' W09l/00725 P~T/US90/036~0 +5.1 (c-1.4, MeOH). MS(CI) m/e 289(m+H) . H
NMR~DMSOd6,300MHz) ~ O.88(apparent q,J=8Hz,6H), 1.18-1.35(m,8H), 1.42-1.58(m,4H), 1.89-1.96(bm,2H), 2.08(s,3H), 2.43-2.67(m,2H), 3.00-3.09(m,lH), 3.13-3.23(m,lH), 3.28-3.38(m,1H), 3.q8-3.57(m,1H), 4.2-4.28(m,1H), 8.17~s,3H).
Exam~le 99 N-(3'-Ouinolylcarbonyl)-R-Methionine-di-n-pentylamide Quinoline-3-carboxylic acid (0.43 g, 2.5 mmol), the product of example 98 (1.0 g, 2.5 mmol), and TEA (697 ~L, 5 mmol) were dissolved in 15 mL of methylene chloride cooled to 4 C and EDCI (0.48 mg, 2.5 mmol) was added. The stirred reaction mixture was allowed to attain room temperature overnight. The volatiles were evaporated and the resi~ue in EtOAc was extracted with 0.1 M citric acid, 0.1 M Na2CO3, water; then dried over MgSO4, filtered and concentrated in vacuo. Silica gel chromatography of the residue eluted with a step gradient of chloroform to 0.5%
ethanol in chloroform yielded an oil, 572 mg, 1.29 mmol (52%). Rf= 0.19 (1:1 hexanes-ethylacetate). [a]D = +8.0 (c=0.85, MeOH). MS(CI) m/e 444(m+H) . H
NMR(CDCl3,300MHz) ~ 0.91(t,J=7Hz,3H), 0.93(t,J=7Hz,3H), 1.23-1.42(m,8H), 1.52-1.62~m,2H), 1.63-1.75(m,2H), 2.02-2.17~m,5H), 2.56-2.72(m,2H), 3.10(t,J=8Hz,0.5H), 3.14(t,J=8Hz,0.5H), 3.25-3.35(m,lH), 3.46-3.55(m,lH), 3.59(t,J=8Hz,0.SH), 3.63(t,J=8Hz,0.SH), 5.28-5.36(m,lH), 7.55(d,J=8Hz,lH), 7.12(dt,J=1,7Hz,lH), 7.81(dt,J=1,8Hz,lH), 7.88(dd,J=1,8Hz,lH), 8.15(d,J=8Hz,lH), 8.54(d,J=2Hz,lH), 9.33(d,J=2Hz,lH).
: ~ .
.
WO91t00725 PCT/US90/03630 f~
2~?755 C, H:, N analysis calculated for C25H37N3O2S, 0.5 H20: C
66.33, H 8.46, N 9.28; found: C 66.33, H 8.19, N 9.25.
Example 100 ouinolylc~~ ylL~-~e~ ioninesulfoxide-di-n pentylamide The product of example 99 (100 mg, 0.23 mmol) was dissolved in 5 mL THF and m-chloroperbenzoic acid (47 mg, 0.23 mmol) was added at room temperature. The reaction was stirred overnight. The volatiles were evaporated and the residue, in EtOAc, was extracted with water until the aqueous extract was neutral (pH=7); then the solution was dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel eluted with methylene chloride and ethanol to provide the product as an oil- t~]D = 8i8 (c=0.73, MeOH). MS(CI) m/e 460(mlH) , 396. H NMR(CDC13,300MHz) ~ 0.92(apparent q,J=7Hz,6H), 1.26-1.40(m,10H), 1.52-1.73(m,3H), 2.14-2.26(m,lH), 2.39-2.52(m,lH), 2.71-3.02(m,3H), 3.08-3 18(m,lH), 3.23-3.35(m,lH), 3.38-3.52(m,lH), 3.58-3.68(m,1H), 5.20-5.34(m,1H), 7.62(tt,J=1,8Hz,2H), 7.72(d,J=7Hz,lH), 7.83(tt,J=1,8Hz,lH), 7.92(d,J=8Hz,lH), 8.17(d,J=8Hz,lH), 8.62~dd,J=2,5Hz,lH), 9.35(dd,J=2,3Hz,lH). C,H,N analysis calculated for C25H37N3O3S, 0.1 EtOAc: C 65.13, H 8.13, N 8.97; found: C
65.31, H 8.30, N 8.73.
.......... . .
"::; ' :. . : . , :
-: -~, . .- ~:
.: .: , ............. , - .: :. . .:
. - ~ .
. . :: , . , , . :, .: : , - . - . . -.
,, . . .
~?~;~5 E~ample lQl N-t-Butyloxycarbonyl-R-Proline-di-n-pentylamide BOPCl (1.18 g, 9.69 mmol) was added to a cooled solution (4C) of N-t-Butyloxycarbonyl-R-Proline (1.0 g, 9.64 mmol), dipentylamine (2.5 mL, 12.5 mmol), in 50 mL of dry THF. The cooling bath was removed and the stirred reaction mixture was allowed to warm to ambient temperature gradually. After 5 hours, the volatiles were evaporated in vacuo. The residue was dissolved in EtOAc and extracted successively with 1 M H3PO4 (3x), 1 M Na2CO3 (3x), brine (3x); then dried over MgSOg, filtered and concentrated in vacuo to yield an oil, 880 mg, 2.48 mmol (54%). Rf= 0.28 (2:1 hexanes-EtOAc). [a]D = +28i7 (c=1.0, MeOH) MS(CI) m/e 355(m+H) , 299, 255. H
NMR(CDC13,300MHz) ~ 0.84-0 94(m,6H), 1 23-1.38(m,8H), 1.41(s,6H), 1.45(s,3H), 1.49-1.58(m,6H), 1.80-1.90(m,lH), 2.0-2.23(m,lH), 3.12-3.33(m,4H), 3.4-3.52(m,lH), 3.56-3.67(m,lH), 4.44(dd,J=4,8Hz,0.6H), 4.58(dd,J=2,8Hz,0.4H).
Example 102 R-Proline-di-n-pentylamide hydrochloride The product of example 101 (800 mg, 2.3 mmol) was mixed with HCl-Dioxane (12.5 mL, 50 mmol, pre-cooled to 4C) under an N2 atmosphere at ambient temperature. After 1 hour, the volatiles were evaporated in vacuo and the residue was mixed with toluene and concentrated (twice) then placed under high vacuum overnight. The residue was utilized directly.
` `' ,:~` . : .
.
...
: - , , . ,, ~ :
WO9l/00725 PCT~US90/03630 2~ 55 ~; ,,~
~a~le 103 N-(2'-IndQlvlcarbonvl)-R-Proline-di-n-~entylamide EDCI (440 mg, 2.3 mmol) was added to a cooled (9C) solution of indole-2-carboxylic acid (371 mg, 2.3 mmol), the product of example 102 (2.3 mmol assumed), HOBt (311 mg, 2.3 mmol), and TEA (321 ~L, 2.3 mmol) in 10 mL
methylene chloride. The stirred reaction was allowed to attain ambient temperature overnight. The volatiles were evaporated and the residue was dissolved in EtOAc and extracted with 1 M H3PO4 (3x), 1 M Na2CO3 (3x), brine (3x); then dried over MgSO4, filtered and concentrated to an orange oil. The crude product was purified by chromatography on silica eluted with 2:1 hexanes-EtOAc to yield 0.92 g, 2.4 mmol (92%) as a slightly yellow glass Rf- 0.22 (2:1 hexanes-EtOAc). The glass was dissolved in hot hexanes-EtOAc, then cooled slowly to -20C. An oil separated out and o~er 24 hours solidified. The solution was decanted and the solid was collected using hexanes to yield 769 mg (84%). mp= 63-7C. [a]D= -20.4 (c=1.0, MeOH). MS(CI) m/e 398(m+H) , 241, 213. 1H
NMR(CDCl3,300MHz) ~ O.88(t,J=7Hz,3H), 0.93(t,J=6Hz,3H), 1.24-1.43(m,8H), 1.51-1.75(m,3H), 1.80-1.90(m,lH), 1.94-2.28~m,3H), 2.32-2.45(m,lH), 3.16-3.37(m,2H), 3~43-3.54(m,2H), 4.0-4.08(m,lH), 4,12-4.2(m,lH), 5.02~dd,J=4,8Hz,lH), 6.96(bs,1H), 7.12(dt,J=1,8Hz,lH), 7.28(dt,J=1,7Hz,lH), 7.48~dd,J=1,8Hz,lH), 7.67(d,J=8Hz,lH), 9.30(s,1H) C,H,N analysis calculated for C24H35N3O2: C 72.50, H 8.87, N 10.57; found: C 72.55, H 8.91, N 10.49.
,. ~ . . .. . . .. . . . . . .
- -.: .. :- :: - .. -.: . : - :: . . . - -:: : : :--:. -: .: ., : .... , .: : . .. :.
WO 91tO0725 PCT/US90/03630 . . . ~
~m~ lQ~
Methyl 2-(3'-Ouinolylcarbonylamino)-2-methylpro~ionate Quinoline-3-carboxylic acid (1.12g, 6.5 mmol~, methyl a-aminoisobutyrate (l.Og, 6.5 mmol) and TEA (1.8 mL, 1.3 mmol) were dissolved in 50 mL methylene chloride and treated with EDCI (1.2g, 6.5 mmol) overnight. The solvent was evaporated and the residue was extracted as in example 71 to give a white solid, 660 mg, 2.58 mmol (40%). mp=
138-140 C. MS(CI) m/e 273(m+H) . H NMR(CDCl3,300MHz) 1.75~s,6H), 3.82(s,3H), 7.06(s,lH), 7.62(d,J=1,7Hz,lH), 7.81(dt,J=1,7Hz,lH), 7.91(dd,J=1,8Hz,lH), 8.15(d,J=8Hz,lH), 8.58(d,J=2Hz,lH), 9.28(d,J=2Hz,lH).
E~ 105 2-(3'-Ouinolvlcarbonvlamino)-2-methvlpropionic acid The product of example 104 (620 mg, 2.42 mmol) was dissolved in 50 mL methanol and treated with 1 N NaOH (2.5 mL, 2.5 mmol). An additional 2.5 mL was added after 1 day. After 2 days, the solvent was evaporated and the residue was dissolved in water and extracted with ethylacetate. The aqueous phase was then acidified and re-extracted with ethylacetate. This second EtOAc layer was dried over MgSO4, filtered and evaporated to yield 406 mg, 1.67 mmol (69%). Rf= 0.3 (80:20:~ CHCl3-CH30H-NH40H).
Example 1062-(3'-Ouinolylcarbo~ylamino)-2-m~thylpropion-di-n-pent~ zmide The product of example 105 (100 mg, 0.413 mmol), dipentylamine (202 ~L, 1.0 mmol) and TEA (59 ~L, 0.42 ' ' . ' ' . ' ' ' ` ' ': ' WO 91~0072~ PCT/US90tO3630 2~ 55 .
- .
mmol) were dissolved in 15 mL methylene chloride, treated with EDCI (80 mg, 0.42 mmol) and stirred at room temperature overnight. The solvent was evaporated and the residue was dissolved in ethylacetate and extracted as in example 71. NMR indicated the presence of undesired dehydrated product (oxazolone). MS(CI) m/e 241(m+H) . lH
NMR(CDCl3,300MHz) ~ 1.61(s,6H), 7.66(dt,J=l,'Hz,lH), 7.86(dt,J=1,7Hz,lH), 7.94(dd,J=1,8Hz,lH), 8.20(d,J=8Hz,lH), 8.74(d,J=2Hz,lH), 8.98(d,J=2Hz,lH). The crude dehydrated product was redissolved in 25 mL THF and treated with dipentylamine (202 ~L, 1.0 mmol). Another 400 mL of dipentylamine was added at 2 and 4 days. After evaporation of the solvent, the residue was purified by chromatography on silica gel eluted with a 4:1 to 1:1 hexane-ethylacetate step gradient to yield 51 mg, 0.13 mmol ~32~). mp= 139-5C. MS(CI) m/e 398(m+H) , 158. lH
NMR(CDC13,300MHz) ~ 0.92~t,J=7Hz,6H), 1.25-1.49(m,12H), 1.90(s,6H), 3.40(bs,4H), 7.61(dt,J=1,7Hz,lH), 7.80(dt,J=1,7Hz,lH), 7.91(dd,J=1,8Hz,lH) 8.15(d,J=8Hz,lH), 8.58(d,J=2Hz,lH), 8.69(s,lH), 9.37(d,J=2Hz,lH). C,H,N
analysis calculated for C24H35N3O2, 0.25 H2O: C 71.69, H
8.90, N 10.45; found: C 71.65, H 8.74, N 10.39.
~xample 107 N-(3'-Ouinolvlcarbonyl)-R-L~rsine-d--n-pentylamide hydrobromide The product of example 62 (1.61 g, 2.64 mmol) was treated with 15 mL of HBr in HOAc (1.1 N, 16.5 mmol) for 2 hours under an inert atmosphere. The solvent was evaporated and the residue was purified by chromatography :: . : .- - - : .
-:
, .: : .
':'.': ' ' ' ' WO9l/00725 PCT~US90/03630 . j, .
2~ 755 on silica gel eluted with a methylene chloride to 1%
ethanol in CH2Cl2 step gradient to yield 1.25 g, 2.39 mmol (91%) as a yellow glass. mp= 85-95 C. H
NMR~DMSOd6,300MHz) ~ 0.85(t,J=7Hz,6H), 1.23-1.83(m,18H), 2.78(t,J=7Hz,2H), 3.06-3.17(m,1H), 3.28-3.44(m,3H), 4.86-4.93(m,lH), 7.57(bs,2H), 7.72(dt,J=1,7Hz,lH), 7.88(dt,J=1,7Hz,lH), 8.10(d,J=8Hz,2H), 8.92(a,J=2Hz,lH), 9.02(d,J=8Hz,lH), 9.32(d,J=2Hz,lH).
ExampLe 108 Na-t3'-Ouinolylcarbonyl)-~-~henylthiolcarbonyl-R-Lysine dipentylamide The product of example 107 (20 mg, 0.045 mmol) was treated with carbonyldiimidazole (8.1 mg, 0.05 mmol) in 10 mL methylene chloride at room temperature overnight.
Thiophenol ~10.3 ~L, 0.10 mmol) and 10 mL THF were added and the mixture was heated to 60C. After 1 day, the reaction was eluted on silica gel with 1% ethanol in methylene chloride to yield an oil. MS(CI) m/e 577(m+H) , 467, 420. H NMR(CDCl3,300MHz) ~ 0.88-0.96(m,6H), 1.23-1.86(m,18H), 3.12(dt,J=7,13Hz,lH), 3.22-3.44(m,4H), 3.59(dt,J=7,13Hz,lH), 5.0-5.17(m,lH), 5.70(t,J=SHz,lH), 7.32-7.37(m,3H), 7.47-7.51(m,3H), 7.62(dt,J=1,8Hz,lH), 7.82(dt,J=1,7Hz,lH), 7.91(dd,J=1,8Hz,lH), 8.16(d,J=8Hz,lH), 8.63(d,J=2Hz,lH), 9.37(s,J=2Hz,lH).
.
, . .
. ~ , ; - :
, i"755 .,, .~, . . .
_99_ ~ample l N-Benzyloxycarbonyl-R-Phenylalycine-(2'-~ropylpiperidinyl)amide N-Benzyloxycarbonyl-R-phenylglycine (1.0 g, 3.5 mmol), 2-propylpiperidine (1 mL, 6.64 mmol), HOBt (475 mg, 3.5 mmol) and TEA (490 ~L, 3.5 mmol) were dissolved in 25 mL of CH2C12 and treated with BOPCl (890 mg, 3.5 mmol).
Additional TEA (490 ~L) and BOPC1(890 mg) were added after 2 days. After 6 days, the solvent was evaporated and the crude reaction was purified by chromatography on silica gel eluted with a 9:1 to 4:1 hexane-ethylacetate step gradient to yield 179 mg, 0.454 mmol (13%). mp= 100-115C. ~a]D= -13.5 (c=1.0, MeOH). MS(CI) m/e 395(m+H) , 261. H ~MR(CDC13,300MHz) ~ 0.52(t,J=7Hz,lH), 0.92(t,J=7Hz,2H), 1.18-1.70(m,10H), 2.56-2.67(m,0.33H), 3.01(dd,J=2,13Hz,0.67H), 3.57(bd,J-12Hz,0.67H), 3.80(bs,0.33H), 4.51(bd,J=13Hz,0.33H), 4.78(bs,0.67H), 4.98(d,J=llHz,lH), 5.12(d,J=llHz,lH), 5.54(d,J=7Hz,0.67H), 5.58(d,J=7Hz,0.33H), 6.46-6.55(m,1H), 7.28-7.43(m,10H).
~ 0 R-Phenylalycine-(2'-propylpiperidinyl)amide The product of example 109 (150 mg, 0.38 mmol) was treated with 25 mg of 10% Pd on carbon ln 5 mL of methanol under one atmosphere of hydrogen for 24 hours. The catalyst was filtered away and the filtrate was evaporated to yield product.
,: . . . . .
:: . . : ' . . :
:: , ' W09l/0072~ PCT/US90/03630 - 1 o o--~L~ 1 1 1 N-(3'-Ouinolylcarhonyl)-R-Dhenylalyc~ne-(2'-propylpi~eridinyl)amide Quinoline-3-carboxylic acid (38.1 mg, 0.22 mmol), the product of example 110 ~31 mg, 0.22 mmol) and TEA ~31 ~L, 0.22 mmol) were dissolved in 4 mL of 1:1 DMF-CH2Cl2 and treated with EDCI ~42.1 mg, 0.22 mmol) with stirring at room temperature overnight. The solvent was evaporated and the residue was extracted as in example 71. Rf= 0.4 ~1:1 hexane-ethylacetate). MS~CI) m/e 416~m+H) , 261, 154, 128. H NMR~CDCl3,300MHz) ~ 0.55~t,Jz7Hz,lH), 0.94~t,J=7Hz,2H), 1.23-1.72(m,10H), 2 71(dt,J=2,13Hz,0;33H), 3.08~dt,J=2,13Hz,0.67H), 3.68(bd,J=13Hz,0.67H), 3.93(bs,0.33H), 4.58(bd,J=13H~,0.33H), 4.85(bs,0.67H), 6.03(d,J-7Hz,0.67H), 6.07(d,J=7Hz,0.33H), 7.3-7.42(m,3H), 7.52-7.63(m,3H), 7.80(dt,J=1,7Hz,lH), 7.90(d,J=8Hz,lH), 8.14(d,J=8Hz,lH), 8.28(t,J=6Hz,lH), 8.59(d,J=2Hz,lH), 9.34(d,J=2Hz,lH). C,H,N analysis calculated for C26H29N3O2, 0.5 H2O: C 73.56, H 7.12, N 9.90; found: C
73.60, H 7.10, N 9.61.
~xamPle 11~
N-(4',8'-Dihydroxy-2'-quinolylcarbonyl)-R-phenylglycine-(2'-propylpiperidinyl)amide 4,8-Dihydroxyquinoline-2-Carboxylic acid (45 mg, 0.22 mmol), the product of example 110 (S2 mg, 0.20 mmol) and TEA (31 ~L, 0.22 mmol) were dissolved in 4 mL of 1:1 DMF-methylene chloride and treated with EDCI (42 mg, 0.22 mmol) with stirring overnight. The reaction was then . ~
. , .. . : . .
~, .: :, :- , .. : , ::
" ,,, W091J0072~ PCT/US~0/03630 , . .
2~ 55 po~red into ethylacetate and extracted as in example 71.
The resulting residue was purified by chromatography on silica gel eluted with a 1% to 9% ethanol in methylene chloride step gradient. MStCI) m/e 448(m+H) , 293. H
NMR~DMSOd6,300MHz) ~ 0.71(t,J=7Hz,lH), 0.81-0.90(m,2H), 1.15-1.70(m,10H), 3.07(bt,J=13Hz,0.67H), 3.33(s,H2O), 3.68(bd,J=12Hz,0.67H), 4.02(bs,0.33H), 4.36(d,J=8Hz,0.33H), 4.68(bs,0.67H), 6.12-6.17(m,lH), 7.09(d,J=7Hz,lH), 7.32-7.56(m,8H), 9.89(d,J=8Hz,0.67H), 10.08(d,J=8Hz,0.33H), 10.23(s,0.67H), 10.24(s,0.33H), 11.73(bs,lH).
Example 113 -Benzyloxvcarbonyl-R-phenvlalvcine-(N-benzyl ~-2'-cyanoeth~l)am;de N-Benzyloxycarbonyl-R-phenylglycine (285 mg, 1.0 mmol), 3-(benzylamino)propionitrile (391 ~L, 2.5 mmol) and TEA (139 ~L, 1.0 mmol) were dissolved in 10 mL of CH2Cl2 and treated with BOPCl (256 mg, 1.0 mmol). After 1 day, another 139 ~L of TEA was added. After 2 days, additional BOPCl (256 mg), amine (391 ~L) and ~MF (5 mL) were added.
After 3 days, the solvents were evaporated and the residue was extracted as in example 71. The crude residue was recrystallized from hexanes-ethylacetate to yield 314 mg, 0.74 mmol (74~). Rf= 0.75 (1:1 hexanes-ethylacetate).
mp= 114-150 C. [a]D= -9. 4 (c=0.67, 1:1 DMF-MeOH).
MS(CI) m/e 428(m+H) , 445, 384, 375. H NMR(CDC13,300MHz) 2.45-2.66(m,2H), 3.33-3.42(m,lH), 3.46-3.52(m,0.5H), 3.66-3.75(m,lH), 4.38~d,J=16Hz,lH), 4.43-4.5(m,0.5H), 4.63(d,J=16Hz,lH), 4.69(s,0.5H), 5.01-5.2(m,3H), ... .. , - ~.:
.
~ ' ', : ' .
WO91/00~2~ PCT/US90/03~30 5.59~d,J=7Hz,0.5H), 5.66(d,J-7Hz,lH), 6.88(s,0.5H), 6.18-6.27(m,1.5H), 6.82(bs,0.5H), 6.95(t,J=4Hz,2H), 7.10-7.18(m,2H), 7.28-7.39(m,15H). C,H,N calculated for C26H25N3O3, 0.1 H2O: C 72.74, H 5.92, N 9.79; found: C
72.79, H 5.99, N 9.40.
Example 114 R-Phenvlglycine-(N-benzyl~N-2'-c~anoethyl)amide The product of example 113 (225 mg, 0.53 mmol) was dissolved in 25 mL of ethanol and treated with 100 mg of 10% Pd/C at room temperature. After 1.5 hours, the catalyst was filtered and the filtrate was evaporated to yield 158 mg, 0.54 mmol(quantitative). MS(CI) m/e 294(m+H) , 241.
~am~le 11~
N-(3'-Ouinolylcarbonyl)-R-phenylalycine (N-benzyl.N-2'-cyanoethyl)amide Quinoline-3~carboxylic acid (35 mg, 0.20 mmol) and the product of example 114 (53 mg, 0.18 mmol) were dissolved in 10 mL of methylene chloride and treated with EDCI (38 mg, 0.20 mmol). After 1 day, the solvent was evaporated and the residue was extracted as in example 71 to give 54 mg, 0.12 mmol (67%). [a]D= -0.42 (c-2.6, CHCl3). mp= 57-63 C. MS(CI) m/e 449(m+H) . H
NMR(CDCl3,300MHz) ~ 1.90-2.02(m,0.25H), 2.27-2.38(m,0.25H), 2.49-2.72(m,1.5H), 3.42(dt,J=7,13Hz,lH), 3.81(dt,J=7,13Hz,lH), 4.46(d,J=16Hz,lH), 4.73(d,J=16Hz,lH), 6.11(d,J=6Hz,0.25H), 6.16(d,J=7Hz,0.75H), 6.98-7.02(m,2H), 7.19-7.22(m,0.5H), .
, .. , : . ' '' :~ -: ~, - : .
WO9l/00725 PCT/US90/03630 21?5~55 7.30-7 33~m,2.5H), 7.38-7.46~m,3H), 7.53-7.64~m,3H), 7.82~dt,J=1,7H,lH), 7.85-7.94~m,2H), 8.15~d,lH,J=8Hz), 8.61~d,J=lHz,lH), 9.33~d,J=lHz,lH). C,H,N analysis calculated for C28H24N42' 0-7 H2 12.15; found: C 72.86, H 5.58, N 11.77.
Exam~le 116 N-(4'.8'-Dihvd~xy-2'-quinolylcarbonyl)-R-phenylqlycine (~-benzyl,N-2'-cyanoethyl)amide 4,8-Dihydroxyquinoline-2-carboxylic acid (41 mg, 0.20 mmol), the product of example 114 ~53 mg, 0.18 mmol), and TEA ~28 ~L, 0.20 mmol) were dissolved in 5 mL of DMF and treated with EDCI ~38 mg, 0.20 mmol). Additional TEA ~28 ~L) and EDCI ~38 mg) were added after 2 hours and 1 day.
After 2 days HOBt (27 mg, 0.20 mmol) was added to the reaction mixture. After 3 days, the solvent was evaporated and the residue was extracted with 0.1 M citric acid, and water and the organic solution was dried over MgSO4 then filtered and concentrated. The crude product was purified by silica gel chromatography eluted with 1:1 hexanes-ethylacetate to provide 22.6 mg, 0.05 mmol ~26~).
Rf= 0.4 ~1:1 hexane-ethylacetate). mp= 218-222 C. ~a]D=
-4.8 ~c=0.42, MeOH). MS~CI) m/e 481(m+H) , 428. lH
NMR~CD30D,300MHz) ~ 2.47-2.58~m,0.33H), 2.6-2.82(m,2H), 3.33-3.62~m,2.33H), 3.68-3.78~m,0.33H), 3.82-3.91~m,lH), 4.53~d,J=16Hz,lH), 4.62~d,J=14Hz,0.33H), 4.76(d,J=16Hz,lH), 4.87(s,H2O), 4.92~d,J=5H2,0.33H), 6.18(s,lH), 7.10~dd,J=1,7Hz,lH), 7.2-7.35~m,7H), 7.39-7.46(m,3H?, 7.51-7.60~m,2H), 7.67(dd,J=1,8Hz,lH).
... , .. . , , . . - - -: - ~, , WO91J00725 PCT/US90tO3630 ~, . . .
Example 111 N-(3'-Ouinolvlcarbonyl)-R-Tyrosine-di-n-pentylamide hydrochlor de hvdrochloride The product of example 80 (1.5 g, 3.0 mmol) was treated with 1.4 N HCl in dioxane (11 mL, 15 mmol) for 10 minutes. The excess reagent was evaporated and the oily residue was triturated with diethylether and filtered to yield 1.3 g, 2.6 mmol (87%) of a pale yellow solid.
MS(CI) m/e 476(m+H) , 958. H NMR(DMSOd6,300MHz) ~
0.84(t,J=7Hz,6H), 1.15-1.62(m,12H), 2.87-3.22(m,3H), 3.29-3.40(m,3H), 5.02(apparent q,J=7Hz,lH), 6.66(d,J=8Hz,2H), 7 11(d,Jz8Hz,2H), 7.78(dt,J=1,8Hz,lH), 7.96(dt,J=1,8Hz,lH), 8.17(t,J-7Hz,2H), 9.04~d,J-2Hz,lH), 9.22(d,J=8Hz,lH), 9.33(d,J-2Hz,lH). C,H,N analysis calculated for C29H37N3O3, 1.3 HCl: C 66.60, H 7.38, N
8.03; found: C 66.43, H 7.38, N 7.99.
Example 118 N-(3'-Ouinolylcarbonvl)-R-Histidine-di-n-pentylamide dihydrochloride The product of example 50 (800mg, 1.78 mmol) was dissolved in 13 mL of 1.4 N HCl in acetic acid for 10 mln and then the volatiles were evaporated to remove excess reagent. The oily residue was dissolved in a small amount of CH2Cl2 and the product was precipitated with hexanes.
The solid was collected to yield 824 mg, 1.58 mmol (89~).
MS(CI) m;e 450(mtH) . H NMR(DMSOd6,300MHZ) ~
, ~, :' . '. , . . ?
, :. ' . . ~ ~ , . . . .. .
: ' :, : - . , . ~ . :-.:
WO 91/0072~ PCT/US90/0363~
0.74(t~J=7Hz,3H), 0.85(t,J=7Hz,3H), 1.12-1.32(m,8H), 1.41-1.52(m,4H), 3.08-3.43(m,6H), 5.24-5.31(m,lH), 7.45(s,lH), 7.77(dt,J=1,7Hz,lH), 7.94(dt,J=1,7Hz,lH), 8.15~dt,J=1,9Hz,2H), 9.02(s,2H), 9.31-9.33(m,2H), 14.18(s,lH), 14.57(s,1H). C,H,N analysis calculated for C26H35N5O2, 2.6 HCl: C 57.36, H 6.96, N 12.87; found: C
57.30, H 6.96, N 12.86.
Example 119 N-(4',8'-Dihydroxy-2'-quinolylcarbonyl)-R-(4'-hydro~yphenyl)-alycine-di-n-pentylamide The reaction was performed in a similar manner to that in example 8 utilizing 0.3 g of the compound of example 64, 4',8'-dihydroxyquinoline-2-carboxylic acid ~0.2 g), EDCI ~0.21 g), HOBt ~0.13 g) and NMM ~0.22 mL).
The product was isolated in 75% yield ~0.37 g). MS~CI) m/e 494~m+H) .
H NMR(DMSOd6,300MHz) ~ 0.85(m,6H), 1.1-1.35(m,10H), 1.38-1.45(m,4H), 3.0-3.5(m,4H), 5.95(d,Jz9Hz,lH), 6.76(d,J=9Hz,2H), 7.08(d,J=9Hz,lH), 7.23(d,J=9Hz,2H), .
7.4(t,J=9Hz,lH), 7.55~m,2H), 9.5~bs,lH), 9.75(d,J=lOHz,lH). C,H,N calculated for C28H35N3O5, 0.5 H2O: C 66.91, H 7.22, N 8.36; found: C 66.76, H 7.20, N
8.18.
Example 120 N-Benzyloxycarbonyl-alycine-di-n-pentylamide The compound was prepared in a manner similar to that in example 1 utilizing N-t-butyloxycarbonylglycine.
MS~CI) m/e 349(m+1) , 305, 241, 215, 184. lH
WO91/00~2~ PCT/US90/03630 ~, 2~ S5 NMR(CDC13,300MHz) ~ 7.30-740(m,5H), 5.86(bs,1H), 5.12(bs,2H), 4.0(bd,J=4.5Hz,2H), 3.32(t,J=7.5Hz,2H~, 3.15(t,J=7.5Hz,2H), 1.50-1.70(m,4H), 1.20-1.40(m,8H), O.9(m,6H).
Example 1~1 N-(2'-Indolylcarbonyl)-~lycine-di-n-pentylamide The product of example 120 was deprotected in a manner similar to that in example 80. The free amine product was then coupled with indole-2-carboxylic acid as in example 4. mp= 98-100 C. MS(EI) m/e 3S7(m) , 287, 184. lH NMR(CDCl3,300MHz) ~ 9.27(s,lH), 7.67~d,J=6Hz,lH), 7.95(bd,J=7Hz,2H), 7.29(dt,J=1,6Hz,lH), 7.14(dt,J=1,6Hz,lH), 6.98(s,lH), 4.27(d,J=9Hz,2H), 3.~9(bt,J=7Hz,2H), 3.25(bt,Jz7Hz,2H), 1.55-1.70(m,4H), 1.25-1.40(m,8H), 0.93(t,J=6Hz,3H), O.91(t,J=6Hz,3H).
C,H,N analysis calculated for C21H31N3O2, 0.3 H2O: C
69.51, H 8.78, N 11.58; found: C 69.45, H 8.58, N 11.47.
Example 122 Ethvl N-(t-Blltyloxycarbonyl~alycinyl-lN-benzyl)alycinate N-t-Butyloxycarbonylglycine and ethyl N-benzylglycinate were coupled in a manner similar to that in example 1 to provide product.
. .
.. : : - ' : . .
.. , . ~ . . ..
, 2~ 755 . . .
~xam~le 12~
Ethyl N-(3'0uinolvlcarbonvl)glycinyl (N-benzyl)alvcinate The product of example 122 was deprotected in a manner similar to that in example 2 and then coupled in a manner similar to that in example 3 to provide product.
MS(CI) m/e 406(m+H) , 334, 194. lH NMR(CDC13,300MHz) 9.37(d,J=2Hz,0.33H), 9.35(d,J=2Hz,0.67H), 8.65(bm,1H), 8.18(bd,J=7Hz,lH), 7.94~m,lH), 7.83~m,lH), 7.63(m,lH), 7.43-7.55(m,lH), 7.30-7.40(m,3H), 7.25(m,2H), 4 73(s,0.67H), 4.67(s,1.33H), 4.51(d,J=4Hz,1.33H), 4.33(d,J=4Hz,0.33H), 4.16-4.25(m,2H), 4.13(s,1.33H), 4.00(s,0.67H), 1.28(m,3H).
., E~melQ 1~4 N-(t-Butyloxvcarbonvl)-R-homo~henvlalanine-di-n-pentylamide The product was prepared in an analogous manner to that in example 1 using t-Butyloxycarbonyl-R-homophenylalanine. MS(CI) m/e 419(m+H) , 363, 345, 319.
H NMR(CDC13,300MHz) ~ 1.85(m,lH), 7.48(m,lH), 7.18-7.32(m,5H), 5.39(bd,J=9Hz,lH), 4.56(m,lH), 3.48(dt,J=7,14Hz,lH), 3.39(t,J=7Hz,lH), 3.08(m,2H), 2.68(m,2H), 1.88(m,2H), 1.45(s,9H), 1.20-1.35(m,8HI, 1.13(m,2H), 0.88(m,6H).
:. ~. , : - .
. ., , . : . -. - , .
: ~ , : - :
:~ ,. , ", Z(.'~ ~ 5~
N-(3'-Ouinolylcarbonyl)-R-homophenylalanir.e-di-n-pentylamide The product was prepared in analogous manner to those in examples 2 and 3 utilizing the product of example 124 as the starting material. MS~CI) m/e 97q(m+H) , 369, 319, 305, 289. H NMR~CDCl3,300MHz) S 9.32~d,J=2Hz,lH), 8.53(d,J=2Hz,lH), 8.16(bd,J=8Hz,lH), 7.90(dd,J=1,8Hz,lH), 7.82(m,lH), 7.62(m,1H), 7.40(bd,J=8Hz,lH), 7.30(m,4H), 7.20(m,lH), 5.19(m,lH), 3.55-3.70(m,lH), 3.05-3.20(m,3H), 2.78(bt,J=7.5Hz,2H), 2.15(m,2H), 1.50-1.65(m,4H), 1.15-1.35(m,8H), 0.90(m,6H).
E~ ~
N-(3'-Q~innlylcarbonyl)al~cine Quinoline-3-carboxylic acid and methyl glycinate hydrochloride were coupled in a manner similar ~o that in example 3. The resulting product was subjected to saponification in methanol with 1 N NaOH. The desired product was extracted with EtOAc from the acidified solution or alternatively allowed to slowly precipitate from the acidified solution. MS(CI) m/e 231(m+H) , 187.
H NMR(DMSOd6,300MHz) S 12.72~bs,1H), 9.32(d,J=9Hz,lH), 9.11(t,J=6Hz,lH), 8.87(d,J=3Hz,lH), 8.12(t,J=7H ,2H), 7.89~t,J=7Hz,lH), ?.71(t,J=7Hz,lH), 4.03(bs,2H).
.: . :: , , . ~
-:
W09lt00725 PCT/US90/03630 2(?~?755 Example 127 N- (3'-Ouinolylcarbonyl~alycine-di-n-pentylamide The product of example 126 and di-n-pentylamine were coupled in a manner similar to that in example 1. The product was isolated by chromatography and solidifies upon concentration. mp= 36-375. MS~CI) m/e 370~m+H) . lH
NMR~CDC13,300MHz) ~ 9.38~d,J=2Hz,lH), 8.65~d,J=1.8Hz,lH), 8.18~d,J=8.5Hz,lH), 7.93~dd,J=1,8Hz,lH), 7.83~m,lH), 7.69(m,2H), 4.32(d,J=3.7Hz,2H), 3.41(bt,J=8Hz,2H), 3.27(bt,J=8Hz,2H), 1.62(m,4H), 1.30-1.45(m,8H), 0.95~t,J=7Hz,3H), 0.92~t,J=7Hz,3H). C,H,N analysis calculated for C32H31N32 C 71-49~ H 8-46~ N 11-37 found: C 71.28, H 8.42, N 11.36.
Example 1~
N-(3'-Ouinolylcarbonyl)alvcine-(~-propyl)piperidinylamide The acid from example 126 and 4-propylpiperdine were coupled as in example 1. mp= 116-117C. MS~CI) m/e 340(m+H) , 279, 254, 201. lH NMR~CDCl3,300MHz) ~
9.36~d,J=2Hz,lH), 8.63~d,J=2Hz,lH), 8.16~d,J=8.5Hz,lH), 7.93~dd,J=1,8Hz,lH), 7.82(m,lH), 7.60(bs,lH), 7.63(m,lH), 4.61(dt,J=2,13Hz,lH), 4.31(m,2H), 3.79(bd,J=lOHz,lH), 3.07(dt,J=3,13Hz,lH), 2.70(dt,J=3,13Hz,lH), 1.81(bm,2H), 1.55(m,lH), 1.05-1.40(m,6H), 0.92(t,J=7Hz,3H). C,H,N
analysis calculated for C20H25N3O2, 0.1 H2O: C 70.40, H
7.44, N 12.31; found: C 70.19, H 7.44, N 12.15.
.. ~ , :
: - , . ::, ,. ~ : -:, , - -:
,, "
WO91/00725 PCT/US90/0363~
2~ J
E~mel~ 129 N-Benzvlo~ycarbonyl-R-phenylalvcine-di-n-~entylamide The product was obtained from the coupling of N-Benzyloxycarbonyl-R-phenylglycine and di-n-pentylamine as in example 1. MS(CI) m/e 425(m+H) , 333, 317, 291. lH
NMR(CDCl3,300MHz) ~ 7.27-7.45(m,10H), 6.48(bd,J=7.5Hz,lH), 5.53(d,J=7.5Hz,lH), 5.12(d,J=12Hz,lH), 5.01(d,J=12Hz,lH), 3.48(m,lH), 3.18(m,2H), 2.97(m,lH), 1.50(m,4H), 1.10-1.35(m,8H), 0.87(t,J=7.5Hz,3H), 0.84(t,J=7.5Hz,3H).
Exam~le 130 R-Phenylalycine-dl-n-pentylamide The product resulted from the hydrogenolysis of the product of example 129. MS(CI) m/e 291(m+H) , 158. H
NMR(CDC13,300MHz) ~ 7.25-7.40(m,5H), 4.65~bs,lH), 3.52~m,lH), 3.08-3.22(m,2H), 2.92(m,lH)j 2.02~bs,2H), 1.50(m,3H), 1.10-1.35(m,9H), 0.88(t,J=7Hz,3H), 0.85(t,J=7Hz,3H).
N-(3~ouinolylcarbonyll-R-phenylalyclne-di-n-pentylamide The product of example 130 was coupled in a similar manner to that in example 3 to provide product. MS(CI) m/e 446(m+H) . H NMR(CDCl3,300MHz) ~ 9.33(d,J=2Hz,lH), 8.58(d,J=2Hz,lH), 8.13(bt,J=8Hz,2H), 7.88(bd,J=8Hz,lH), 7.79(m,lH), 7.62(m,1H), 7.55(m,2H), 7.32-7.42(m,3H), 6.03(d,J=6Hz,lH), 3.55(m,3H), 1.15-1.40(m,9H), 0.90(t,J=7Hz,3H), 0.86(t,J=7Hz,3H).
.. ~ .......... . . .
,: .- . . . :~, - ,- . . . :.:
WO91/On~25 PCT/US90/03630 `:
Z~. 5,_7155 Example 1~2 N-(4',8'-Dihydro~y-~'-~inQlylc~arbonyl)-R-Phenylglycine-di-n-~entylamide The product of example 130 was coupled in a similar manner to that in example 8 to provide the title compound.
mp= 89-91C. MS(CI) m/e 478(m+H) , 293, 190, 177. lH
NMR(DMSOd6,300MHz) ~ 9.91(bd,J=8Hz,lH), 7.55(m,2H), 7.35-7.45(m,7H), 7.08(dd,J=1,7.5Hz,lHj, 6.11(bd,J=8Hz,lH), 3.05-3.30(m,4H), 1.60(m,lH), 1.48(m,2H), 1.13-1.35(m,9H), 0.85(t,J=7Hz,3H), 0.78(t,J=7Hz,3H). C,H,N analysis calculated for C28H35N34' 0-3 H2 8.70; found: C 69.61, H 7.40, N 8.65.
Example 133 N-(3'-Chlorophenylaminocarbonyl)-R-phenylglycine-di-The product of example 13b was reacted with 3-chlorophenylisocyanate to provide the title compound.
MS(CI) m/e 444(m+H) , 425, 317, 291, 259, 242. lH
NMR(CDC13,300MHz) ~ 7.95(bs,1H), 7.42(m,1H), 7.22-7.34(m,5H), 7.13(d,J=7.5Hz,lH), 7.08(m,2H), 6.89(m,lH), 5.92(d,J=8Hz,lH), 3.50(m,lH), 3.00-3.30(m,4H), 1.43-1.63(m,3H), 1.10-1.30(m,8H), 0.84(t,J=7Hz,3H), 0.78(t,J=7Hz,3H).
,. . i, , :- , .: , : : .
. . ,. : . -- . -:
, ,~ ...
- :
: . - . !
,'' ~ ~ ' " ',' ' W09l/00725 P~T/US90/03630 2~ , SS
~m~l~ 134 N-(3'-Methylphenylaminocarbonyl)-R-phenylqlYcine-di-n-pentylamide The product of example 130 was reacted with 3-methylphenylisocyanate to provide the title compound.
MS(CI) m/e 424(m+H) , 374, 317, 291, 276, 239, 228. H
NMR(CDCl3,300MHz) ~ 7.27-7.48(m,5H), 7.18~m, L H), 7.12~d,J=8Hz,lH), 7.06~m,2H), 6.82~bd,J=8Hz,lH), 6.77(bd,J=8Hz,lH), 5.87(d,J=8Hz,lH), 3.51~m,lH), 3.20~m,2H), 3.04~m,1H), 2.28~s,3H), 1.50~bm,qH), 1.10-1.30~m,8H), 0.84~t,J=7Hz,3H), 0.82~t,J=7Hz,3H).
Example 135 N-(5'-Fluoroindolylcarbonyl)-R-p:~enylalycine-di-n-pentylamide The product of example 130 was reacted with 5-fluoroindole-2-carboxylic acid in a manner similar to that in example 4 to provide the desired product. mp= 94-6C.
MS~CI) m/e 452~m+H) , 276, 267, 184. H NMR(CDCl3,300MHz) 9.36(bs,lH), 7.96(d,J=7Hz,lH), 7.50~m,2H), 7.30-7.40~m,3H), 7.36~s,lH), 7.33(m,lH), 6.98(dt,J=2.5,9Hz,lH), 6.91(m,lH), 5.94(d,J=7Hz,lH), 3.53(m,lH), 3.13-3.30(m,2H), 3.04(m,lH), 1.45-1.65~m,4H), 1.10-1.40~m,8H), 0.89(t,J=7Hz,3H), 0.85(t,J=7Hz,3H). C,H,N analysis calculated for C27H34FN3O2: C 71.81, H 7.59, N 9.31;
found: C 71.53, H 7.50, N 9.30.
.: . :
,: . . . : . . . -.. . : . ~,: - : -. . . ~, , : .
.
., :
.. , . . .. ~ . . . . .
WO91/00725 PCT/US90/0363~
2~5~isS
E~m~l~ 13~
N-(5'-Chloroindolylcarbonyl)-R-phenylalycine-di-n-pentylamide The product of example 130 was reacted with 5-Chloroindole-2-carboxylic acid in a manner similar to that in example 4 to provide the title compound. MS~CI) m/e 468(m+H) , 434, 302, 276, 212. H NMR~CDC13,300MHz) 9.36(bs,lH), 7.97~d,J=7Hz,lH), 7.59(m,lH), 7.50(m,2H), 7.35(m,3H), 7.22(m,2H), 6.89(m,lH), 5.94(d,J=7Hz,lH), 3.53(m,lH), 3.15-3.30(m,2H), 3.04~m,lH), 1.45-l.60(m,9H), 1.10-1.40~m,8H), 0,89~t,J=7Hz,3H), 0.85~t,J=7Hz,3H).
C,H,N analysis calculated for C27H34ClN3O2: C 69.29, H
7.32, N 8.98; found: C 69.49, H 7.36, N 8.95.
E~ ~
N-(2'-Ouinolylcarbonyl)-~-Phenylalycine-di-n-~entylamide The product of example 130 was coupled in a similar manner to that in example 5 to provide the desired compound. mpz 116-7 C. MS~CI) m/e 446~m+H) , 289, 277, 261, 246. H NMR~CDCl3,300MHz) ~ 9.62~d,J=8Hz,lH), 8.24(bs,2H), 8.17~d,J=8Hz,lH), 7.83~d,J=8Hz,lH), 7.74~m,lH), 7.59~m,3H), 7.30-7.40~m,3H), 6.06~d,J=8Hz,lH), 3.61~m,lH), 3.32~m,lH), 3.0-3.20~m,2H), 1.50-1.65~m,4H), 1.15-1.40~m,8H), 0.89~t,J=7Hz,3H), 0.87~t,J=7Hz,3H).
C,H,N analysis calculated for C28H35N3O2: C 75.47, H 7.92, N 9.43; found: C 75.45, H 7.91, N 9.43.
- . .
~ ',, ', ' ':' `, ~- , ' ' - :, , ; .......... : . "
- ;, . . .
WO91/0072~PCTJUS90/0363~
~. :., .
21?~755 E~
N ' - (t-Butyloxycarbonyl)-l-amino-cvclch~x~ne-(di-n-pentyl)carboxamide The product was prepared as in example 1 from di-n-pentylamine and N ' -t-Butyloxycarbonyl-l-aminocyclohexane carboxylic acid. MS(CI) m/e 383(m+H) . H
NMR~CDCl3,300MHz) ~ 4.70(bs,1H), 3.20-3.50(m,4H), 1.85-2.0(m,4H), 1.45-1.70(m,8H), 1.42(bs,9H), 1.20-1.90(m,10H), 0.92(bt,J=7Hz,6H).
~xample 139 N ' - (3'-Ouinolylcarbonyl~ amino-cyclohexane-(di-n-pentyl)carboxamide The desired product was prepared via deprotection of the product of example 138 ~in a manner similar to that in example 2) and coupling with quinoline-3-carboxylic acid as in example 3. mp= 136-137C.
Example 140 N ' - (t-Butyloxycarbonyl)-l-am~n~=ÇYclohexane(N-pentyl)carboxamide The product was prepared via coupling of N'-t-Butyloxycarbonyl-l-aminocyclohexane carboxylic acid and pentylamine as in example 1. MS(CI) m/e 313~m+H) , 257, 239, 213, 198. H NMR(CDC13,300MHz) ~ 6.70(s,lH), 4.52(bs,lH), 3.23(m,2H), 1.80-2.05(m,4H), 1.65(m,4H), 1.99(s,9H), 1.25-1.38(m,8H), 0.88(t,J=7Hz,3H).
: ~: j ,. : . . . . . : . - .
i i . , .-; - ~ : : . . .
. : ~ ; , ,: . :.
WO9l/0072~ PCT/US90/03630 . :
2(~ 7SS
. .
. . ..
E~ ~
N'-(3'-Ouinolylcarbonyl~-l-amino-cyclohexane-(N-pentyl)carboxamide The product was obtained in a similar manner to that in example 139 using the product of example 140 as the starting material. MS(CI) m/e 368~m+H) . H
NMR(CDCl3,300MHz) ~ 9.38(d,J=2Hz,lH), 8.58(d,J=2Hz,lH), 8.18(d,J=8Hz,lH), 7.94(bd,J=8Hz,lH), 7.83(m,lH), 7.65(m,lH), 7.12(bs,lH), 6.27(bs,lH), 3.38(m,2H), 2.34(m,2H), 2.03(m,2H), 1.65-1.80(m,4H), 1.50-1.60(m,4H), 1.25-1.40(m,9H), 0.88(t,J=7Hz,3H). C,H,N analysis calculated for C22H29N3O2: C 71.91, H 7.95, N 11.43;
found: C 71.73, H 7.95, N 11.33.
N-(4',8'-Dihydroxy-2'-quinolylcarbonyl)alycine-di-n-pentylamide The product of example 120 was deprotected in a manner similar to that in example 80 and the resulting amine was then coupled in a manner similar to that in example 8 to yield the title compound. mp= 158.5-159.5C.
MS~FAB) m/e 402(m+H) , 386, 245, 217. H
NMR(DMSOd6,300MHz) ~ 9.90~bs,lH), 9.80(bs,lH), 7.55(bt,J=8Hz,lH), 7.52(bs,lH), 7.42(m,lH), 7.11(bd,J=8Hz,lH), 4.20(bd,J=6Hz,2H), 3.36(bs,H20), 3.20 -3.33(m,4H), 1.58(m,2H), 1.48(m,2H), 1.20-1.33(m,8H), 0.85(m,6H). C,H,N analysis calculated for C22H31N3O4, H2O: C 62.99, H 7.93, N 10.02; found: C 53.12, H 8.02, N
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Z~ . 55 Exam~le 143 N-(2'-NaDhthovl)~lycine-di-n-~entylamide The product of example 120 was deprotected in a manner similar to that in example 80 and the resulting amine was then coupled in a manner similar to that in example 17 to yield the title compound. MS~CI) m/e 369(m~H) , 200, 184, 172. H NMR(CDCl3,300MHz) S
8.38(s,lH), 7.85-7.95~m,4H), 7.50-7.60(m,3H), 9.30~d,J=4Hz,2H), 3.40(t,J=7.SHz,2H), 3.26(t,J=7.SHz,2H), 1.60(m,4H), 1.25-1.45(m,8H), 0.94(t,J=7Hz,3H), 0.92(t,J=7Hz,3H). C,H,N analysis calculated for C23H32N2O2: C 74.96, H 8.75, N 7.68; found: C 74.44, H
8.75, N 7.55.
N-(6'-Hvdroxy-2'-nanhthoyl)alycine-di-n-pentylamide The product of example 120 was deprot~cted in a manner similar to that in example 80 and the resulting amine was then coupled with 6-hydroxy-2-naphthoic acid in a manner similar to that in example 17 to yield the title compound. MS(CI~ m/e 385~m+H) , 228, 200, 184. 1H
NMR(DMSOd6,300MHz) S 8.58(bt,J=6Hz,lH), 8.36(bs,lH), 7.86(m,2H), 7.63(d,J=8Hz,lH), 7.15(m,2H), 4.14(d,J=5Hz,2H), 3.20-3.35(m,4H), 1.60(m,2H), 1.45(m,2H), 1.20-1.35(m,8H), 0.89(t,J=7Hz,3H), 0.86(t,J=7Hz,3H). C,H,N
analysis calculated for C23H32N2O3: C 71.84, H 8.39, N
7.29; found: C 71.73, H 8.36, N 7.21.
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WO91/00725 PCT~US90/03630 ':
~ample 145 N-~'-Methylphenylaminocarbonvl)alvcine-di-n-E~nt~lamide The product of example 120 was deprotected in a manner similar to that in example 80 and the resulting amine was then coupled with 3-methylphenylisocyanate to yield the title compound. mp= 66-7C. MS(CI) m/e 348(m+H) , 241, 215, 200, 184. H NMR(CDCl3,300MHz) 7.08-7.20(m,3H), 7.03~bs,lH), 6.86(bd,J=7Hz,lH), 6.21(bs,lH), 4.13(bs,2H), 3.32(bt,J=7.SHz,2H), 3.21(bt,J=7.5Hz,2H), 2.30(s,3H), 1.45-1.65(m,4H), 1.20-1.40(m,8H), 0.92(t,J=7Hz,3H), 0.86(t,J=7Hz,3H). C,H,N
analysis calculated for C20H33N3O2:
C 69.13, H 9.57, N 12.09; found: C 68.99, H 9.56, N 12.04.
~xample 196 N-(2'-Chloro~henylaminocarbonyl3-(2R.3S~-(O-benzvl)Threonine-di-n-pentylamide The reaction was performed in a similar manner as in the example above utilizing 0.35 g of the hydrochloride salt of example 30, 2-chlorophenylisocyanate (0.16 g), and TEA (0.135 mL). The product was purified using chloroform and methanol as the elutant mixture. The oily product was isolated in 83% yield (0.42 g). [a]D= +21.8 (c=0.11, MeOH). MS(CI) m/e 502(m+H) . H NMR(CDCl3,300MHz) ~
0.85(m,6H), 1.23(m,11H), 1.43-1.65(m,4H), 3.0-3.21(m,2H), 3.55(m,2H), 3.33(m,lH), 4.57(d,J=lSHz,lH), 4.63(d,J=15Hz,lH), 4.98(m,1H), 6.48(d,J=9Hz,lH), 6.95(t,J=7Hz,lH), 7.2(m,2H), 7.3(m,6H), 8.11(d,J=9Hz,lH).
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C,H,N analysis calculated for C28H40ClN3O3, 0.3 CH~13: C
63.19, H 7.55, N 7.81; found: C 63.21, H 7.39, N 7.82.
~m~l~ 147 N-(4' 8'-Dihydroxy-2'-quinolylcar~onyl)-(2R 3S)-(O-benzyl)-Threonine-di-n-pentylamide The reaction was performed in a similar manner as in example 8 utilizing 0.35 g of the hydrochloride salt of example 30 4,8-dihydroxyquinoline-2-carboxylic acid (0.21 g), EDCI ~0.22 g), HOBt (0.14 g), and NMM (0.22 g). The oily product was isolated in 60% yield (0.32 g)- [~]D=
+8.0 (c=0.125, MeOH). MS(CI) m/e 536(m+H) . 1H
NMR(DMSOd6,300MHz) ~ 0.82(m,6H), 1.15-1.3(m,11H), 1.4-1.6(m,4H), 3.2-3.65(m,~H~, 4.08(m,lH), 4.52(d,J=12Hz,lH), 4.63(d,~-12Hz,lH), 4.98(t,J=9Hz,lH), 7.12(m,SH) 7.42(t,J=gHz,lH), 7.55(m,2H), 9.8(d,J=9Hz,lH), 10.4(bs,1H), 11 72(bs,2H) C,H,N analysis calculated for C31H41N3O5, H2O: C 67.25, H 7.83, N 7.59; found: C 67.19, H 7.60, N 7.38.
Example lq8 Methyl Boc-R-Methionine-S-(p-hydroxy)-phenylalycinate Boc-R-methionine (250 mg, 1 mmol) , methyl p-hydroxyphenylglycinate hydrochloride (217 mg, 1 mmol) and triethylamine (139 ~L, 1 mmol) were combined in 10 mL of dichloromethane at 0C and treated with BOPCl (254 mg, lmmol). Additional BOPCl (254 mg) and TEA (134 ~L) were added after one day. After two days, the reaction mixture was poured into EtOAc and extracted successively with 0.1%
citric acid, 0 1 M NaHCO3 and water. The solution was . . . . .
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W09l~00725 PCT/US90/03630 2~ ?~S
therl dried over MgSO4, filtered and evaporated to yield 288 mg, 0.7 mmol (70%). Rf = 0.56 ~1:1 hexanes - EtOAc) mp = 158C ~dec). MS~CI) m/e 413(m+H)+, 357, 313.
1HNMR~CDCl3,300MHz) d 1.43(s,9H), 3.72(s,3H), 6.73(d,J=8Hz,2H), 7.17(d,J=8Hz,2H), 7.33~bs,1H).
Example 149 Methyl R-Methionine-S-(p-hydroxy)-phenylalycinate hvdrochloride The product of the example 148 ~250 mg, 0.6 mmol) was treated with 5 mL of 4 N HCl in dioxane at room temperature under a nitrogen atmosphere. After 30 minutes, the excess reagent was evaporated to yield quantitatively the product.
~xampl~ 150 Methyl N-(3'-Ouinolylcarbonyl)-R-Methionine-S-(p-hydrox.y)-phenylalycinate The hydrochloride salt of example 149 ~50 mg, 0.14 mmol), 3-quinoline carboxylic acid ~26 mg, 0.15 mmol) and TEA ~21 ~L, 0.15 mmol) were dissolved into 5 mL
methylenechloride and treated with EDCI ~29 mg, 0.15 mmol) for 4 hours. The reaction was poured into EtOAc and extracted with 0.1% citric acid and water followed by drying over MgSO4. The resultant filtrate was concentrated and chromatographed over silica gel eluting with a 2:1 to 1:2 hexane - EtOAc gradient to yield 29 mg, 0.06 mmol (44%). MS~CI) m/e 468(m+H)+, 393, 287.
1HNMR(CDC13,300MHz) ~ 2.04~s,3H), 2.12-2.20~m,2H), 2.42-.. "
:, :.
2~ _755 2.52(m,lH), 2.57-2.67(m,lH), 3.65(s,3H), 5.05(q,J=7Hz,lH), 5.41(d,J=6Hz,lH), 6.77(d,J=8Hz,2H), 7.16(d,J=8Hz,2H), 7.59(dt,J=1,7Hz,lH), 7.73-7.82(m,3H), 7.83(d,J=8Hz,lH), 8.12(d,J=8Hz,lH), 8.61(d,J=2Hz,lH), 9.30(d,J=2Hz,lH).
C,H,N analysis calculated for C2qH25N3O5S 0.5 H2O: C
60.99, H 5.60, N 8.81; found: C 60.69, H 5.63, N 8.35.
Example 151 N-(3'-Ouinolylcarbonyl)-R-Serine-di-n-pentylamide BTFA (trifluoroacetoxyboronate) 0.154 g, 0.4 mmol was added to the product of example 27 (71 mg, 0.145 mol) dissolved in 2 mL of methylene chloride. Another mL of methylene chloride was added and the reaction was monitored by tlc. After 20 minutes of stirring at ambient temperature, the starting material was consumed and the solvents with methanul were evaporated under vacuum. This evaporation sequence using methanol was repeated several times . The residue was separated by chromatography using EtoAc-hexane ~1:1) as the elutants. An oily product was isolated in 69~ yield (40 mg). MS(CI) m/e 400 (m+H)+.
lHNMR(CD30D,300MHz) ~ 0.94 (m,6H), 1.26-1.44 (m,8H), 1.54-1.64(m,2H), 1.68-1.86(m,3H), 3.25-3.35(m,lH), 3.43-3.62(m,3H), 3.82-3.96(m,2H), 5.22(t,J=6Hz,lH), 7.73(t,J=6Hz,lH), 7.91(t,J=6Hz,lH), 8.07(d,J=9Hz,lH), 8.12(d,J=9Hz,lH), 8.9(s,lH), 9.28(s,lH).
E~ample 152 N-(8'-~ydro~.y-2-quinolylcarbonyl)-alycine-di-n-pentylamide :. . :. . . . . , ~
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Similar to example 121, the product of example 120 was deprotected and coupled to 8-hydroxy-2-quinolinic carboxylic acid in a standard fashion utilizing EDCI etc.
to provide the product. MS(CI) m/e 386 (m+H)+.
lHNMR(CDC13,300MHz) ~ 8.96(bs,lH), 8.23(s,2H), 8.02(s,lH), 7.53(t,J=7.5Hz,lH), 7.36(dd,J=1,7.5Hz,lH), 7.23(dd,J=1,7.5Hz,lH), 4.34(d,J=5Hz,2H), 3.42(bt,J=8hz,2H), 3.28(bt,J=8Hz,2H), 1.55-1.70(m,4H), 1.25-1.40(m,8H), 0.93(apparent q,6H). C,H,N analysis calculated for C22H31N3O3 0.2 H2O: C 67.91, H 8.13, N
10.80; found: C 67.90, H 8.14, N 10.69.
Example 153 N-Methyl-N-(3'Ouinolylcarbonyl)-alycine-di-n-pentylamide The product of example 127 was methylated using bistrimethylsilylamide and methyl iodide in TH~ at -78C
warming to ambient temperature to provide product after standard workup and purification. MS(DCI) m/e 384(m+H)+.
Example 154 N-(3'-Iodo-2'-indolylcarbonyl)-alycine-di-n-pentylamide The product of example 121- was iodinated with N-iodosuccinimide to provide product after chromatographic purification. MS(DCI) m/e 484(m+H)+. C,H,N analysis calculated for C21H30IN3O2: C 52.18, H 6.25, N 8.69;
found: C 52.09, H 6.21, N 8.49.
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found: C 70.76, H 9.03, N 11.17.
The ability of the compounds of Formula I to interact with CCK receptors and to antagonize CCK can be demonstrated 1~ vitro using the following protocols.
~harmacoloaical Methods CCK8 ~Asp-Tyr(SO3H)-Met-Gly-Trp-Met-Asp-Phe-NH2] was purchased from Peptide International (Louisville,XY) or Cambridge Research Biochemicals (Atlantic Beach, NY) EGTA, HEPES and BSA were purchased from Sigma Chemical Co.
(St. Louis, MO). [125I]BH-CCK8 tspecific activity, 2200 Ci/mmol) and Aquasol-2 scintillation cocktail were obtained from New England Nuclear (Boston, MA). Bestatin and phosphoramidon were purchased from Peptide International. Male guinea pigs, 250 to 325 g, were obtained from Scientific Small Animal Laboratory and Farm (Arlington Heights, IL).
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Pr~tocol fQL B~si~aL~am~ ~i~di~a Experiments 1. Guinea Pig Cerebral Cortical and Pancreatic Membrane ~reparations Cortical and pancreatic membranes were prepared as described ~Lin and Miller; J. Pharmacol. E~. Ther. 232, 775-780, 1985). In brief, cortex and pancreas were removed and rinsed with ice-cold saline. Visible fat and connective tissues were removed from the pancreas.
Tissues were weighed and homogenized separately in approximately 25 mL of ice-cold 50 mM Tris-HCl buffer, pH
7.4 at 4C, with a Brin~man Poloytron for 30 sec, setting 7 The homogenates were centrifuged for 10 min at 1075 x g and pellets discarded. The supernatants were saved and centrifuged at 38,730 x g for 20 min The resultant pellets were rehomogenized in 25 mL of 50 mM Tris-HCl buffer with Teflon-glass homogenizer, 5 up and down strokes. The homogenates were centrifuged again at 38,730 x g for 20 min. Pellets were then resuspended in 20 mM
HEPES, containing 1 mM EGTA, 118 mM NaCl, 4.7 mM KCl, 5 mM
MgC12, 100 ~M bestatin, 3 ~M phosphoramidon, pH 7.4 at 22C, with a Teflon-glass homogenizer, 15 up and down strokes. Resuspension volume was 15-18 mL per gram of original wet weight for the cortex and 60 mL per gram for the pancreas.
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,. ~ , . , W09l/00725 PCT~US90/03630 ,~--2~ ~ . 5 ~ -124-2. Incubation Conditions ~ I~Bolton-Hunter CCX8 ([1 I]BH-CCK8), and the test compounds were diluted with HEPES-EGTA-salt buffer (see above) containing 0.5% bovine serum albumin (BSA).
To 1 mL Skatron polystyrene tubes were added 25 ~L of [ I]BH-CCK8, and 200~L of membrane suspension. The final BSA concentration was 0.1%. The cortical tissues were incubated at 30C for 150 min and pancreatic tissues were incubated at 37C for 30 min. Incubations were terminated by filtration using Skatron Cell Harvester and SS32 microfiber filter mats. The specific binding of [125I]BH-CCK8, defined as the difference between binding in the absence and presence of 1 ~M CCK8, was 85-90% of total binding in cortex and 90-95% in pancreas. IC50's were determined from the Hill analysis. The results of these binding assays are shown in Table 1.
Protocol for Amylase Release This assay was performed using the modified protocol of Lin et al., J. pharmacol. E~- ~h~. 236, 729-739, 1986.
1. Guinea Pia a~ini Preparation Guinea pig ocean were prepared by the method of Bruzzone et al. (Biochem. J. 226, 621-624, 1985) as follows. The pancreas was dissected and connective tissues and blood vessels were removed. The pancreas was cut into small pieces (2 mm) by a seizure and placed in a " . ... . .
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, , WO91/0~72~ PCT/US90/03fi30 2~?~55 15 mL conical plastic tube containing 2.5 mL of Krebs-Ringer HEPES (KRH) buffer plus 400 units per mL of collagenase. The composition of the KP~H buffer was:
HEPES, 12.5 mM; NaCl, 118 mM; KCl, 4.8 mM; CaCl2, 1 mM;
KH2PO4, 1.2 mM; MgS04, 1.2 mM; NaHC03, 5 mM; glucose, 10 mM at pH 7.4. The buffer was supplemented with 1% MEM
vitamins, 1% MEM amino acids and 0.001% aprotinin. The tube was shaken by hand until the suspension appeared homogeneous, usually 5-6 min. Five mL of the KRH, without collagenase and with 0.1% BSA, was added and the tube was centrifuged at 50 x g for 35 sec. The supernatant was discarded and 6 mL of the KRH was added to the cell pellet. Cells were triturated by a glass pipette and centrifuged at 50 x g for 35 sec. This wash procedure was repeated once. The cell pellet from the last centrifugation step was then resuspended in 15 mL of KRH
containing 0.1% BSA. The contents were filtered through a dual nylon mesh, size 275 and 75 ~M. The fil~rate, containing the acini, was centrifuged at 50 x g for 3 min.
The acini were then resuspended in 5 mL of KRH-BSA buffer for 30 min at 37C, under 100% oxygen atmosphere (2)' with a change of fresh buffer at 15 min.
2. Amylase Assay After the 30 min incubation time, the acini were resuspended in 100 volumes of KRH-BSA buffer, containing 3 ~M phosphoramidon and 100 ~M bestatin. While stirring, 400 ~L of acini were added to 1.5 mL microcentrifuge tubes .. . ~ .
WO9l/007~5 PCT/US90/03630 Z~ , 55 containing 50 ~L of CCK8, buffer, or test compounds. The final assay volume was 500 ~L. Tubes were vortexed and placed in a 37C water bath, un-ler 100% 2~ for 30 min.
Afterward, tubes were centrifuged at 10,000 g for 1 min.
Amylase activity in the supernatant and the cell pellet were separately determined after appropriate dilutions in 0.1% Triton X-100, 10 mM NaH2P04, pH 7.4 by Abbott Amylase A-gent test using the Abbott Bichromatic Analyzer 200.
The reference concentration for CCK8 in determining the IC50's of the compounds of Formula I was 3 x 10 OM. The results of this assay are shown in Table 2.
In Vitro Results The preferred compounds of Formula I are those which inhibited specific ~125I]-BH-CCK8 binding in a concentration dependent manner. Analysis of [125I]-BH-CCK8 receptor binding in the absence and presence of the compounds of formula I indicated the compounds of formula I inhibited specific [125I]-BH-CCK8 receptor binding. The IC50 values of the compounds of Formula I are presented in Table 1.
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W09l/00725 PCT/us9O/03630 [ 25I]-BH-CCK8 Binding Compound ofIC50 ~nM) Exam~le Pancreas Cortex 3 40 17,000 4 100 ~10,000 S 27 >10,000 7 290 >10,000 8 12 <10,000 13 190 1-10,000 17 200 ~100,000 23 87 ~10,000 24 170 >10,000 31 73 ~10,000 32 23 210,000 33 30 ~10,000 34 9 >10,000 37 210 ~10,000 47 320 ~10,000 19 2qO0 53 24 ~10,000 56 530 >10,000 41 <10,000 66 150 1-10,000 :~ . . ,~ . ,,- :.- ~ . . . : , WO 91/00725 PCr/US90~03630 ~ .~
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:, 260~10,000 73 180>10,000 74 70~10, 000 160>10, 000 .
76 92>10, 000 37~10,000 82a 250>30, 000 87 29>10, 000 93 195~10,000 99 56~10,000 100 63~10,000 117 7428, 000 118 42 3, 300 119 110 6,200 125 160~10, 000 131 9.3 1600 132 3.1 1700 133 210~10,000 142 160>10, 000 147 86 2,900 150 980>10, 000 152 520>10,000 155 230<10,000 ~, .'~ ` - - ~........ -: ' ., ~, ' , ' '` ' .
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The results herein also indicate that compounds of the invention possess selectivity for the pancreatic (type A) CCK receptors.
Inhibition of CCK8-induced Compound of Amylase Release E~m~le IC~Q ~nM) 4 <100,000 8 <100,000 17 <30,000 31 <100,000 32 <1000 34 <100,000 <100,000 59 -100,000 <100,000 74 <100,000 <10,000 81 <10,000 .. . ,. . - :
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91 <10,000 99 <10,000 131 <100,000 132 <100,000 141 <30,000 151 <10,000 These results indicate that compounds of the invention are CCK antagonists.
In Vivo Results The ability of the compounds of Formula I to interact with CCK receptors and to antagonize CCK n vivo can be demonstrated using the following protocols.
Ll~inn ~ Induced ,Gastric Emptyina Three fasted mice were dosed (p.o.) with the test compound. CCK8 (80 ~g/kg s.c.) was administered within 60 minutes and charcoal meal (0.1 mL of 10% suspension) was given orally 5 minutes later. The animals were sacrificed within an additional 5 minutes.
Gastric emptying, defined as the presence of charcoal within the intestine beyond the pyloric sphincter, is inhibited by CCK8. Gastric emptyinq observed in 2 or 3 mice (greater than 1) indicates antagonism of CCK8.
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Compound Number of mice gf example Dose (p.o.) with Gastric Emptyina 118 100 mg/kg 2 Measurement of Plasma In~lin Level Followina Treatment ~l~h ~ and a Compound of Formula I
The ability of the compounds of Formula I to antagonize CCK induced hyperinsulinemia can be demonstrated in vivo using the following protocol.
Male mice, 20-30 g, were used in all experiments.
The animals were fed with laboratory lab chow and water ad libitum. The compound of Formula I (1-100 mg/kg in 0.2 mL
of 0.9% saline) was administered i.p. Ten minutes later CCK8 (0.2 to 200 nmole/kg in 0.2 mL of 0.9% saline) or saline was injected into the tail vein. Two minutes later the animals were sacrificed and blood was collected into 1.5 mL heparinized polypropylene tubes. The tubes were centrifuged at 10,000 x g for 2 minutes. Insulin levels were determined in the supernatant (plasma) by an RIA
method using kits from Radioassay Systems Laboratory (Carson, CA.) or Novo Biolabs (MA.).
Antagonism of ~ Mediated Behavioral Effect n Mice ~i~h Compounds of Formula I
Male Swiss CD-l mice (Charles River) (22-27 g) are provided ample food (Purina Lab Chow~ and water until the time of their injection with the test compounds.
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2~ 55 ICV injections were given by a free-hand method similar to that previously described ~aley and McCormick, ~L~ J- Pharmacol- Chemother. 1~, 12-15 1957). The animals were placed on a slightly elevated metal grid and restrained by the thumb and forefinger at the level of the shoulders, thus immobilizing their heads. Injections were made with a 30 gauge needle with a "stop" cor.sisting of a piece of tygon tubing to limit penetration of the needle to about 4.5 mm below the surface of the skin. The needle was inserted perpendicular to the skull at a midline point equidistant from the eye and an equal distance posterior from the level of the eyes such that the injection site and the two eyes form an equilateral triangle. The injection volume (5 ~L) was expelled smoothly over a period of approximately 1 second.
Immediately after the injections the mice were placed in their cages and allowed a 15 minute recovery period ~rior to the beginning of the behavioral observations.
For the behavioral observations, the mice were placed in clear plastic cages. Each cage measured 19 x 26 x 15 centimeters and contained a 60-tube polypropylene test tube rack (NALGENE #5970-0020) placed on end in the center of the cage to enhance exploratory activity. Observations were made every 30 seconds for a period of 30 minutes.
sehavior was compared between drug and CCK8 treated micei CCK8 treated mice; and mice treated with an equal volume of carrier (usually 0.9~ saline or 5% dimethylsulfoxide in water). Locomotion as reported here consisted of either floor locomotion or active climbing on the rack.
Differences among groups were analyzed by Newman-Kewels -. ':
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analysis and a probability level of p< 0.05 was accepted as significant. Each group tested consisted of 10 animals. The results of this test indicate that compounds of Formula I are antagonists of CCK in vivo. Minimally effective doses ~MED) are defined as that dose at which a statistically significant reversal of CCK-induced inactivity was observed when the test compound of formula I and CCK8 were coadministered.
Compound of Dose of 43 3 nmol 3 nmol The compounds of Formula I antagonize CCK which makes the compounds useful in the treatment and prevention of disease states in mammals ~especially humans) wherein CCX
or gastrin may be involved, for example, gastrointestinal disorders such as irritable bowel syndrome, ulcers, excess pancreatic or gastric secretion, hyperinsulinemia, acute pancreatitis, GI cancers ~especially cancers of the gall bladder and pancreas), motility disorders, pain ~potentiation of opiate analgesia), central nervous system disorders caused by CCK's interaction with dopamine such as neuroleptic disorders, tardive dyskinesia, Parkinson's disease, psychosis, including schizophrenia, or Gilles de la Tourette Syndrome; disorders of the appetite regulatory ' ' ' ,., .' , '', ' . ', ; " , . .
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systems, bulimia, Zollinger-Ellison syndrome, and central G cell hyperplasia, and the treatment of substance abuse.
The compounds of the present invention can be used in the form of salts derived from inorganic or organic acids.
These salts include but are not limited to the following:
acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptonate, glycerphosphate, hemisulfate, heptonate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproplonate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate Also, the basic nitrogen-containing groups can be quaternized with such agents as loweralkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates, long chain halides such as decyl, lauryl, myristyl, and stearyl chlorides, bromides and iodides, arylalkyl halides like benzyl and phenethyl bromides, and others. Water or oil-soluble or dispersible products are thereby obtained.
The pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of Formula I which contain a basic or acidic moiety Dy conventional methods. Generally, the salts are prepared by reacting the free base or acid with stoichiometric amounts or with an excess of the desired salt forming inorganic or organic - - .. : .
~: : ~: : - : - -: . -.. .. - . .. :.. .
: : -: .
:. : . .
:::: - : :. - ,. . .
:: . ... -:. :
WO9l/0072~ PCT/US90/03630 2~ 5S
acid or base in a suitable solvent or various combinations of solvents.
Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid and phosphoric acid and such organic acids such as oxalic acid, maleic acid, succinic acid and citric acid. Other salts include salts with alkali metals or alkaline earth metals, such as -sodium, potassium, calcium, or magnesium or with organic ~ases.
The pharmaceutically acceptable salts of the acid of Formula I are also readily prepared by conventional procedures such as treating an acid of Formula I with an appropriate amount of base, such as an alkali or alkaline earth metal hydroxide e.g. sodium, potassium, lithium, calcium, or magnesium, or an organic base such as an amine, e.g., dibenzylethylenediamine, cyclohexylamine, dicyclohexylamine, triethylamine, piperidine, pyrrolidine, benzylamine, and the like, or a quaterary ammonium hydroxide such as tetramethylammonium hydroxide and the like.
When a compound of Formula I is used as an antagonist of CCK or gastrin in a human subject, the total daily dose administered in single or divided doses may be in amounts, for example, from 0.001 to 1000 mg a day and more usually 1 to 1000 mg. Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose.
The amount of active ingredient thzt may be combined with the carrier materials to produce a single dosage form :.: . . .: ::
WO91/00725 PCT/US90~03630 Z~75~;
will vary depending upon the host treated, the particular treatment and the particular mode of administration.
It will be understood, however, that the specific -dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the severity of the particular disease undergoing therapy.
The compounds of the present invention may be administered orally, parenterally, by inhalation spray, rectally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired.
The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques.
Injectable preparations, for example, sterile injectable aqueous or oleagenous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butandiol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. ~or t~is purpose any bland fixed oil may be employed includinc synthetic mono-:: , .:. : : :- :.
, , . .
" ':
WO91100725 PCT/US~0/03630 -2(~?755 .
or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules.
In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents.
Tablets and pills can additionally be prepared with enteric coatings.
Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsion, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
The present agents can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-. ~ . . . . .
- ; . ,~. : ~
.
2~ J S S
lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposo~es can be used. The present compositions in liposome form can contain, in addition to the compounds of the present invention, stabilizers, preservatives, excipients, and the like. The preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic.
Methods to form liposomes are known in the art. See, for example, Prescott, Ed., ~ethods 1~ Cell Bioloay Vol.
XIV, Academic Press, New York, N. Y. 1976, p.33 et seq.
The foregoing is merely illustrative of the invention and is not intended to limit the invention to the disclosed compounds. Variations and changes which are obvious to one skilled in the art are intended to be within the scope and nature of the invention which are defined in the appended claims.
. .
.. . .
' ~
. .
The term "heterocyclicalkylcarbonyloxy" as used herein refers to RsgC~O)O- wherein R5g is a heterocyclicalkyl group.
The term "heterocyclicalkylene" as used herein refers to a heterocyclic group appended to an alkylene radical.
The term "heterocyclicalkoxy" as used herein refers to RsgO- wherein Rsg is a heterocyclicalkyl group.
The term "N-protecting group" or "N-protected" as used herein refers to those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undesirable reactions during synthetic procedures or to prevent the attack of exopeptidases on the compounds or to increase the solubility of the compounds and includes, but is not limited to, sulfonyl, acyl, acetyl, pivaloyl, t-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz), benzoyl or an a-aminoacyl residue, which may itself be N-protected similarly.
The term "hydroxyl protecting group" as used herein refers to a substituent which protects hydroxyl groups against undesirable reactions during synthetic procedures and includes, but is not limited to, substituted methyl ethers, for example methoxymethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzyl, and triphenylmethyl; terahydropyranyl ethers;
substituted ethyl ethers, for example, 2,2,2-trichloroethyl and t-butyl; silyl ethers, for example, trimethylsilyl, t-butyldimethylsilyl and -:
;
. .
2~?5~755 t-butyldiphenylsilyl; cyclic acetals and ketals, for example, methylene acetal, acetonide and benzylidene acetal; cyclic ortho esters, for example, methoxymethylene; cyclic carbonates; cyclic boronates; and esters, for example acetates or benzoates.
Exemplary compounds of the present invention include:
N-(3'-Quinolylcarbonyl)-R-Valine-di-n-pentylamide;
N-(2'-Indolylcarbonyl)-R-Valine-di-n-pentylamide;
N-(4',8'-Dihydroxy-2'-quinolylcarbonyl)-R-Valine-di-n-pentylamide;
N-(2'-Naphthoyl)-R-Valine-di-n-pentylamide;
N-~3'-Quinolylcarbonyl)-R-Norleucine-di-n-pentylamide;
N-(2'-Indolylcarbonyl)-R-Norleucine-di-n-pentylamide;
N-(3'-Quinolylcarbonyl-R-(O-benzyl)Serine-di-n-pentylamide;
N-(3'-Quinolylcarbonyl)-(2R,3S)-(O-benzyl)Threonine-di-n-pentylamide;
N-(3'-Quinolylcarbonyl)-(2R,3S)-Threonine-di-n-pentylamide;
N-(3'-Quinolylcarbonyl)-(2R,3S)-(O-acetyl)Threonine-di-n-pentylamide;
N-(3'-Quinolylcarbonyl)-(2R,3S)-(O-methyl)Threonine-di-n-pentylamide;
N-(3'-Quinolylcarbonyl)-3-(2'-thienyl)-R-Alanine-di-n-pentylamide;
N-(2l-Indolylcarbonyl)-R-Histidine-di-n-pentylamide;
N-(3'-Quinolylcarbonyl)-R-Histidine-di-n-pentylamide;
N -(3'-Quinolylcarbonyl)-N -(benzyloxycarbonyl)-R-Lysine-di-n-pen~ylamide;
:,,' '- , :. , .: ,: . : .
, , , - , : :
. . , , :.
29~ 55 N-~3'-Quinolylcarbonyl)-R-Phenylalanine-di-n-pentylamide;
Na-(3'-Quinolylcarbonyl)-N-(2'-chlorobenzyloxycarbonyl)-R-Lysine-di-n-pentylamide;
N-(3'-Quinolylcarbonyl)-R-(4'-hydroxyphenyl)glycine-di-n-pentylamide;
Na-(3'-Quinolylcarbonyl)-NE-(acetyl)-R-Lysine-di-n-pentylamide;
N-(2'-Indolylcarbonyl)-R-Tyrosine-di-n-pentylamide;
N-(3',4'-Dichlorobenzoyl)-R-Tyrosine-di-n-pentylamide;
N-(2'-Naphthoyl)-R-Tyrosine-di-n-pentylamide;
N-(3'-Quinolylcarbonyl)-R-Tyrosine-di-n-pentylamide;
Methyl N-(3'-Quinolylcarbonyl)-R-Tyrosyl-S-phenylglycinate;
N-(2'-Indolylcarbonyl)-R,S-Homoserine-di-n-pentylamidei N-~3'-Quinolylcarbonyl)-R,S-Homoserine-di-n-pentylamide;
N-(2'-Indolylcarbonyl)-R-MethioninesulfGxide-di-n-pentylamide;
N-(3'-Quinolylcarbonyl)-R-Methionine-di-n-pentylamide;
N-(3'-Quinolylcarbonyl)-R-Methioninesulfoxide-di-n-pentylamide;
- Na-(3'-Quinolylcarbonyl)-N~-phenylthiolcarbonyl-R-Lysine-di-n-pentylamide;
N-(3'-Quinolylcarbonyl)-R-Tyrosine-di-n-pentylamide hydrochloride;
N-~3'-Quinolylcarbonyl)-R-Histidine-di-n-pentylamide dihydrochloride;
N-(2'-Indolylcarbonyl)-glycine-di-n-pentylamide;
N-(3'-Quinolylcarbonyl)glycine-di-n-pentylamide;
N-(3'Quinolylcarbonyl)-R-phenylglycine-di-n-pentylamide;
' ~
-, ,- , ~' -i WO91/00725 PCT/US9OtO3630 ., 21~
N-(4',8'-Dihydroxy-2'-quinolylcarbonyl)-R-Phenylglycine-di-n-pentylamide;
N-~5'-Fluoroindolylcarbonyl)-R-phenylglycine-di-n-pentylamide;
N-(4',8'-Dihydroxy-2'-quinolylcarbonyl)glycine-di-n-pentylamide;
N-(2'-Naphthoyl)glycine-di-n-pentylamide;
N-(3'-Methylphenylaminocarbonyl)glycine-di-n-pentylamide;
N-(4',8'-Dihydroxy-2'-quinolylcarbonyl)-R-(4'-hydroxyphenyl)-glycine-di-n-pentylamide;
N-(q',8'-Dihydroxy-2'-quinolylcarbonyl)-(2R,3S)-(O-benzyl)-Threonine-di-n-pentylamide;
Methyl N-(3'-Quinolylcarbonyl)-R-Methionine-S-(p-hydroxy)-phenylglycinate;
N-(3'-Quinolylcarbonyl)-R-Serine-di-n-pentylamide;
N-~8'-Hydroxy-2-quinolylcarbonyl)-glycine-di-n-pentylamide;
N-Methyl-N-~3'Quinolylcarbonyl)-glycine-di-n-pentylamide;
N-(3'-Iodo-2'-indolylcarbonyl)-glycine-di-n-pentylamide; and N-(2'-Indolylcarbonyl)-R-Alanine-di-n-pentylamide.
The compounds of the invention may be made as shown in the following scheme(s). The compounds of the invention having one asymmetric center can exist as separate enantiomers or as mixtures or enantiomers. The compounds of the invention which contain two or more asymmetric carbon atoms can exist as pure diastereomers, mixtures of distereomers, dias~ereomeric racemates or mixtures of diastereomeric racemates. The present ., ~ , , . ~ - ~ . - . .. . .. . ..
: : :. - . . : . .. ... .
.:
..
- ... . . :
WO9l/00725 PCT/US90~03630 2(~
.`:` . ~`.
invention includes within its scope all of the isomeric forms A number of synthetic pathways exist for the production of a-amino acids and their derivatives. The invention is not limited to those methods discussed here -for the synthesis of a-amino acids but is meant to include those variations and methods encompassed by ~he prior art as discussed in the chemical literature in its entirety.
a-Amino acids ~refer to Scheme 1) can be produced directly by the displacement of a-halogenated esters (1, x is halo) and the like or other a-situated leaving sroups by ammonia and or other substituted amines (Rg is hydrogen, loweralkyl, carboxyester-substituted alkyl) and/or their analogs ~e.g., carbamates, hydrazines, azides) (e.g., Marvel nL~ ~YUL;h ~Q, 81, 1940; 106, 1940; ~1, 60, 1941;
79, l9ql; Birnbaum, ~ h8m, 333, 1953). The amino group is then unmasked, for example by reduction, and the ester group (amide, etc.) is saponified to the acid in a standard fashion.
A second method involves the condensation of an a-ketoester (amide, etc) with an amine or amine equivalent (e.g., hydroxylamine, hydrazine, carbamate, etc.) and the subsequent reduction of this product (2) to the a-aminoester (amide, acid, etc. (e.g., Can ~ Chem, 29, 427, 1951; J Ora hem, 38, 822, 1973; J Q~ ~h~m, ~, 878, 1941~). Alternatively, an organometalic reagent can be added to the oxime 2 ~imine, etc.) to provide as final products either monosubstituted a-amino acids in the case where D is hydrogen, or disubstituted amino acids in the .
, : .
Z~755 case where D is other than hydrogen (e.g., Tetrahedron L~S~ 2), 4973, 1987).
A third method is the alkylation of a carbanion resulting from compound (3) with an electrophilic nitrogen source ~eg. diethylazodicarboxylate). The intermediate product can subsequently be unmasked to provide the desired a-amino acid. A similar method involves alkylation of the carbanion derived from compound (4) with an appropriate alkylating agent. This method also allows for the possibility of disubstitution of the a center.
A fifth route involves the Strecker reaction and its modifications. Reaction of cyanide and ammonium on aldehydes and ketones (S) provides the amino acid.
A last method involves the direct reduction of unsaturated heterocyclic carboxylic acids (6) to directly provide the cyclic amino acids (7), (wherein D and R9 are encompassed in a ring).
With suitably available a - amino acids (8) (Scheme 2) the amino group is protected with an N protecting group (most frequently Boc or Cbz) and, if the carboxylic acid has not been unmasked, it is saponified with base to provide the parent carboxylic acid (9). The N-protected intermediate is then coupled with the amine HNR1R2 using any of a number of standard coupling techniques (carbodiimide, BOPCl, chloroformates, oxalylchloride, etc.). Preferred secondary amines are of the type where R
and R2 are alkyl, arylalkyl, aryl, or represent another amino acid. The resulting product (10) is then N-deprotected using HCl or trifluoroacetic acid to remove a Boc group and hydrogenolysis or HBr to remove a Cbz group.
.. .
: ~ ' ' , , . ~ , . . '' , . .
WO91/00~25 PCT/US90/03630 2 ~ 5 5 The resultant amine ~11) is then coupled with aromatic carboxylic acids, aromatic acid halides, heteroaromatic carboxylic acids, aromatic isocyanates, aromatic sulfonic acids, aromatic sulfonyl chlorides, and the like using standard coupling techniques to provide the desired products ~12), (13), (14), and (15). Preferred acyl coupling partners groups include: quinoline carboxylic acids, indole carboxylic acids, substituted benzoic acids and benzoyl chlorides, arylisocyanates and arylisothiocyanates, naphthoic acids, benzothiofuranyl carboxylic acids and the like.
WO 9l/00725 PCI`/USgO/03630 21?~755 Scheme 1 O H2~R9 1 D I D
o H2/cDtDlyst (Rlo=H) H O
R g _ N~l~ o ~ R r R ~ ~ o R
D 2 Rlo~ R10 D
0 1. bDse IH O
~O R R ~N ~I~O ~R
D 3 2. ":~H2 ' D
1. bDse/DX ,H O
`1/~ ~o.R , R ~N~I~ R
2. H D
o Strecker l O
RgJ~D Rlo D
C~ U, ... : ' .
~ . . ~ . . ..
WO gl/00~25 PCI'/US90/03630 Z~755 : i . . .
, ,. . . .. ~
Scheme 2 ~N3~ `H D~o Rg Rg 0 9 coupling agent D R10 R1 D R10 ~R1 R2 deprotect P N~ R2 \\ \
~rCOz~ I \ \ArSO3H/coupllng agent or \ ArS02CI
coupllng¦ \ \ArNCO
agent ~
0~ N ~ N `R \ Ar r3~ R2 Rg O O D R10 ,R1 14 12 ~N~N.R D R10 , Ar Rg O NH ~N~ 'R2 1~ Alr R g O
.. ~ . . . . ,, , . -. , , ~ . .
. . .
.
2~ S5 Intermediates for the preparation of the compounds of formula I include compounds of the formula:
D R1o P~- N
Rg O
whereln G is (l) NH2 or ~2) substituted amino;
Rg is ~l) hydrogen, ~2) loweralkyl, ~3) carboxy-substituted alkyl or ~4) carboxyester-substituted alkyl;
Rlo is (l) hydrogen, (2) loweralkyl, (3) functionalized alkyl or (4) cycloalkyl;
D is (l) hydrogen, (2) loweralkyl, (3) functionalized alkyl, (4) cycloalkyl, (5) aryl, (6) functionalized oxyalkyl or ~ 7) heterocyclic;
or Rlo t~ken together with D is ~l) C4 to C6 alkylene, , :;: . '' : '~
ZC?5-77~55 . `. .: `
(2) - (CH2) q~V~ (CH2) r~ wherein q is 1 to 3, r is 1 to 3 and V is (i) --o--, ( i i ) --S--, (iii) -CH2- or ~iv) -N(R25)- wherein R2s is hydrogen, loweralkyl, haloalkyl, alkoxyalkyl, arylalkyl, aryl or an N-protecting group;
or Rg taken together with D is (1) C3 to C5 alkylene or (2) -(CH2)p-V-(CH2)t- wherein p is 1 to 3, t is 1 to 3 and V is defined as above; and P1 is hydrogen or an N-protecting group.
Other intermediates for the preparation of compounds of the formula I include compounds of ~he formula:
~ B ~ Z
wherein Z is (1) --C (O)--, (2) -C(S)- or (3) -S(0)2-;
B is (1) absent, (2) alkylene, (3) alkenylene, (4) substituted alkenylene, ~5~ -R2Ç-R27- wherein R2ç is absent, or -C~2- and R27 is -O-, -S-, -NH- or -N(lo~-eralkyl)- or ', . .- !' . .
., ` . . . .
' ' . '".,. '' ' ', ' , WO9l/0072~ PCT/US90/03630 ,~
2~ ? ~ S 5 ~6) -R27-CH2- wherein R27 is defined as above;
Ar is (1) aryl or ~2) a heterocyclic group; and Z' is an activating group; or B-Z-Z' taken together represent -N=C=O, -N=C=S, -CH2-N=C=O or -CH2-N=C=S.
Activating groups are those functional groups which activate a carboxylic acid or sulfonic acid group toward coupling with an amine to form an amide or sulfonamide bond. Activating groups Z' include, but are not limited to, -OH, -SH, alkoxy, thioalkoxy, halogen, formic and acetic acid derived anhydrides, anhydrides derived from alkoxycarbonyl halides such as isobutyloxycarbonylchloride and the like, N-hydroxysuccinimide derived esters, N-hydroxyphthalimide derived esters, N-hydroxybenzotriazole derived esters, N-hydroxy-5-norbornene-2,3-dicarboxamide derived esters, 4-nitrophenol derived esters, 2,4,5-trichlorophenol derived esters and the like.
The following examples will serve to further illustrate preparation of the novel compounds of this invention.
Example 1 N-(t-Butvlo~ycarbonyl)-R-Valine-di-n-pentylamide N-t-Butyloxycarbonyl-R-Valine (2.5 g, ll.S mmol) was stirred at 0 C in 30 mL of methylene chloride ~CH2Cl2) with bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOPC1, 3.5 g, 13.8 mmol) and 1.5 mL (11.5 mmol) of triethylamine (TEA). To this reaction mixture was added dl-n-pentylamine (11.6 mL, 58 mmol). The mi:cture was stirred overnight and allowed to warm to room temperature.
. . . .
~'' ` . .
WO9l/00725 PCT/US90/03630 2~ 55 r An additional equivalent of BOPCl was added after 18 hrs and the reaction mixture was stirred an additional day at ambient temperature. The solvents were evaporated in vacuo and the residue taken up in ethylacetate ~EtOAc) and washed with water, 1 N hydrochloric acid (HCl) solution, saturated sodium bicarbonate solution (NaHCO3), water.
The organic solution was dried over magnesium sulfate (MgSO4). After filtration and concentration of the filtrate in vacuo, the residue was chromatographed using ethyl acetate-hexane as the solvent system in the ratio (1:4). The product was isolated as an oil 79% yield (3.25 g). ~a]D= +21.2 (c=1.5, MeOH). MS~CI) m/e 357(m+H) .
1H NMR(CDCl3,300MHz) ~ 0.85-1.0(m,12H), 1.32(m,8H), 1.4-1 5(m,4H), 1.5(s,9H), 1.84(m,lH), 3.05(m,lH), 3.2(m,lH), 3.35(m,lH), 3.55(m,lH), 4.42(m,lH), 5.25(d,J-7Hz,lH).
R-Valine-di-n-pentylamide hydrochloride The product of example 1 (0.2 g, 0.6 mmol) was dissolved in 4 N HCl in dioxane (10 mL) and stirred under inert atmosphere (N2) for an hour. When the reaction was complete by tlc the solvents were evaporated in vacuo and hexane and diethylether were added. The residue was triturated with these two solvents and the solvents again evaporated in vacuo. This procedure was repeated several times until product was obtained as a glass in quantitative yield. MS(CI) m/e 293(m+H) .
-- . ~: . , : :
.: .,, , ., :: ~,- ~ : . . .
WO 91/00725 PCI`/US90/03~30 .. ;: .
z~ 755 Example 3 N-(3'-Ouinolylcarbonyl)-R-Valine-di-n-~entvlamide The hydrochloride of example 2 (150 mg, 0.5 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI, 100 mg), HOst (135 mg) and quinoline-3-carboxylic acid (88 mg) were stirred at 0C under nitrogen in 5 mL of anhydrous CH2C12. To this mixture was added 120 IlL of N-methylmorpholine (NMM) and the mixture was stirred overnight (warming to ambient temperature). The reaction mixture was poured into ethyl acetate and water and the organic extract was washed successively with water, 10g~
citric acid solution, and saturated aqueous NaHCO3. The solution was dried over MgSO4, filtered and concentrated.
The residue was chromatographed using ethylacetate ~EtOAc) and hexane as the elutant mixture to provide 110 mg of an oil (54~ yield) after removal of the volatiles. [a]D= -14.8 ~cz0.5, MeOH). MS(CI) m/e 412(m+H) . lH
NMR(CDC13,300MHz) ~ O.92(m,6H), 1.05(m,6H), 1.35 (m,8H), 1.5-1.7(m,4H), 2.15(m,lH), 3.05(m,lH), 3.3-3.4(m,lH), 3.5(m,lH), 3.65(m,lH), 5.08(dd,J=3, 9Hz,lH), 7.25(d,J=9Hz,lH), 7.62 (t,J=7Hz,lH), 7.8(t,J=7Hz,lH), 7.91(d,J=lOHz,lH), 8.16(d,J=lOHz,lH), 8.6(d,J=3Hz,lH), 9.35(d,J=3Hz,lH). Analysis calculated for C25H37N3O2: C
72.95, H 9.06, N 10.21; found: C 72.61, H 9.21, N 9.97.
Example 4 N-(2'-Indolylcarbonyl)-~ aline-~ -pentylamide The hydrochloride of example 2 ~130 mg, 0.45 mmol), EDCI (90 mg), HOBt (120 mg) and indole-2-carboxylic ac d , - . :
W09lt00725 PCT/US90tO3630 2~ SS
~,,.. ...:,...
(75 mg) were stirred at 0C under nitrogen in 5 mL of anhydrous CH2Cl2. To this mixture was added 100 ~L of NMM
and the mixture was stirred overnight (warming to ambient temperature). The reaction mixture was poured into ethylacetate and water and the organic extract was washed successively with water, 10% citric acid solution, and saturated aqueous NaHCO3. The solution was dried over MgSO4, filtered and concentrated. The residue was chromatographed using ethylacetate and hexane as the elutant mixture to provide 36 mg of product (75% yield) after evaporation of the volatiles. mp= 132-4C. [a~D= -9.2 (c=0.5, MeOH). MS(CI) m/e 400(m+H) . lH
NMR~CDCl3,300MHz) ~ 0.9(t,J=7Hz,6H), 1.0(m,6H), 1.2-1.4(m,8H), 1.5-1.6(m,4H), 2.12(m,lH), 3.05(m,lH), 3 3(m,lH), 3.42(m,lH), 3.63(m,lH), 5 0(q,J=3,6Hz,lH), 7.0(m,1H), 7.1(d,J=9Hz,lH), 7.25~t,J=7.5Hz,lH), 7.3(t,J-7.5Hz,lH), 7.41(d,J=7Hz,lH), 7.65(d,J=7Hz,lH), 9.3(bs,1H). C,H,N analysis calculated for C2qH37N3O2 C
72.14, H 9.34, N 10.52; found: C 72.52, H 9.25, N 10.49.
Example ~
N-(2'-Ouinolylcarbonvl)-R-Valine-di-n-pentylamide The reaction was performed in a similar manner to that in example 3 utilizing 0.2 g of the hydrochloride salt of example 2, quinoline-2-carboxylic acid (0.12 g), EDCI (0.15 g), HOBt (0.1 g), and NMM (0.18 mL). The product was isolated in 80% yield (0.225 g). mp= 78-79C.
[a)Dc -13.1 (c=l.l, MeOH). MS(CI) m/e 412(m+H) . lH
NMR(CDC13,300MHz) ~ 0.9(m,6H), 1.05(m,6H), 1.2-1.4(m,8H), 1.55(m,4H), 2.22(m,lH), 3.08(m,lH), 3.4(m,2H), 3.64(m,lH), .
' W09l/00725 PCT~US90/~3630 21?~55 5.0~dd,J=3,7Hz,lH), 7.62~t,J=7Hz,lH), 7.78~t,J=7Hz,lH), 7.85~d,J=9Hz,lH), 8.15(d,J=9Hz,lH), 8.35(m,2H), 8.85(d,J=10Hz,lH). C,H,N analysis calculated for C25H37N3O2, H2O: C 72.17, H 8.96, N 10.10; found: C
72.36, H 8.93, N 10.03.
Example 6 N-~E-2'-Cyano-3'-~4''-hydro~yphenyl)prop-2'-enoyll-R-Valine-di-n-pentylamide The hydrochloride of example 2 (300 mg, 1.03 mmol)~
EDCI (200 mg), HOBt (280 mg) and a-cyano-q-hydroxycinnamic acid (195 mg) were stirred at 0C under nitrogen in 15 mL
of anhydrous CH2Cl2. To this mixture was added 250 ~L of NMM and the mixture was stirred overnight (warming to ambient temperature). The reaction mixture was poured into ethylacetate and water and the organic extract was washed successively with water, 10% citric acid solution, and saturated aqueous NaHCO3. The solution was dried over magnesium sulfate, filtered and concentrated. The residue was chromatographed using ethylacetate and hexane as the elutant mixture to provide 225 mg of an oily product (57 yield) after evaporation of the volatiles. [~]D= -9.8 (c=1.15, MeOH) MS(CI) m/e 428(m+H) . H
NMR(CDCl3,300MHz) ~ O.92(m,6H), 1.08(m,6H), 1.35(m,8H), 1.56-1.75(m,9H), 2.15(m,lH), 3.1(m,lH), 3.3-3.5(m,2H), 3.7(m,lH), 4.65(m,lH), 6.73(d,J=9Hz,lH), 6.85(d,J=9Hz,2H), 7.65(d,J=9Hz,2H), 7.72(s,1H), 9.28(s,1H). C,H,N analysis calculated for C25H37N3O3: C 70.22, H 8.72, N 9.83, found:
C 69.88, H 8.39, N 9.60.
- - . . - . - . - - - . - -: : , ~
W091t00725 PCT/US90/03630 Z~ SS
Example 7 N-(2'-Benzothiofuranylcarbonyl)-R-Valine-di-n-p~ntylamide The reaction was performed in a similar manner to that in example 3 utilizing 0.3 g of the hydrochloride salt of example 2, benzothiofuran-2-carboxylic acid (0.205 g), EDCI (0.22 g) HOBt (0.28 g), and NMM (0.22 mL). The oily product was isolated in 58% yield, 0.28 g [a]D= ~
5.85 (c=2.0, MeOH). MS(CI) m/e 417(m+H) , 158. H
NMR(CDCl3,300MHz) ~ 0.g-l.l(m,12H), 1.2-1.3(m,8H), 1.5-1.6(m,4H), 2.15(m,lH), 3.05(m,lH), 3.3(m,lH), 3.42(m,lH), 3.65(m,lH), 5.0(q,J=3,6Hz,lH), 7.00(d,J=9Hz,lH), 7.41(m,2H), 7.80(s,lH), 7.86(m,2H). C,H,N analysis calculated for C24H36N22S' 0-25 H2O
6.65; found: C 68.73, H 8.48, N 6.71.
~m~l~ 8 N- (4 ' . 8 ' -Dihydroxy-2'-quinolylcarbonyl)-~-Valine-di-n-pentylamide The hydrochloride salt of example 2 (0.95 g, 3.22 mmol) was stirred in 25 mL of CH2C12 with NMM (0.7 mL) under nitrogen at 0 C. EDCI (0.7 g) and HOBt (0.11 g) were added followed by the addition of 4,8-dihydroxyquinoline-2-carboxylic acid (0.66 g, 3.22 mmol).
The reaction mixture was stirred overnight (warming to ambient temperature). The solvents were evaporated in vacuo and the residue taken up in ethylacetate and washed successively with water, 0.1 N solution of HCl, water and brine. The organic solution was dried over MgSO4 and then filtered. Solvents were evaporated in vacuo and the crude product subjected to flash chromatography using , . -- ~:: , . , . : .
- ::
~`
. , , ' . ' ';
Zc`~-~'55 ethylacetate, hexane and methanol as the elutant mixture.
The product was crystallized from methanol-water to provide 0.82 g ~56%). mp= 233-235C. ~a]D = -15.6 (c=0.5, MeOH). MS(CI) m/e 444(m+H) . lH .
NMR(DMSOd6,300MHz) ~ 0.84(m,6H), 0.92(m,6H), 1.1-1.35(m,8H), 1.4-1.6(m,4H), 2.33(m,lH), 3.1-3.45(m,2H), 3.55(m,2H), 4.67(m,1H), 7.1(d,J=9Hz,lH), 7.42(t,J=7Hz,lH), 7.55(m,2H), 9.62(d,J=9Hz,lH), 10.3(s,lH), 11.75(s,lH).
C,H,N calculated for C25H37N3O4: C 67.69 H 8.41, N 9.47;
found: C 67.47 H 8.45, N 9.39.
Examp~e ~
N-(2l-Benzofuranvlcarbonvl)-R-Valine-di-n-~entvlamide The reaction was performed in a similar manner to that in example 8 utilizing 0.3 g of the hydrochloride salt of example 2, benzofuran-2-carboxylic acid (0.19 g), EDCI (0.22 g~, HOBt (0.28 g), and NMM (0.22 mL). Product was isolated in 56% yield (0.225 g). [a]D= -29.2 (c=l.l, MeOH). MS(CI) m/e 401(m+H) . H NMR(CDC13,300MHz) ~
0.9-1.0(m,6H), 1.05(m,6H), 1.25-1.4(m,8H), 1.5-1.68(m,4H), 2.15(m,lH), 3.1(m,lH), 3.28-3.5(m,2H), 3.62(m,lH), 5.0(dd,J=3,6Hz,lH), 7.28(t,J=8Hz,lH), 7.4(t,J=8Hz,2H), 7.45(s,lH), 7.52(d,J=9Hz,lH), 7.65(d,J=9Hz,lH). C,H,N
analysis calculated for C24H36N2O3: C 71.96, H 9.06, N
6.99; found: C 72.09, H 9.08, N 6.99.
: ~ . . :
W09t/00725 PCT/US90/03630 .
Z ~ ~ ? 7 5 5 ..
~xam~le lQ
~-r4'-Hydroxy-2'-phenyl-3'-quinolylcarbonyll-R-Valine- ~
~ '.
The reaction was performed in a similar manner to that in example 8 utilizing 0.2 g of the hydrochloride salt of example 2, 4-hydroxy-2-phenyl-quinoline-3-carboxylic acid (0.18 g), EDCI (0.16 g), HOBt (0.19 g), and NMM (0.16 mL). Product was isolated in 64% yield (0.22 g). mp= 154-155C. [a]D = -30.0 (c=0.4, MeOH).
MS(CI) m/e 504(m+H) . H NMR(DMSOd6~300MHz) 0.82(m,14H), 1.2(m,8H), 1.38(m,4H), 1.94(m,lH), 3.02tm,2H), 3.2~m,lH), 3.4(m,lH), 4.55(m,lH), 7.43(m,5H), 7.7(m,2H), 8 2 ~d,J=7Hz,lH), 12.02(s,lH). C,H,N analysis calculated for C31H41N3O3: , , found: C 73.73, H 8.18, N 8.34.
Example 11 ~-(4'-Hydroxy-7'-~-ifluoro-3'-quinolylcarbonyl~
Valine-di-n-pentvlamide The reaction was performed in a similar manner to that in example 8 utilizing 0.21 g of the hydrochloride salt of example 2, 4-hydroxy-7-trifluoro-quinoline-3-carboxylic acid (0.185 g), EDCI (0.15 g), HOBt (0.2 g), and NMM (0.16 mL). Product was isolated in 37~ yield, 0.16 g. mp= 194-195C. [a]D = -79.2 (c=0.5, MeOH).
MS~CI) m/e 497(m+H) . lH NMR(DMSOd6,300MHz) ~
0.88(m,12H), 1.35(m,8H), 1.45(m,2H), 1.6(m,2H), 2.05(m,lH) 3.0(m,2H), 3.25-3.4(m,2H), 3.48(m,lH), 4.85(dd,J-3,9Hz,lH), 7.8(d,J=7Hz,lH), 8.1(s,lH), 8.45(d,J=7Hz,lH), 8.9(s,1HJ, 10.2(d,J=7Hz,lH), 12.9(bs,1H) . . .:, ~ : . .
:-: . . : . - . : .
. , .; :
.
Z ~ ~ ? 7 5 5 C,H,N analysis calculated for C26H26F3N3O3, 0.2 H2O: C
62.56, H 7.35, N 8.41; found: C 62.57, H 7.17, N 8.38.
Example 1~-(7'-Chloro-4'-~ydroxy-3'-auinolylcarbonyl~-R-Valine-di-n-pentylamide The reaction was performed in a similar manner to that in example 8 utilizinq 5.0 g of the hydrochloride salt of example 2, 4-hydroxy-7-chloro-quinoline-3-carboxylic acid (3.8 g), EDCI (3.5 g), HOBt (4.6 g), and NMM (3.8 mL) and 10 mL DMF. Product was isolated in 54%
yield, 4.25 g. mp= 205-206 C. ~a]D = -93.8 (c=0.5, MeOH). MS~CI) m/e 463~m+H) . H NMR~DMSOd6,300MHz) 0.95(m,6H), 1.15(d,J=8Hz,3H), 1.26(d,J-8Hz,3H), 1.38(m,8H), 1 65(m,2H), 1.8(m,lH), 2.0(m,lH), 2.23(m,lH), 3.15(m,lH), 3.35(m,lH), 3.48(m,lH), 3.72(m,lH), 4.6(t,J=6Hz,lH), 7.2(dd,J=3,9Hz,lH), 7.6(d,J=9Hz,lH) 7.68(d,J=2Hz,lH), 8.26(d,J=7Hz,lH), 10.25(d,J=6Hz,lH), 12.25(d,J=9Hz,lH). C,H,N analysis calculated for C25H36ClN3O3: C 64.98, H 7.85, N 9.09, Cl 7.67; found: C
65.16, H 8.04, N 8.94, Cl 7.91.
Example 13 N-(9'-Hydroxy-2'-quinolylcarbonyl)-~-Valine-di-n-pentylamide The reaction was performed in a similar manner to that in example 8 utilizing 0.2 g of the hydrochloride salt of example 2, 4-hydroxyquinoline-2-carboxylic acid ~0.13 g) EDCI (0.14 g), HOBt ~0.19 g), and NMM /0.15 mL).
Product was isolated in 71~ yield (0.207 g). mp= 70-, ..
' ~ " ' ' ' ' WO9l/00725 PCT/US90/03630 2~ 7S5 ~'.' '`.''':,;
71C [~]D = -13.3 (c=0.6, MeOH). MS(CI~ m/e 428(m+H) .
H NMR~DMSOd6,300MHz) ~ 0.85-l.l(m,12H), 1.2-1.4(m,8H), 1.5-1.7(m,4H~, 2.15(m,lH), 3.02(m,1H), 3.25(m,lH), 3.45(m,lH), 3.64(m,lH), 4.95(dd,J=3,6Hz,lH), 6.7(bs,lH), 7.35-7.5(m,2H), 7.6~(t,J=7Hz,2H), 8.35(d,J=8Hz,lH), 10.4(bs,1H). C,H,N analysis calculated for C25H37N3O3: C
70.22, H 8.72, N 9.83; found: C 69.91, H 8.71, N 9.68.
Example 1N-r5'-(N-Allylcarbamyl)pyridyl-3'-carbonyll-R-Valine-di-n-pentylamide The hydrochloride salt of example 2 (0.20 g, 0.69 mmol) was stirred in 15 mL of CH2C12 with NMM, (0.15 mL, 1.4 mmol) under nitrogen at 0C. EDCI (0.135 g, 0.69 mmol) and HOBt (0.19 g, 0.14 mmol) were added followed by the addition of 5-allylcarbamylnicotinic acid (0.142 g, 0.69 mmol). The reaction mixture was stirred overnight (warming to ambient temperature). The solvents were evaporated in vacuo and the residue taken up in ethylacetate and washed successively with water, saturated NaHCO3, a saturated solution of citric acid, water, and brine. The organic solution was dried over MgSO4 and then filtered. Solvents were evaporated in vacuo and the crude product subjected to flash chromatography using ethylacetate and hexane as the elutant mixture. The oily product was isolated in 56% yield (0.17 g). MS(CI) m/e 445 (m+H) . H NMR(CDC13,300MHz) ~ 0.85-l.l(m,12H), 1.2-1.4(m,8H), 1.5-1.6(m,4H), 2.1(m,lH), 3.05(m,lH), 3.3(m,lH), 3.48(m,lH), 3.65(m,lH), 4.15(m,2H), 5.0(dd,J=3,6Hz,lH), 5.25(m,2H), 5.95(m,lH), 6.95(m,lH), ' ,' ," . : ':, "~ ', "' ' : ' , ,' . ' ', ''. ., ' ' " , ~ . ' WOgl/0072~ PCT/US90/03630 .
~' . . ;'' Zc~ 5S
7.15~d,J=9Hz,lH), 8.98(s,1H), 9.15(s,2H). C,H,N analysis calculated for C25HgoN403 C 67.53, H 9.07, N 12.60;
found: C 67.27, H 8.97, N 12.53.
~
N-(l'-Ethyl-7'-methvl-4'-oxo-1',8'-na~hthyridinyl-3'-carbonyl)-R-Valine-di-n-pentvlam~de The hydrochloride salt of example 2 (0.2 g, 0.69 mmol) was stirred in 15 m~ of CH2Cl2 with NMM (0.15 mL, 1.4 mmol) under nitrogen at 0 C. EDCI (0.135 g, 0.69 mmol) and HOBt (0.190 g, 1.38 mmol) were added followed by the addition of nalidixic acid (0.160 g, 0.69 mmol). The reaction mixture was stirred overnight (warming to ambient temperature). The solvents were evaporated in vacuo and the residue was taken up in ethylacetate and washed successively with water, saturated NaHCO3, a saturated solution of citric acid, water and brine. The organic solution was dried over MgSO4 and then filtered.
Solvents were evaporated in vacuo and the crude product subjected to flash chromatography using ethylacetate and hexane as the elutant mixture. The purification provided 0.19 g (59%) of an oil. MS(CI) m/e 471(m+H) . lH
NMR(CDC13,300MHz) ~ 0.9(m,6H) 1.05(m,3H), 1.20-1.4(m,10H), 1.48-1.8(m,8H), 2.1(m,lH), 2.65(s,3H), 3.05(m,lH), 3.4(m,2H), 3.6(m,lH), 4.5(dd,J=3,9Hz,lH), 4.6(m,lH), 4.95(dd,J=3,6Hz,lH), 7.25(m,2H), 8.68(m,lH), 8.85(m,lH).
C,H,N analysis calculated for C27H42O3N4, 0.25 H2O: C
68.34, H 9.03, N 11.82; found: C 68.12, H 8.83, N 12.07.
~. . .
.
WO91/0072~ PCT/US90/03630 ~?~ 55``-~ ~ .
N-~Z-2'-Fluoro-3'-Dhenyl~ro~-2'-enoyll-R-Valine-di-n-~ntylamide The reaction was performed in a similar manner to that in example 3 utilizing 0.27 g of the hydrochloride salt of example 2, a-fluorocinnamic acid (0.16 g~, EDCI
~0.19 g), HOBt (0.25 g), and NMM (0.21 mL). The oily product was isolated in an 68% yield, 0.25 g [a] D= +7.1 (c=l.1, MeOH). MS(CI) m/e 405(m+H) . H
NMR(CDCl3,300MHz) ~ O.82-1.0(m,12H), 1.2-1.5(m,8H), 1.5-1.7(m,4H), 2.1(m,lH), 3.05(m,lH), 3.25(m,lH), 3.4(m,lH), 3.6(m,lH), 4.85(m,lH), 7.05~d,J=42Hz,lH), 7.1(d,J=laHz,lH), 7.3-7.45~m,3H), 7.62(d,J=9Hz,2H). C,H,N
analysis calculated for C24H37FO2N2: C 71.25, H 9.22, N
6.93; found: 70.99, H 9.14, N 6.95.
E~mRle 17 N-(2' Naphthoyl)-R-Valine-di-n-~entvlamide The reaction was performed in a similar manner to that in example 3 utilizing 0.2 g of the hydrochloride salt of example 2, 2-naphthoic acid (0.12 g), EDCI (0.13 g), HOBt (0.18 g), and NMM ~0.16 mL). The product was isolated as an oil in 72% yield, 0.2 g. [a]D= -13.0 ~c=1.0, MeOH). MS~CI) m/e 411(m+H) . H
NMR(CDCl3,300MHz) ~ 0.8-0.9(m,6H), l.l(m,6H), 1.2-1.4(m,8H), 1.55-1.67(m,4H), 2.13(m,lH), 3.0-3.1(m,lH), 3.25-3.3(m,lH), 3.5lm,lH), 3.65(m,lH), 5.08(dd,J=3,6Hz,lH), 7.11(d,J=9Hz,lH), 7.52(m,2H), 7.9(m,4H), 8.33(s,lH). C,H,N analysis calculated for ~::.. : . .- . . . , : . ~:
WO9l/00725 PCTtUS90/03630 C26H38N2O2: C 76.05, H 9.33, N 6.82; found: C 76.20, H
9.32, N 6.98.
~xample 1~
N-r3'-(3''-Pyridyl)prop-2'- noyll-R-Valine-di-n-pentyl~mide The reaction was performed in a similar manner to that in example 3 utilizing 0.3 g of the hydrochloride salt of example 2, 3-(3'-pyridyl)acrylic acid (0.17 g), EDCI (0.22 g), HOBt ~0.28 g), and NMM (0.22 mL). An oil was isolated in 76~ yield, 0-3 g [a~D = +10.0 (c=0.85, MeOH). MS(CI) m/e 388(m+H) . lH NMR(CDCl3,300MHz) 0.8-1.05(m,12H), 1.2-1.4(m,8H), 1.45-1.72(m,4H), 2.06(m,lH), 3.1(m,lH), 3.2-3.5(m,2H), 3.5-3.65(m,lH), 4.92(dd,J=2,6Hz,lH), 6.6(d,~z15Hz,lH), 7.28(d,J=9Hz,lH), 7.3(m,lH), 7.6(d,J=15Hz,lH), 7.8(d,J-9Hz,lH), 8.58(d,J=6Hz,lH), 8.74(d,J=2Hz,lH). C,H,N analysis calculated for C23H37N3O2, 0.75 H2O Ç
10.48; found: C 68.74, H 9.31, N 10.21.
Example 1~
N-(1',2'.(3'S) 4'-Tetrahvdrocarbolinyl-3'-carbonvl)-R-Valine-di-n-~entylamide The reaction was performed in a similar manner to that in example 3 utilizing 250 mg of the hydrochloride salt of example 2, N-L-1,2,3,4-tetrahydroharman-3-carboxylic acid ~270 mg), EDCI (160 mg), HOBt (235 mg), and NI~M (190 mL). The oily product was isolated in 38%
yield (148 mg). [a]D= -5.5 (c=0.2, MeOH). MS(CI) m/e 455(m+H) . H NMR(CDC13,300MHz) ~ 0.8-1.0(m,12H), 1.2-., .
. ~
~ ' ' ,~ ' ' - , WO91/~0725 PCT/US90/03630 ~ ~ 5 ? ~ 5 S
1.35~m,8H), 1.5(m,4H), 1.6(m,lH), 2.05(m,lH), 2.55-2.82(m,lH), 3.1-3.4(m,4H), 3.55(m,2H), 4.1(m,lH), 4.75(m,lH), 7.0-7.15(m,2H), 7.25(d,J=9Hz,lH), 7.45(d,J=9Hz,lH), 7.8(bs,1H), 7.85(bs,1H), 8.26(s,1H).
C,H,N analysis calculated for C27H42N4O2, 0.75 H2O: C
69.27, H 9.36, N 11.97; found: C 69.58, H 9.16, N 11.91.
Example 20 N-(l'-Hydroxy-2'-naphthoyl)-R-Valine-di-n-pentylamide The reaction was performed in a similar manner to that in example 3 utilizing 250 mg of the hydrochloride salt of example 2, 1-hydroxy-2-naphthoic acid (160 mg), EDCI (180 mg), ~OBt ~240 mg), and NMM ~200 ~L). Product was isolated in 85~ yield ~310 mg). mp= 85-86C. ta]D=
+90.5 ~c=0.6, MeOH). MS(CI) m/e 427(m~H) . H
NMR(CDCl3,300MHz) ~ O.9(m,6H), 1.05(m,6H), 1.25-1.4(m,8H), 1.5-1.7(m,4H), 2.15(m,lH), 3.05(m,lH), 3.25(m,lH), 3.5(m,lH), 3.65(m,lH), 5.06(dd,J=3,9Hz,lH), 7.2(d,J=9Hz,lH), 7.35~d,J=lOHz,lH), 7.45~d,J=lOHz,lH), 7.5(dd,J=3,6Hz,lH), 7.6(dd,J=3,6Hz,lH), 7.75(d,J=7Hz,lH), 8.4(d,J=9Hz,lH), 10.6(bs,lH). C,H,N analysis calculated for C26H38N2O3: C 73.20, H 8.98, N 6.57; found: C 73.24, H 9.02, N 6.55.
Example 21 ~ -(t-Butyloxycarbonyl)-R-Norleucine-di-n-pentylamide N-(t-Butyloxycarbonyl)-R-Norleucine (1.2 g, 5.2 mmol) was sti.red at 0 C in 40 mL of CH2Cl2 with BOPCl (1.5 g, 5.9 mmol?, and TEA (0.7 mL, 5.2 mmol). To this reaction mixture was added di-n-pentylamine (2.5 mL, 10.5 mmol).
.
WO ~l/00725 PCT/US90/03630 The mixture was stirred overnight and allowed to warm to room temperature. An additional equivalent of BOPCl was added after 18 hrs and the reaction stirred an additional day at ambient temperature. The solvents were evaporated in vacuo and the residue taken up in ethylacetate and washed with water, 1 N HCl, saturated NaHCO3 solution, water and then the organic solution was dried over MgSO4.
After filtra~ion and concentration of the filtrate in vacuo, the residue was chromatographed using ethylacetate-hexane as the solvent system in the ratio (1:4). The product was isolated as an oil in 75% yield (1.45 g).
MS(CI) m/e 371(m+H) , lH NMR(CDC13,300MHz) ~ 0.9-1 2~m,9H), 1.24-1 35~m,12H), 1.5~s,9H), 1.55-1.6~m,4H), 1.88~m,2H), 3.1~m,lH), 3.32~m,lH), 3.92~m,lH), 3.6~m,lH), 5.15(m,lH), 6.9~d,J=lOHz,lH).
ExampLe ~
R-Norleucine-di-n-pentylamide hydrochloride The product of example 21 (1.4g, 3.8 mmol) was dissolved in 4 N HCl in dioxane (25 mL) and stirred at room temperature for an hour. When the reaction was complete by tlc the solvents were evaporated in vacuo and hexane and diethylether were added. The residue was triturated with these solvents and the solid product was filtered away in quantitative yield. [a]D= -1.4 ~c=0.6, MeOH). MS(CI) m/e 271(m+H) . H NMR(DMSOd6,300MHz) 0.87(m,9H), 1.2-1.4(m,12H), 1.42-1.6(m,4H), 1.7(m,2H), 3.0(m,lH~, 3.1-3.3(m,2H), 3.53(m,lH), 4.14(bs,lH), 8.25(bs, 2r;, .
:
:, . . . . - , ~:
. " .. . ..
W09l/00725 PCTtUS90/03630 .:
2~ 55`
Example 23 N-(3'-Ouinolylcarbonyl~-R-Norleucine-di-n-pentylamide The hydrochloride of example 22 (240 mg, 0.87 mmol), EDCI (170 mg), HOBt (240 mg) and quinoline-3-carboxylic acid (150 mg) were stirred at 0C under nitrogen in 20 mL
anhydrous CH2C12. To this mixture was added 200 ~L of NMM
and the mixture was stirred overnight (warming to ambient temperature). The reaction mixture was poured into ethylacetate and water and the organic extract was washed successively with water, 10% citric acid solution, and saturated aqueous NaHCO3. The solution was dried over MgSO4, filtered and concentrated. The residue was purified by chromatography using ethylacetate and hexane as the elutant mixture to provide 200 mg of the glassy product (54% yield) after evaporation of the volatiles.
[a]Ds -10.5 (c=1.0, MeOH). MS(CI) m/e 426(m+H) . 1H
NMR(CDCl3,300MHz) ~ 0.9(m,9H), 1.35(m,12H), 1.55(m,2H), 1.65-1.80(m,4H), 3.10(m,lH), 3.25-3.35(m,lH), 3.4(m,lH), 3.55-3.6(m,lH), 5.15(m,lH), 7.4(d,J=9Hz,lH), -7.6(dd,J=3,7Hz,lH), 7.8(dd,J=3,7Hz,lH), 7.9(d,J=9Hz,lH), 8.15(d,J=9Hz,lH), 8.6(d,J=2Hz,lH), 9.35(d,J=3Hz,lH).
C,H,N analysis calculated for C26H39N3O2, 0.3 EtOAc: C
72.27, H 9.23, N 9.27; found: C 72.26, H 9.01, N 9.54.
Example 24 N-(2'-Indolylcarbonyl)-R-Norleucine-di-n-pentylamide The hydrochloride salt of example 22 (0.30 g, 1.0 mmol) was stirred in 10 mL of CH2C12 with NMM (0.2 mL, 2.0 mmol) under nitrogen at 0 C. EDCI (0.2 g, 1.1 mmol) and HOBt (0.27 g, 2.0 mmol) were added followed by the .. . . , .. . ( ,, - . . - .
.
:. , -: : . : . --;: :. -' .: :
5~
addition of indole-2-carboxylic acid (0.162 g, 1.0 mmol).
The reaction mixture was stirred overnight (warming to ambient temperature). The solvents were evaporated in vacuo and the residue taken up in ethylacetate and washed successively with water, saturated NaHCO3, a saturated solution of citric acid, water and brine. The organic solution was dried over MgSO4 and then filtered. Solvents were evaporated in vacuo and the crude product subjected to flash chromatography using ethylacetate and hexane as the elutant mixture. The product was crystallized from ethylacetate and hexane to provide a glass 0.285 g (69~).
[a]D= -10.6 (c=0.8, MeOH). MS(CI) m/e 414(m+H) . lH
NMR(CDC13,300MHz) ~ 0.9(m,9H), 1.2-1.4(m,10H), 1.5-1.7~m,6H), 1.86(m~2H), 3.15(m,1H), 3.3-3.4(m,2H), 3.58(m,lH), 5.1(m,lH), 7.0(d,J=2Hz,lH), 7.15(dd,J=3,7Hz,lH), 7.3(m,2H), 7.4(d,J=9Hz,lH), 7.67(d,J=9Hz,lH), 9.4(s,1H). C,H,N analysis calculated for C25H39N3O2, 0.75 H2O: C 70.30, H 9.55, N 9.84; found:
C 70.38, H 9.20, N 9.85.
Example 25 N-(t-Butyloxycarbonyll-R-(O-benzvl)Serine-di-n-pentylamide N-(t-Buiyloxycarbonyl)-R-(O-benzyl)serine (3.0 g, 10.15 mmol) was stirred at 0C in 50 mL of CH2C12 with BOPCl (2.8 g, 11 mmol) and 2.0 mL (1.5 mmol) of TEA. To this reaction mixture was added di-n-pentylamine (7 mL, 35 mmol). The mixture was stirred overnight and allowed to warm to room temperature. An additional equivalent of BOPCl was added after 18 hrs and the reaction stirred an , - :
.. .
' , 55 ~ . ..
additional day at ambient temperature. The solvents were evaporated in vacuo and the residue taken up in ethylacetate and washed with water, 1 N HCl solution, saturated NaHCO3, water and then the organic solution was dried over MgSO4. After filtration and concentration of the filtrate in vacuo, the residue was purified by chromatography using ethylacetate-hexane as the elutant system in the ratio (1:9). The product was isolated as an oil in 44% yield (1.9 g). MS(CI) m/e 435(m+H) . H
NMR(CDCl3,300MHz) ~ 0.89(m,6H), 1.28(m,8H), 1.4(s,9H), 1.55(m,4H), 3.05-3.2(m,2H), 3.4-3.65(m,4H), 4.5(m,2H), 4.85(m,lH), 5.35(d,J=7Hz,lH), 7.31(m,5H).
~L~ ~ '.
R-(O-Ben ~ drochloride The product of example 25 (0.43 g, 1.0 mmol) was dissolved in 4 N HCl in dioxane (10 mL) and stirred under inert atmosphere (N2) for a~ hour. When the reaction was complete by tlc the solvents were evaporated in vacuo and hexane and diethylether were added. The residue was triturated with these two solvents and the solvents again removed in vacuo. This procedure was repeated several times until the product was obtained as a glassy solid in 93% yield (0 35 g). [a]D= +1.6 (c=0.5, MeOH). MS(CI) m/e 335(m+H) .
::
-. . , ~(~ ? ~ 5 5 ~mL1~ 27 N-(3'~Ouinolylcarbonyl-R-(O-benzyl)Serine-di-~-pentylamide The hydrochloride salt of example 26 (0.35 g, 0.95 mmol) was stirred in 25 mL of CH2C12 with NMM, (0.22 mL, 2 mmol) under N2 at 0C. EDCI (0.19 g, 1.0 mmol) and HOBt (0.27, 2 mmol) were added followed by the addition of quinoline-3-carboxylic acid (0.165 g, 0.95 mmol). The reaction mixture was stirred overnight (warming to ambient temperature). The solvents were evaporated in vacuo and the residue taken up in ethylacetate and washed successively with water, saturated NaHCO3, a saturated solution of citric acid, water and brine. The organic solution was dried over MgSO4 and then filtered. Solvents were evaporated in vacuo and the crude product subjected to flash chromatography using ethylacetate and hexane as the elutant mixture. The product was crystallized from ethylacetate and hexane to provide a semisolid, 0.44 g (94%). [a]D= -4.0 (c=0.45, MeOH). MS(CI) mte 490~m+H) . H NMR~CDC13,300MHz) ~ 0.9(m,6H), 1.2-1.4~m,8H), 1.5-1.6~m,4H), 3.05-3.28~m,2H), 3.5-3.7~m,2H), 3.8(m,2H), 4.57(m,2H), 5.4(m,lH), 7.3(m,5H), 7.4(d,J=9Hz,lH), 7.62(dd,J=2,7Hz,lH), 7.81(dd,J=2,7Hz,lH), 7.9(d,J=8Hz,lHj, 8.15(d,J=9Hz,lH), 8.58(d,J=3Hz,lH), 9.3(d,J=3Hz,lH). C,H,N analysis calculated for C30H39N3O3, 0.75 H2O: C 71.61, H 8.11, N 8.35; found: C
71.73, H 8.01, N 8.21.
.
.: .
2 ~ ~ ? ~ 5 5; ;
Exam~le 28 N-(t-Butyloxycarbonyl)-R-Phenvlalanine-di-n-pentylamide The reaction was performed in a similar manner to that in example 2 utilizing N-(t-Butyloxycarbonyl)-R-Phenylalanine (0.8 g, 3.1 mmol), BOPCl (1.2, 4.06 mmol), dipentylamine (3.1 mL, 15 mmol), and TEA (0.4 mL, 3.1 mmol). The oily product was isolated in 65.5% yield (0.87 g). [a]D= +7.0 (c=1.0, MeOH). MS(CI) m/e 405(m+H) .
H NMR(CDC13,300MHz) ~ 0.85(m,6H), 1.15-1.45(m,8H), 1.5(s,9H), 1.55-1.6(m,4H), 2.9-3.1(m,5H), 3.5(m,lH), 4.25(m,lH), 5.3~d,J=9Hz,lH), 7.25~m,SH).
Exam~le 22 N-(t-Butyloxycarbonyl)-(2R 3S)-(O-benzyl)Threonine-di-n-Dentylamide The reaction was performed in a similar manner to that in example 1 utilizing N-~t-Butyloxycarbonyl)-D-(O-benzyl)- threonine ~5 g, 16.2 mmol), BOPCl ~8.2 g, 16.2 mmol), dipentylamine (16 mL, 78.5 mmol), and TEA (2.1 mL, 16.2 mmol). The product was isolated in 58% yield (4.15 g). MS(CI) 449(m+H) . H NMR(CDCl3,300MHz) ~
0.85(t,J=6Hz,6H), 1.18(d,J=6Hz,3H), 1.2-1.35(m,8H), 1.45(s,9H), 1.5-1.6(m,4H), 3.0-3.18(m,2H), 3.41-3.63(m,2H), 3.75~m,lH), 4.57(dd,J=12,18Hz,2H), 4.65(m,lH), 5.5(d,J=9Hz,lH), 7.30(m,SH).
.. . ..... ... . ~. , . ': .. :. ' : .
. .- , ....
WO91/00725 PCT/US9OtO3~30 r~_, ,'755 Example 30 (2R 3S~-(O-Benzyl)Threonine-di-n-~entylamide hydrochloride The product of example 29 (1 g, 2.22 mmol) was deprotected and isolated in a similar manner to that in example 2. The product was isolated as an oil. [a] D =
+13.3 (c=l.l, MeOH). MS(CI) m/e 359(m+H) . H
NMR(DMSOd6,300MHz) ~ 0.86(m,6H), 1.08-1.32(m,11H), 1.48(m,4H), 3.03(m,2H), 3.42~m,2H), 3.88(m,lH), g.2(d,J-6Hz,lH), 4.56(m,2H), 7.35(m,5H), 8.35(bs,2H).
~ ~ .
N-~3'-Ouinolvlcarbonyl)-(2R.3S)-lO-ben~yl)Threonine-di-n-pentylamide The hydrochloride salt of example 30 (0.25 g, 0.65 mmol) was stirred in 15 mL of CH2C12 with NMM (0.175 mL, 1.3 mmol) under nitrogen at 0C. EDCI (0.15 g, 0.8 mmol) and HOBt (0.18 g, 1.3 mmol) were added followed by the addition of quinoline-3-carboxylic acid (0.115 g, 0.65 mmol). The reaction mixture was stirred overnight (warming to ambient temperature). The solvents were evaporated in vacuo and the residue taken up in ethylacetate and washed successively with water, saturated NaHC03, a saturated solution of citric acid, water and brine. The organic solution was dried over MgS04 and then filtered. Solvents were evaporated in vacuo and the crude product subjected to flash chromatography using ethylacetate and hexane as the elutant mixture. The oily product was isolated in 62% yield (0.2g). [a~D= -4.1 - . - , . , :
.
: , . ~ . , WO9l/~0725 PCT/US90tO363~
, . .
2~ 55 .- ,, lc-1.0, MeOH). MS(CI) m/e 504(m+H) . H
NMR(CDCl3,300MHz) ~ 0.9(m,6H), 1.2-1.45~m,11H), 1.5-1.7~m,4H), 3.0-3.25~m,2H), 3.56-3.7~m,2H), 3.9~m,lH), 4.5~m,2H), 5.3~apparent q,J=4.5Hz,lH), 7.2-7.3~m,5H), 7.56~d,J=6Hz,lH), 7.65~t,J=7Hz,lH), 7.8~t,J=7Hz,lH), 7.92~d,J=9Hz,lH) 8.15~d,J=9Hz,lH), 8.63~d,J=2Hz,lH), 9.35~d,J=3Hz,lH). C,H,N analysis calculated for C31H41N3O3, 1.6 H2O: C 69.92, H 7.89, N 8.37; found: C
69.81, H 7.78, N 8.08.
E~m~l~ 32 N-(3'-Ouinolvlcarbonyl)-(2R 3S)-Threonine-di-n-pentylam;de The product of example 31 (1 g, 2 mmol) was stirred in 20 mL of CH2C12 and 7 mL of borontristrifluoroacetate ~1.0 M solution in trifluoroacetic acid) was added at 0C.
The mixture was stirred approximately 1 hour The tlc revealed some starting material therefore ano~her 5 mL of borontristrifluoroacetate and 5 mL trifluoroacetic acid were added. The reaction proceeded overnight to completion by tlc analysis. The reaction mixture was diluted with MeOH and then concentrated in vacuo. The residue was purified by chromatography using ethylacetate and hexane as the elutant mixture. The pure fractions were pooled together and the desired product characterized as the di-trifluoroacetic acid salt. mp= 84-6 C. [~]D= -11.6 ~c=0.55, MeOH). MS~CI) m/e 414~m+H) . 1H
NMR~CDC13,300MHz) ~ 0.85~m,6H), 1.13~d,J=7Hz,3H), 1.15-1.38~m,8H), 1.48~m,2H), 1.6~m,2H), 3.1~m,1H), 3.32-3.53(m,4H), 4.05~m,1H), 4.9~t,J=6Hz,lH), 7.7~t,J=6Hz,lH), ! . . , , ~
' , ~, , ` ' ' ` : ' ' ' :
WO91/0072~ PCT/US90/03630 ~5 ~75~5 7 88~t,J-7Hz,lH), 8.1~d,J=9Hz,lH), 8.8~d,J=9Hz,lH), 8.93~bs,lH), 9.31~bs,lH), 10.02~bs,lH). C,H,N analysis calculated for C24H35N33~ 2 CF3C2 6.55; found: C 52.31, H 5.62, N 6.66.
Example ~
N-(3'-Ouinolylcarbonyl)-(2R 3S)-(O-acet-~l)Threonine-di-n-pentylamide Pyridine ~20 ~L) and acetic anhydride ~60 ~L) were added to the product of example 32 ~51 mg, 0.125 mmol) which was dissolved in acetonitrile ~2 mL). The reaction mixture w~s stirred overnight at room temperature.
Ethylacetate was added and this solution was washed ~uccessively with water and brine. The organic solution was dried over MgSO4. After filtration and concentration of the filtrate in vacuo, the residue was purified by chromatography using ethylacetate and hexane as the elutant system in the ratio ~9:1). The product was isolated as a glass in 44% yield (25 mg). MS~CI) m/e 456(m+H) . H NMR~CDC13,300MHz) ~ 0.9~m,6H), 1.25-1.45~m,11H), 1.52~m,2H), 1.7~m,2H), 2.05~s,3H), 3.1(m,2H), 3.3-3.6 (m,3H), 5.28(m,lH), 5.44(m,lH), 7.35~d,J=9Hz,lH), 7.65~t,J=7Hz,lH), 7.82~t,J=7Hz,lH), 7.95~d,J=7Hz,lH), 8.18~d,J=9Hz,lH), 8.6~d,J=3Hz,lH), 9.35~d,J=3Hz,lH).
C,H,N analysis calculated for C26H37N3O4, 0.4 H2O: C
67.48, H 8.23, N 9.08; found: C 67.69, H 8.20, N 8.60.
.. . , . . - . : .~
: .- ~ . : ., - .
. : '', . . .
WO91/00725 PCT/US90/0363~
. .
2a~?~ss~ ~;;, ~--' ~xamDle N-(3'-Ouinolvlcarbonyl)-~2R.3S)-~O-methyl)Threonine-di-n-pentylamide Lithium bis(trimethylsilyl)amide in THF ~0.15 mL of 1.0 M solution in THF) was added to a cooled ~-10C) solution of the product of example 32 ~55 mg, 0.14 mmol) in 2 mL tetrahydrofuran (THF) and then methyl iodide ~0.015 mL) was added. The reaction mixture was stirred approximately 1 hour and slowly wa-med to room temperature. Tlc revealed some starting material therefore another equivalent of methyl iodide t0.01 mL) was added. The reaction then proceeded to completion by tlc. The reaction mixture was concentrated in vacuo.
Ethylacetate was added to the residue, which was then washed with water and brine. The ethylacetate extract was dried over MgSO4. Filtration and concentration of the filtra~e in vacuo, provided a residue which was purified by chromatography using ethylacetate and hexane as the elutant mixture. An oil was isolated in 47% yield (28 mg).
MS(CI) m/e 428(m+H) . H NMR(CDCl3,~00MHz) ~ 0.92(m,6H), 1.25(d,J=6Hz,3H), 1.25-1.4(m,8H)j 1.55-1.6(m,4H), 3.05(m,lH), 3.2-3.3(m,2H), 3.35(s,3H), 3.58-3.82(m,2H), 5.25(m,lH), 7.45(d,J=9Hz,lH), 7.65(t,J=6Hz,lH), 7.8(t,J=6Hz,lH), 7.9(d,J=9Hz,lH), 8.18~d,J=9Hz,lH), 8.6(d,J=3Hz,lH), 9.35(d,J=3Hz,lH).
. :., ' ~ : .
; : -WO9l/00725 PCT/US90/0363 ~, :
2~ 5~
N-(t-Butyloxycarbonyl)-3-(2'-thienyl)-R-Alanine-di-n-~ ,.
N-~t-Butyloxycarbonyl)-R-3-~2'-thienyl)-Alanine ~0.78 g, 3.25 mmol) was stirred at 0C in 25 mL of CH2Cl2 with BOPCl ~0.44 g, 3.25 mmol) and 0.5 mL, (3.25 mmol) of TEA.
To this reaction mixture was added di-n-pentylamine ~2 mL, 10 mmol). The mixture was stirred overnight and allowed to warm to room temperature. An additional equivalent of BOPCl was added after 18 hrs and the reactions stirred an additional day at ambient temperature. The solvents were evaporated in vacuo and the residue taken up in ethylacetate and washed with water, 1 N HCl solution, saturated NaHCO3 solution, water and then the organic soluti~n was drièd over magnesium sulfate. After filtration and concentration of the filtrate in vacuo, the residue was purified by chromatography using ethylacetate-hexane as the solvent system in the ratio (1:4). The product was isolated as an oil in 57~ yield ~0.76 g).
[a~D= -2.27 (c=0.66, MeOH). MS(CI) m/e 411(m+H) , 355, 311. lH NMR(CDCl3,300MHz) ~ 0.85(m,6H), 1.15-1.38(m,10H), 1.45(s,9H), 1.51(m,2H), 3.1(m,4H), 3.22(m,lH), 3.4(m,lH), 4.75(apparent q,J=lOHz,lH), 5.45(d,J=9Hz,lH), 6.83(d,J=6Hz,lH), 6.9(t,J=4Hz,lH), 7.15(d,J=6Hz,lH).
- : .
: - ~
. ~ ',, - .:
..
.
WO 91~00725 PCT/US90/0363 :' 2~755 -, .,~
~xample R-3-(2'-Thienyl)-Alanine-di-n-pentylamide hydrochlorid~
The product of example 35 (0.22 g, 0.59 mmol) was deprotected and isolated in the same manner as that in example 2 in quantitative yield. MS(CI) m/e 327~M+H) .
Example 37 N-(3'-Ouinolylcarbonyl)-3-(2'-thienyl)-R-Alanine-di-n-pentylamide The reaction was performed in a similar manner to that in example 3 utilizing ~80 mg, 0.23 mmol) of the hydrochloride salt of example 36, quinoline-3-carboxylic acid ~40 mg), EDCI ~50 mg), HOBt (62 mg), and NMM (51 ~L).
An oil was isolated in 45% yield, ~48 mg). MS~CI) m/e 466~m+H) . H NMR~CDC13,300MHz) ~ 0.9~m,6H), 1.2-1.4(m,8H), 1.45-1.65~m,4H), 3.05-3.4(m,4X), 3.45-3.6~m,2H), 5.35~dd,J=6,7Hz,lH), 6.87~d,J=3Hz,lH), 6.99~m,lH), 7.18~d,J=6Hz,lH), 7.4~d,J=9Hz,lH), 7.63~dd,J=3,7Hz,lH), 7.8(dd,J=3,7Hz,lH), 7.9(d,J=8Hz,lH), 8.15(d,J=8Hz,lH), 8.6~d,J=3Hz,lH), 9.32~d,J=3Hz,lH).
C,H,N analysis calculated for C27H35N3O2S, 0.9 H2O: C
67.29, H 7.70, N 8.72; found: C 67.60, H 7.47, N 8.98.
E~ample 38 N-(t-Butyloxycarbonyl)-S-Valir.~-di-n-pentylamide The reaction and product isolation were performed in a similar manner to that in example 1 utilizing N-~t-Butyloxycarbonyl)- S-Valine (2.5 g, 11.5 mmol), BOPCl (3.5 g, 13.8 mmol) and dipentylamine (11.6 mL, 58 mmol), and ' -WO91/0072~ PCT/US90/~3630 ~': '' ` ' ,' , ;~?~755 TEA (1.6 mL, 12 mmol). The oily product was isolated in 55% yield (2.25 g). [a]D= -21.1 (c=1.0, MeOH). MS(CI) m/e 357~m+H) . H NMR(CDC13,300MHz) ~ O.9(m,6H), 1.05(m,6H), 1.25-1.35(m,8H), 1.95(s,9H), 1.5-1.55(m,4H), 1.95(m,lH), 3.0(m,lH), 3.2(m,lH), 3.36(m,lH), 3.6(m,lH), 4.4(dt,J=3,7Hz,lH), 5.24(d,J=9Hz,lH).
Example 39 S-Valine-di-n-pentylamide hydrochloride The product of example 38 (0.2 g, 0.57 mmol) was deprotected and the product isolated as in example 2 in quantitative yield. MS(CI) m/e 257(m+H) .
~xample ~Q
N-(3'-Ouinolylcarbonyl)-S-Valine-di-n-pent~lamide The reaction sequence was performed in a similar manner to that in example 3 utilizing 175 mg of the hydrochloride salt of example 39, quinoline-3-carboxylic acid (110 mg), EDCI (125 mg), HO~t (165 mg), and NMM (75 ~L). The glassy product was isolated in 80% yield, (198 mg)- [a]D= +12.95 (c=0.8, MeOH). MS(CI) m/e 412(m+H) .
H NMR(CDCl3,300MHz) ~ 0.8-1.05(m,12H), 1.2-1.44(m,8H), 1.55(m,4H), 2.15(m,lH), 3.1(m,lH), 3.3(m,lH), 3.5(m,lH), 3.65(m,1H), 5.1(dd,J=3,6Hz,lH), 7.25(d,J=7Hz,lH), 7.62(t,J=7Hz,lH), 7.8(t,J=7Hz,lH), 7.9(d,J=8Hz,lH), 8.15(d,J=9Hz,lH), 8.61(d,J=3Hz,lH), 9.35(d,J=3Hz,lH).
C,H,N analysis calculated for C25H37N3O2, 0.25 H2O: C
72.16, H 9.09, N 10.10; found: C 72.41, H 9.21, N 9.97.
, : , , : -. . .. .: , WO91/00725 PCT/US9OtO3630 2C?5~5S
.. ...
. ....
N-tt-Butyloxycarbonyl)-~im-tosyl)-R-Histidine-di-n-pentylamide N-(t-Butyloxycarbonyl)-R-(Nim-tosyl)-histidine, (4.95 g, 12.6 mmol) was stirred at 0C in 50 mL of CH2C12 with BOPCl (3.2 g, 12.6 mmol) and 1.65 mL (12.6 mmol) TEA. To this reaction mixture was added di-n-pentylamine (7.7 mL, 38 rnmol). The mixture was stirred overnight and allowed to warm to room temperature. An additional equivalent of BOPCl was added after 18 hrs and the reaction stirred an additional day at ambient temperature. The solvents were evaporated in vacuo and the residue was taken up in ethylacetate and washed with water, 1 N HCl solution, saturation NaHC03, water. The organic solution was dried over MgS04. After filtration and concentration of the filtrate in vacuo, the residue was purified by chromatography using ethylacetate-hexane as the solvent system in the ratio (1:4). The product was isolated as an oil in 75% yield (5.1 g). [a]D= +8.8 (c=1.0, MeOH).
MS(CI) m/e 549(m+H) . H NMR(DMSOd6,300MHz) ~ 0.85(m,6H), 1.05-1.46(m,21H), 2.42(s,3H), 2.67(m,2H), 3.03-3.15(m,4H), 4.52(m,1H), 7.0(s,1H), 7.28(d,J=7Hz,lH), 7.49(d,J=7Hz,2H), 7.9(d,J=7Hz,2H), 8.28(s,lH). C,H,N analysis calculated for C28H44N405S: C 61.28, H 8.08, N 10.21; found: C 61.04, H 8.05, N 10.10.
~ '' ' .
.... . . .
WO91/0072~ PCT/US90/0363~
~' E~ample~ 42 (Nim-Tosyl)-R-Histidine-di-n-pentylamide To a solution of the product of example 41 (6.7 g, 12.21 mmol) in CH2C12 (100 mL) was added trifluoroacetic acid (TFA, 40-50 mL). The reaction mixture was stirred at room temperature 60 minutes. When reaction was complete by tlc, the solvents were evaporated several times in vacuo and CH2C12 was added with a saturated solution of NaHCO3. The reaction mixture was stirred vigorously another 1 hr and after separation of layers, the organic layer was washed several times with water and brine. The - -CH2C12 layers and washings were dried over magnesium sulfate. The product was then concentrated in vacuo. The semisolid product was isolated and dried in a vacuum oven over P2O5 at room temperature, 5.1 g (93% yield).
[a]D= -9.4 (c=1.0, MeOH). MS~CI) m/e 449(m+H) , 264, 295. lH NMR(CDCl3,300MHz) ~ O.85(m,6H), 1.1-1.35(m,8H), 1.47-1.6(m,4H), 2.45(s,3H), 2.9-3.2(m,6H), 3.4-3.55(m,2H), 4.5(m,lH), 7.18(s,lH), 7.35(d,J=8Hz,2H), 7.82(d,J=8Hz,2H), 7.95(s,lH).
Example 43 N-(2l-Indolylcarbonyl)-R-~istidine-di-n-pentylamide The compound of example 42 (170 mg, 0.5 mmol), EDCI
(105 mg), HOBt (135 mg) and indole-2-carboxylic acid (85 mg) were stirred at 0 C under nitrogen in 10 mL of anhydrous CH2C12. To this mi:cture was added 110 ~L of NMM
and the mlxture was stirred overnight (warming to ambient temperature). The reaction mixtu e was poured into ' .. : ' .'.. . . -- :- .. , , . ' :. , . ~: .. . . .. . . -: ~
:-, . - . : ,. :- . - : -- : .. : . . . .
WO 9l/00725 PCTtUS90/03630 ethylacetate and water and the organic extract was washed successively with water, 10% citric acid solution, and saturated aqueous NaHCO3. The soiution was dried over MgSO4, filtered and concentrated. The residue was purified by chromatography using chloroform/methanol/
ammonia as the elutant mixture to provide 98 mg of the semisolid product (45% yield) after evaporation of the ~olatiles. [a]D= +9.8 (c=0.46, MeOH). MS(CI) m/e 438(m+H) , 253, 281. H NMR(CDCl3,300MHz) ~ O.75-0.95(m,6H), 1.2(m,8H), 1.5(m,4H), 3.13(m,4H), 3.3(m,lH), 3.4(m,lH), 3.5(m,2H), S.32(m,lH), 6.8(s,lH), 6.9(s,lH), 7.1(t,J=7Hz,2H), 7.2(t,J=7Hz,2H), 7.35(d,J=9Hz,lH), 7.59(d~J=9Hz,lH)~ 9.8(s,lH). C,H,N analysis calculated for C25H35N5O2, 0.5 H2O: C 67.23, H 8.13, N 15.68; found:
C 67.24 H 8.06, N 15.24.
~am~le 44 -(t-Butyloxycar~on~ N -(benzyloxycarbonyl)-R-Lysine-di-n-pentylamide The reaction was performed in a similar manner to that in example 1 utilizing N -t-Butyloxycarbonyl-R-(N -benzyloxycarbonyl)Lysine (S g, 13.1S mmol), BOPCl (6.7 g, 26.3 mmol), di-n-pentylamine (26 mL, 131 mmol) and TEA
(1.8 mL, 13.S mmol) in CH2Cl2 (25 mL). The oily product was isolated in 64.5% yield (4.4 g). [a]~= +65.3 (c=0.15, MeOH). MS(CI) m/e 520(m+H) . H
NMR(CDCl3,300MHz) ~ 0.9(m,6H), 1.2-1.35(m,12H), 1.41(s,9H), l.S-1.66(m,4H), 3.05-3.25(m,9H), 3.3(m,2H), 3.5(m,2H), 9.53(m,lH), 4.9~m,lH), 5.1(s,2H), 5.38(d,J=9Hz,lH), 7.3(m,SH).
:: . , . -: : - --: "
::
z~755 ~ample q5 N-(t-Butyloxycarbonyl)-3-(1'-naphthvl)~R-~lanine-di-n-pentylamine N-(t-Butyloxycarbonyl)-3-~1'-naphthyl)-R-Alanine (0.35 g, 1.1 mmol) was stirred at 0C in 25 mL of CH2C12 with BOPCl, (0.3 g, 1.2 mmol), and 0.15 mL of TEA (1.2 mmol). To this reaction mixture was added di-n-pentylamine (0.8 mL, 4 mmol). The mixture was stirred overnight and allowed to warm to room temperature. An additional equivalent of BOPC1 was added after 18 hrs and the reaction stirred an additional day at ambient temperature. The solvents were evaporated in vacuo and the residue taken up in ethylacetate and washed with water, 1 N HC1 solution, saturated NaHCO3, water and then the organic solution was dried over MgSO4. After filtration and concentration of the filtrate in vacuo, the residue was purified by chromatography using ethylacetate-hexane as the solvent system in the ratio (1:4). The product was isolated as an oil in 65% yield (0.25 g).
MS(CI) m/e 455(m+H) . H NMR(CDC13,300MHz) ~ 0.7-0.8(m,6H), 0.9(m,8H), 1.2-1.3(s,4H), 1.35(s,9H), 3.0(m,2H), 3.35(m,2H), 3.5-3.6(m,2H), 4.3(m,lH), 7.4(m,lH), 7.45-7.55(m,2H), 7.6(m,lH), 7.8 (d,J-9Hz,lH), 7.85(d,J=9Hz,lH), 8.35(d,J=9Hz,lH), 8.9(bs,lH).
Ex~mple 46 3-(l~-Naphthy~ lanine-di-n-pent~lamide hydrochloride The product of example 45 (0.32 g, 0.72 mmol) was dissolved in 4 N HCl in dioxane ~10 mL) and stirred under . .
. - : . : , , : ::: -: : .
W09l/00725 PCr/US90/03630 .
inert atmosphere (N2) for an hour. When the reaction was complete by tlc the solvents were evaporated in vacuo and hexane and diethylether added. The residue was triturated with these two solvents until the product was obtained as a glassy solid in quantitative yield.
MS(CI) m/e 391(m+H) . lH NMR(CDC13,300MHzl: ~ 0.63(m,3H), 0.85(m,3H), l.OS-1.45(m,10H), 1.5-1.72(m,2H), 2.62(m,lH), 2.85(m,lH), 3.6-3.92(m,4H), 4.85(m,lH), 9.73(m,2H), 7.36(m,lH), 7.5(m,lH), 7.7(d,J=6Hz,lH), 7.75(d,J=6Hz,lH), 8.35(d,Jz8Hz,lH), 8.92(bs,2H), 9.9(s,lH).
E~mple 47 N-~3'-Ouinolylcarbonyl)-3-(l'-Naphthyl)-R-Alanin~-di-n-pentylamide The hydrochloride of example 96 (200 mg, 0.52 mmol), EDCI, HO~t (70 mg) and quinoline-3-carboxylic acid (90 mg) were stirred at 0C under N2 in 5 mL of anhydrous CH2Cl2.
To this mixture was added lO~L of NMM and the mixture was stirred overnight (warming to ambient temperature). The reaction mixture was poured into ethylacetate and water and then the separated organic extract was washed successively with water, 10% citric acid solution, and saturated aqueous NaHC03. The solution was dried over MgS04, filtered and concentrated. The residue was purified by chromatography using ethylacetate and hexane as the elutant mixture to provide 180 mg of the oily product (68% yield) after removal of the volatiles.
MS(CI) m/e 510(m+H) , 280. lH NMR(CDC13,300MHz) ~
0.72(m,3H), O.9(m,3H), 1.1-1.45(m,10H), 1.5.1-6(m,2H), 2.38-2.6(m,2H), 2.85(m,lH), 3.47(m,2H), 3.9(m,lH), .. ~.... ...
.. : . , ,.. ;., - ' ~ ~ . . :
: .
Z~ ,, S5 5.6(m,lH), 7.35(d,J=6Hz,2H), 7.52(t,J=7Hz,2H), 7.6-7.7(m,3H), 7.72-7.93(m,3H), 8.15(d,J=9Hz,lH) 8.55(d,J=9Hz,lH), 8.6(d,J=3Hz,lH), 9.4(d,J=3Hz,lH).
ExamDle ~
N-(t-Butyloxycarbonyl)-3-~2'-naphthyl)-R-Alanine-di-n-pentylamide N-(t-Butyloxycarbonyl)-3-(2'-naphthyl)-R-Alanine (0.31 g, 1.0 mmol) was stirred at 0C in 25 mL of CH2Cl2 with BOPCl, (0.38 g, 1.5 mmol) and 0.2 mL of TEA (1.5 mmol). To this reaction mixture was added di-n-pentylamine (0.7 mL, 3.5 mmol). The mixture was stirred overnight and allowed to warm to room temperature. An additional equivalent of BOPCl was added after 18 hrs and the reaction stirred an additional day at ambient temperature. The solvents were evaporated in vacuo and the residue taken up in ethylacetate and washed with water, 1 N HCl solution, saturated NaHCO3, and water.
The organic solution was dried over MgSO9. After filtration and concentration of the filtrate in vacuo, the residue was purified by chromatography using ethylacetate-hexane as the solvent system in the r~tio (1:4). The product was isolated as an oil in 62% yield (0.28 g).
MS(CI) m/e 455(m+H) , 355.
Ex~-m-pl~ 49 3-(2'-Naphthvl~-R-Alanine-di-n-~entylamide h~drochloride The product of example 48 (0.28 g, 0.6 mmol) was dissolved in 4 N HCl in dioxane ~10 mL) and stirred under N2 for an hour. When the reaction was complete by tlc the ,,. , . ~ -~: ., .. - ....................... . .
,: . : : . ~ . . .
, .
2~ 5S
solvents were evaporated in vacuo and then hexane and diethylether were added. The residue was triturated with these two solvents until the product was obtained as a glassy solid in 93% yield. MS(CI) m/e 355(m+H) .
Example 50 N-(3'-Ouinolylcarbonyl)-R-Histidine-di-~-pentylamide The free base of example 42 ~3.7 g, 9.26 mmol), EDCI, (1.7 g, 9 mmol), HOBt (3.65 g) and 1.5 g quinoline-3-carboxylic acid were stirred at 0C in 50 mL of anhydrous ~imethylformamide (DMF) and CH2Cl2 in 1:1 ratio. After reaction was complete by tlc, solvents were evaporated under vacuum and the residue dissolved in large excess of ethylacetate (300 mL). Water was added and the organic extract was washed with 10% citric acid solution, and saturated NaHCO3. The solution was dried over MgSO4, filtered and concentrated. The residue was purified by chromatography using chloroform-methanol and ammonium hydroxide as the elutant mixture to provide 1.98 g (68.3~) product. [~]D= -6.9 (c=0.25, MeOH). MS(CI) m/e 450(m+H) , 156. H NMR(CDC13,300MHz) ~ 0.9(m,6H), 1.29(m,8H), 1.45-1.6(m,4H), 3.08-3.2(m,3H), 3.23-3.4(m,2H), 3.5-3.6(m,lH), 5.3(apparent q,J=9Hz,lH), 6.85(s,lH), 7.6(m,3H), 7.(t,J=6H,lH), 7.88(d,J=8Hz,lH), 7.97(d,J=8Hz,lH), 8.15(d,J=8Hz,lH), 8.6(d,J=3Hz,l~), 9.3(d,J=3Hz,lH). N-(3'-Quinolylcarbonyl)-(Nim-tosyl)-R-histidine-di-n-pentylamide ~0.2 g) also was isolated refer to example 51.
. . -: . - - .:
~, , ' , . ' .
' . ', . .
WO91~00725 PCT/US90/03630 ~
',~
i ~1?~ 55 Exam~le ~1 N-3'-Ouinolylcarbonyl-(Nlm-tosyl)-R-Histidine-di-n-pentylamide The title compound of example 51 was isolated as a side product in the procedure in example 50. la]D= +13.3 (c=1.05, MeOH). MS(CI) m/e 604~m+H) , 450. H
NMR(CDC13,300MHz) ~ 0.9~m,6H), 1.3(m,8H), 1.45-1.7(m,4H), 2.25~s,3H), 3.0-3.13(m,3H), 3.25(m,1H), 3.35(m,1H), 3.5(m,1H), 5.36(apparent q,J=6Hz,lH), 7.15(m,3H), 7.6(t,J=7Hz,2H), 7.7(d,J=9Hz,2H), 7.8-7.9(m,2H), 7.95(d,Jz2Hz,lH), 8.13(d,J=7Hz,lH), 8.45(d,J=3Hz" H), 9.18(d,J=3Hz,lH). C,H,N analysis calculated for C33H41N5O9S: C 65.64, H 6.85, N 11.60; found: C 65.58, H
6.84, N 11.50. ?
Example 52 ~_(Benzyloxycarbony~ -R-Lvsin~-di-n-oentylamide hydroc~1o~;~e The compound was prepared in similar manner to example 2 via deprotection of the product of example 44 using 4 N HCl in dioxane. The product was isolated in quantitative yield. MS(CI) m/e 420(m+H) .
~xample 53 Na-(3'-Ouinolylcarbonyl)-N -(benzyloxycarbonyl)-~-Lysine di-n-oentyl2mide The reaction was performed in the similar manner to that in example 3 utilizing 1.0 g of hydrochloride salt of example 52 quinoline-3-carboxylic acid (0.38 g), EDCI
(0.95 g), HOBT (0.6 g), and NMM (0.48 mL). The oily : ,:: ' -. .: -, , .. . . . . .
r -2(~ ~jr?~s5 , product was isolated in 72~ yield. [~D= +2.7 (c=0.7, MeOH). MS(CI) m/e 575(m+H) . lH NMR(C~Cl3,300MHz) 0.9(m,6H), 1.3-1.62(m,8H), 1.53(m,6H), 1.65(m,2H), 1.85(m,2H), 3.05-3.55(m,lH), 5.05(m,lH), 5.15(m,2H), 7.28(m,SH), 7.55(t,J=8Hz,lH), 7.8(m,3H), 8.18(d,J=9Hz,lH), 8.58~d,J=2Hz,lH), 9.32~d,J=2Hz,lH). C,H,N calculated for C34H96N4O4: C 71.05, H 8.07, N 9.75; found: C 71.00, H
8.18, N 9.68.
Ex~mRle 54 N-(3'-Ouinolylcarbonyl~-R-~ysine-di-n-pentylamide To a suspension of 0.5 g 10~ Pd/C in methanol ~MeOH, 25 mL) and cyclohexadiene (3 mL) under N2 was added a solution of the product of example 53 (0.51 g, 0.89 mmol) in methanol via cannula. The reaction mixture was stirred overnight at ambient temperature. Cyclohexadiene (2 mL) was added and the reaction was continued overnight. The mixture was filtered through celite and washed several times with methanol. The filtrate and washings were combined and concentrated in vacuo. The residue was subjected to flash chromatography using chloroform-methanol and ammonium hydroxide 90:10:1 as the elutant mixture. Lyophilization provided product in 64% yield (0.25 g). MS(CI) m/e 441(m+H) . H NMR(DMSOd6,300MHz) 0.85(m,6H), 1.15-1.35(m,8H), 1.4-1.65(m,4H), 1.7(m,2H), 1.75(m,2H), 2.7(m,2H), 3.1-3.5(m,8H), 4.9(m,lH), 7.7~t,J=6Hz,lH), 7.88(t,J=6Hz,lH), 8.1(d,J=8Hz,2H), 8.9(d,J=3Hz,lH), 9.0(d,J=3Hz,lH), 9.3(d,J=3Hz,lH). C,H,N
analysis calculated for C26H40N402, H2O: C 69.45, H 8.97, N 12.46; found: C 69.98, H 8.76, N 12.03.
: - ,, . :: . , ,: . ~' . ' ~ ' ' WO~1/00725 PCT/US90/03630 ~' 2~5~755 ExampleN-(t-Butyloxycarbonyl)-R-(4'-Hydroxy~henyl)~lycine-di-n-pentylamide The reaction was performed in a similar manner to that in example 1 utilizing N-~t-Butyloxycarbonyl)-R-4'-hydroxy phenylglycine (5 g, 18.7 mmol), BOPCl (5.1 g, 20 mmol), dipentylamine (8 mL, 37 mmol), and TEA (2.6 mL).
The product was isolated in 78% yield (5.9 g). MS(CI) m/e 407(m+H) . H NMR(CDC13,300MHz) ~ 0.85(m,6H), 1.1-1.35~m,8H), 1.3(s,9H), 1.45-1.58(m,9H), 3.0(m,lH~, 3.15(m,2H), 3.45~m,lH), 5.42~d,J=9Hz,lH), 6.02~d,J=9Hz,lH), 6.5~s,lH), 6.75~d,J=9Hz,2H), 7 18~d,J-gHz,2H).
FxampleN-(8'-~ydroxy-2'-~uino~lcz hony~ al;~-d;-n-pe~tylamide The title compound was prepared in a similar fashion to that in example 3. mp= 143-4 C. MS~CI) m/e 428~m+H) , 293, 158. lH NMR~CDC13,300MHz) ~ 8.58~d,J=lOHz,lH), 8.31(s,2H), 8.09(s,lH), 7.54(m,lH), 7.39(dd,J=1,8Hz,lH), 7.24(m,lH), 5.01(dd,J=7,10Hz,lH), 3.65(dt,J=7,16Hz,lH), 3.28-3.55(m,2H), 3.06(dt,J=7,14Hz,lH), 2.22(septet,J=7Hz,lH), 1.50-1.75(m,9H), 1.25-1.42(m,8H), 1.06(d,J=7Hz,3H), 1.03(d,J=7Hz,3H), 0.92(t,J=7Hz,3H), 0.89~t,J=7Hz,3H). C,H,N analysis calculated for C25H37N3O3, 0.1 H2O: C 69 93, H 8.73, N 9.79; found: C
69.78, H-8.51, N 9.61.
' ' ~ . ' ! : ~ , WO91/0072~ PCT~US90/03630 2~'5~5S
., ;, , E~a~le 57 R-Phenylalanine-di-n-pentylamide hydrochloride The compound was prepared in similar manner to example 2 via deprotection of N-t-Butyloxycarbonyl-R-Phenylalanine- di-n-pentylamide, the product of example 28, using 4 N HCl in dioxane. The product was isolated in quantitative yield. MS(CI) m/e 305(m+H) .
Example ~
N-(3'-Ouinolylcarbonyl)-R-Phenylalanine-di-n-pentylamide The hydrochloride of example 57 (870 mg, 2.46 mmol), EDCI (550 mg), HOBt ~300 mg), and quinoline-3-carboxylic acid (430 mg) were stirred at 0C under N2 in 25 mL of anhydrous CH2CL2. To this mixture was added 550 ~L of NMM
and the mixture was stirred overnight (warming to ambient temperature). The reaction mixture was poured into ethylacetate and water and the organic solution was separated. The organic extract was washed sùccessively with water, 10% citric acid solution, and saturated aqueous NaHCO3. The solution was dried over MgSO4, filtered and concentrated. The residue was purified by chromatography using ethylacetate and hexane as the elutant mixture to yield 870 mg of product (77%) after removal of the volatiles. [a]D= +12.9 (c=1.05, MeOH).
MS(CI) m/e 460~m+H) . lH NMR(CDC13,300MHz) ~ 0.9(m,6H), 1.15-1.4(m,8H), 1.5-1.55~m,4H), 2.9-3.12tm,3H), 3.2(m,2H), 3.48-3.6(m,lH), 5.35(m,lH), 7.27~m,5H), 7.48(d,J=10Hz,lH), 7.62(t,J=8Hz,lH), 7.8(t,J=8Hz,lH), 7.9(d,J=9Hz,lH), 8.15(d,J=9Hz,lH), 8.55(d,J=3Hz,lH), 9.38(d,J~3Hz,lH).
- .
~,:
.
~ .
SS
C,H,N analysis calculated for C29H37N3O2, 0.5 H2O: C
74.32, H 8.39, N 8.97; found: C 73.92, H 8.05, N 8.83.
~L~ ~
N-(2'-MethylDhenylaminocarbonyl)~R-Valine-di-n-~entylamide A solution of hydrochloride of example 2 (0.15 g, 0.52 mmol), 2-methyl-phenylisocyanate ~0.1 g) and triethylamine (0.1 mL) was allowed to react at ambient temperature. The solvent was removed in vacuo and the residue dissolved in ethylacetate. Water was added and the mixture extracted several times with EtOAc. The combined ethylasetate extracts were washed with brine and dried over MgS04. The volatiles were removed in vacuo and the residue purified by chromatography. The oily product was isolated in 80% yield. [a~D= +1.5 (c=0.4, MeOH).
MS(CI) m/e 390~m+H) . H NMR~CDCl3,300MHz) ~ 0.8-1.0(m,12H), 1.12-1.41(m,8H), 1.42-1.78~m,4H), 2.01~m,lH), 2.22~s,3H), 3.25~m,lH), 3.35~m,2H), 3.51(m,lH), 4.7~m,lH), 6.5~m,lH), 6.7~s,lH), 7.04~t,J=6Hz,lH), 7.16~m,2H), 7.53~d,J=9Hz,lH). C,H,N analysis calculated for C23H39N3O2: C 70.91, H 10.09, N 10.79; found: C 70.57, H
9.46, N 10.57.
Example 60 Na-(t-Butyloxycarbor.yl)-N (2'-chlorobenzyloxycarbonyl)-R-L~sine-di-n-pentylamide N -~t-Butyloxycarbonyl)-N -~2'-chlorobenzyloxyCarbonyl)-R-Lysine ~1.0 g, 2.4 mmol) was stirred at 0 C in 25 mL of CH2Cl2 with BOPCl, ~0.65 g, 2.6 ~ ., . . ,, , .. - - . , . . , : .
. . , ~ , , ,, . : , .~ : -,. , ,: . ~ .; , . - :
.
wo 9l/00725 PCrtVS90/03630 f:- ;
2~ 55 ~ . ! ', ' '. .
mmol), and TEA (0.35 mL, 2.4 mmol). To this reaction mixture was added di-n-pentylamine (2.5 mL, 12 mmol). The mixture was stirred overnight and allowed to warm to room temperature. An additional equivalent of BOPCl was added after 18 hrs and the reaction stirred an additional day at ambient temperature. The solvents were evaporated in vacuo and the residue taken up in ethylacetate and washed with water, 1 N HCl solutionj saturated NaHCO3, and water.
The organic solution was dried over MgSO4. After filtration and concentration of the filtrate in vacuo, the residue was purified by chromatography using ethylacetate-hexane as the solvent system in the ratio ~1:4). The product was isolated as an oil in 53~ yield ~0.7 g).
MS~CI) m/e 554~m+H) , 326. 1H NM~CDC13,300MHz) ~
0.g(m,6H), 1.2-1.38~m,12H), 1.42~s,9H), 1.5-1.7~m,4H), 3.02-3.45~m,4H), 3.48~m,4H), 4.5~m,lH), S.01~m,lH), 5.2~s,2H), 5.4~d,J=9Hz,lH), 7.25~m,2H), 7.3-7.45~m,2H).
Example 61 _(2'-Chlorobenzyloxycarbonyl)-R-Lysine-di-n-pentylamide hydrochloride The compound was prepared in similar manner to example 2 via deprotection of the product of example 60, using 4 N HCl in dioxane. The product was isolated in quantitative yield. MS(CI) m/e 454(m+H) , free base.
.. . .. . .
. . .
~ '55 -68-Exam~le ~2 ~ -(3'-Ouinalylcarbonyl~-N -(2'-chlorobenzyloxycarbonyl)-R-Lysine-di-n-pentylamide The hydrochloride salt of example 61 (0.5 g, 1.02 mmol) was stirred in 15 mL of CH2C12 with NMM (0.29 mL, 2.2 mmol) under N2 at 0C. EDCI (0.25 g, 1.3 mmol) and HOBt (0.3 g, 2.2 mmol) were added followed by the addition of quinoline-3-carboxylic acid (0.1 g, 1.1 mmol). The reaction mixture was stirred overnight and allowed to slowly warm to ambient temperature. The solvents were evaporated in vacuo and the residue taken up in ethylacetate and washed successively with water, saturated NaHCO~, a saturated solution of citric acid, water and brine. The organic solution was dried over MgSO4 and then filtered. Solvents were evaporated in vacuo and the crude product subjected to flash chromatography using ethylacetate and hexane as the elutant mixture. The product was isolated as an oil, 0.46 g (74~). MS(CI) m/e 609(m+H) . H NMR(CDCl3,300MHz) ~ 0.8-0.96(m,6H) 1.16-1.42(m,12H), 1.45-1.6(m,2H), 1.8-2.0(m,2H), 2.7(m,2H), 3.07-3.45(m,4H), 3.5-3.65(m,2H), 5.15(m,3H), 6.85(d,J=12Hz,lH), 7.2(d,J=9Hz,2H), 7.4(d,J=9Hz,2H), 7.6(m,2H), 7.8(t,J=7Hz,lH), 7.9(t,J=7Hz,lH), 8.15(d,J=9Hz,lH), 8.6(s,1H), 9.35(d,J=3:-.7,1H). C,H,N
analysis calculated for C34H45ClN404, 0.6 H2O: C 65.86, H
7.41, N 9.04; found: C 65.63, H 7.29, N 9.92.
... .... ~ . . , -. . .: . - , . . .
. . , ~, . . .
.~ . . .
WO 9l/00725 PCT/US90/03630 !
S~
~1m~l~ 63 N-(3'-Ouinolylcarbonyl)-3-(2'-Naph~hyl)-R-Alanine-di-n-dipentylamide The reaction was performed in a similar manner to that in example 3 utilizing 75 mg of hydrochloride salt of example 49, quinoline-3-carboxylic acid (34 mg), EDCI (q0 mg), HOBt (50 mg), and NMM (22 ~L). The oily product was isolated in 31% yield, (32 mg). MS(CI) m/e 510(m+H) .
lH NMR(CDC13,300MHz) ~ 0.85(m,6H), 1.06-1.35(m,12H), 2.85(m,lH), 3.0(m,2H), 3.35(m,2H), 3.55(m,lH), 5.45(apparent q,J=7Hz,lH), 7.32-7.5(m,4H), 7.62(t,J=6Hz,lH), 7.68-7.82(m,5H), 7.88(d,J=7Hz,lH), 8.15(d,J=7z,lH), 8.52~d,J=2Hz,lH).
E~ample 64 R-~4'-Hydroxyphenyl)-glycine-di-n-pe~ L~mide hydrochloride The compound was prepared in similar manner to example 2 via deprotection of the product of example 55, using 4 N HCl in dioxane. The oily product was isolated in 90% yield. []D= -87.0 (c=0.2, MeOH). MS(CI) m/e 307(m+H) H NMR(DMSOd6,300MHz) ~ 0.82(m,6H), 1.02-1.2(m,8H), 1.3-l.S(m,4H), 3.05-3.3(m,2H), 3.32-3.4(m,2H), 5.22(bs,lH), 6.83(d,J=9Hz,2H), 7.25(d,J=9Hz,2H), 8.4(bs,3H).
"' ' ;. .
-, . .
WO91/0072~ PCT/US90/03630 ~' Z~?si~755 Fxample 65 N-~3 -Ouinolylcarbonyl)-R-(4 -hydroxyphenyl~alycine-di-n-pentylamide The reaction was performed in a similar manner to that in example 3 utilizing (300 mg, 2.6 mmol) of hydrochloride salt of example 64, quinoline-3-carboxylic acid ~450 mg), EDCI (550 mg), HOBt (380 mg), and NMM (0.62 mL). Product was isolated in 53% yield (0.78 g). mp= 79-80 C. (a]D= -99.6 (c=1.0, MeOH). MS(CI) m/e 462(m+H) .
lH NMR(CDC13,300MHz) ~ 0.85(t,J=7Hz,6H), 1.1-1.3(m,10H), 1.4-1.5(m,2H), 3.1-3.2(m,2H), 3.25-3.5(m,2H), 5 9(d,J=9Hz,lH), 6.6(d,J=9Hz,2H), 7.25(d,J=9Hz,2H), 7 7(t,J=7Hz,lH), 7.85(t,J-7Hz,lH), 8.08(d,J=9Hz,2H), 3.9(d,J=3Hz,lH), 9.1(d,J=6Hz,lH), 9.25(d,J=3Hz,lH), 9.53(s,1H). C,H,N analysis calculated ~or C28H35N3O3: C
72.85, H 7.64, N 9.10; found: C 72.65, H 7.65, N 9.08.
Example 66 N -~3 -Ouinolylcarbonyl~-N -(acetyl)-R-~ysine-di-n-pentylamide The reaction was performed in a si~ilar manner to that in example 33 utilizing 60 mg of t:~e product of example 54 and pyridine with acetic anhydride. The oily product was purified by standard chroma=ography and isolated in 33% yield (22 mg). [a]D= -1.3 (c=0.5, MeOH).
MS(CI) m/e 483(m~H) . H NMR (CDC13,30~MHz) ~ 0.92(m,6H), 1.23-1.4(m,8H), 1.45-1.7(m,8H), 1.8~m,2:-), 1.98~s,3H), 3.1~m,lH), 3.25(m,2H), 3.32(m,lH), 3.6~.~,2H), 5.15(m,lH), 5.85(bs,lH), 7.5(d,J=8Hz,lH), 7.65(t,J=-.Hz,lH), .
~, .. . . . . . . . .
-, ., ~ . - : -' - ~
.
, .. .. .
WO9l/00725 PCT/US90/03630 z~'?7S5 7.82~t,J=6Hz,lH), 7.94~d,J=8Hz,lH), 8.18~d,J=8Hz,lH), 8.62~d,J=2Hz,lH), 9.36~d,2Hz,lH).
~
N-(5'-Hydroxyindolyl-2'-carbonyl)-R-Valine-di-n-pentylamide The 5-hydroxyindole-2-carboxylic acid ~95 mg), hydrochloride of example 2 (150 mg), NMM (0.12 mL), HOBt (70 mg), and EDCI (105 mg) reacted under similar conditions to those described in example 3. The product was isolated in 74~ yield. MS(CI) m/e 916(m+H) . 1H
NMR~CDCl3,300MHz) ~ 0.9~m,6H), 1.0(apparent q,J=7Hz,6H), 1.32~m,8H), 1.62(m,4H), 2.11(m,lH), 3.15(m,lH), 3.2(m,lH), 3.43~m,lH), 3.62~m,lH), 4.95~m, lH), 5 . 6 ~ s, lH), 6 . 78~m,lH), 6.88~dd,J=2,9Hz,lH), 6.98~d,J=9Hz,lH), 7.02~d,J=2Hz,lH), 7.25~d,J-9Hz,lH), 9.3~s,lH).
Example 68 N-(4'-Chlorobenzenesulfonyl)-~-Valine-di-n-pentylamide The hydrochloride of example 2 (60 mg, 0.22 mmol), NMM (25 ~L), was dissolved in 10 mL of CH2C12 and 4-chlorophenylsulfonyl chloride (46 mg) was added to this reaction mixture and stirred overnight (warming to ambient temperature). The solvent was evaporated in vacuo and ethylacetate and water both in large ~xcess were added to the residue. The organic extrac~s were successively washed with saturated aqueous NaHCO3, 0.1 HC1 solution and brine. The combined extracts were dried over MgSO9, .. ~ :.' ' ' ':, Zl?~75~
filtered and concentrated. The product was purified by chromatography using ethylacetate and hexane as elutants.
The pure product was isolated in 75% yield (59 mg). mp=
89-90 C. [~]D= -61.8 (c=0.5, MeOH). MS(CI) m/e 431(m+H) . H NMR(CDC13,300MHz): ~ 0.9(m,12H), 1.15(m,8H), 1.3~m,4H), 1.85(m,lH), 2.9(m,2H), 3.02(m,lH), 3.22(m,lH), 3.8(m,lH), 5.75(d,J=9Hz,lH), 7.43(m,2H), 7.75(m,2H). C,H,N analysis calculated for C21H35ClN2O3S:
C 58.52, H 8.18, N 6.50; found: C 58.56, H 8.22, N 6.48.
Exam~le 69 4-Chlorocinnamic acid N-hydroxysuccinimide ester To a solution of 4-chlorocinnamic acid (0.8g, 4.38 mmol) in CH2C12 was added N-hydroxysuccinimide (0.55 g, 4.8 mmol) and EDCI and the reaction mixture was stirred at ambient temperature overnight. The solvents were removed in vacuo and the residue dissolved in ethylacetate and water. Combined EtOAc extracts were dried over MgSO4 and the solution concentrated in vacuo. The residue was crystallized from a mixture of ethylace-ate and hexane.
The product was isolated in 72% yield (0.88g). mp= 192-193 C. MS(CI) m/e 297(m+NH4 ). H NMR(DMSOd6,300MHz) 2.87(s,4H), 7.05(d,J=17Hz,lH), 7.56(d,J=9Hz,2H), 7.92(d,J=9Hz,2H), 7.99(d,J=17Hz,lH).
~.,.. ,......... ~: :
. .
.~
. . ' ' .
~' , . ' ' WO 91/00725 PCT~US90/03630 . .
2(?~55.
. :., .
Exam~le 70 -(3'-Oui~lylcarbonyJIL-N-rE-3'-(4''-chlorophenyl)prop-2'-enoyll-R-Lysine-di-n-pentylamide To a solution of example 54 (60 mg, 0.14 mmol) in dimethylformamide (8 mL) cooled to 0C were added NMM (35 ~L) and the active ester of example 69 (40 mg,0.14 mmol).
The mixture was stirred overnight with warming to ambient temperature. The DMF was removed in vacuo and the residue was chromatographed on silica using ethylacetate-hexane as the elutant mixture. The oily product was isolated in 40%
yield (35 mg). MS(CI) m/e 605(m+H) . H NMR(CDCl3,300MHz) ~ 0.92(m,~H), 1.3(m,8H), 1.62(m,8H), 1.83(m,2H), 3.14~m,lH), 3.35(m,4H), 3.58(m,lH), 5.15(m,lH), 6.18~m,lH), 6.35(d,J-17Hz,lH), 7.25~m,6H), 7.48(d,~=17Hz,lH), 7.62(t,J=8Hz,lH), 7.83(t,J=8Hz,lH), 8.15(d,J=9Hz,lH), 8.62(d,J=2Hz,lH), 9.37(d,J=2Hz,lH).
Example 71 N-(t-Butyloxycarbonyl)-R-Tyrosine-di-n-pentylami~
N-t-Butyloxycarbonyl-R-Tyrosine (4.5 g, 15.4 mmol) was stirred with BOPCl (3.92 g, 15.4 mmol) and dipentylamine (7.9 mL, 39 mmol) in 100 mL of tetrahydrofuran (THF) at 4C and allowed to warm to room temperature overnight. After one day, additional BOPCl (800 mg) was added and, after two days, the volatiles were evaporated. The residue, dissolved in EtOAc, was extracted with 0.1 M citric acid solution, 0.1 M sodium carbonate (Na2CO3) solution, and water; then dried over magnesium sulfate (MgSO4), filtered and concentrated in ,: . . .
:; ~ ' ' . , : ' ,: , ' . . . .
: . . -~.;
vacuo to yield an oil, 5.67 g, 13.4 mmol ~87.4%). Rf=
0.45 (2:1 hexanes-EtOAc). la]D = +2.8 (c=0.76, MeOH).
MS(CI) m/e 421(m+H) . lH NMR(CDC13,300MHz) ~
0.88(apparent q,J=7Hz,6H), 1.15-1.32(m,10H), 1.36-1.47(m,11H), 2.80-3.07(m,5H), 3.38-3.48(m,1H), 4.72(apparent q,J=6Hz,lH), 5.41(d,J=8Hz,lH), 6.70(d,J=8Hz,2H), 7.02(d,J=8Hz,2H).
Example 72 R-Tyrosine-di-n-pentylamide hydrochloride The product of example 71 (2.0 g, 4.75 mmol) was dissolved in 4 N HCl in dioxane (20 mL, 80 mmol) that was precooled to 4C. After 3 hours, the excess reagent was evaporated and the oily residue was placed under high vacuum overnight to yield a glass, 1.5 g, 4.2 mmol (87%).
[a~D = -42.8 (c=1.2, MeOH). MS(CI) m/e 321(m+H) . lH
NMR(DMSOd6,300MHz) 8 0.82-0.89(m,6H), 1.1-1.4(m,12H), 2.70-3.04(m,5H), 3.37-3.50(m,lH), 4.22(dd,J=5,7Hz,lH), 6.70(d,J=8Hz,2H), 6.99~d,J=8Hz,2H), 8.37(bs,3H), 9.48(s,lH).
E~m~L~ 73 N~O-Di-(3'-Ouinolylcarbonyl)-R-Tyrosine-di-n-pentylamide The product of example 72 (357 mg, 1 mmol), quinoline-3-carboxylic acid (173 mg, 1 mmol), HOBt (13 mg, 0.1 mmol), and TEA (279 ~L, 2 mmol) were dissolved in 10 mL methylene chloride and EDCI (191 mg, 1 mmol) was then added in one portion. After 3 days, the volatiles were evaporated and the residue, in EtOAc, was e:~tracted as in example 71. The residue was then purifie~ by . ~, . . . .
:'~ : ; ', ' '' ',, : ' , , " : ~
: . -/
chromatography on silica gel eluted with 1% ethanol in chloroform to provide first the mono-acylated material (19 mg, see example 80) followed by an oily product, (108 mg, 0.17 mmol, 17% yield). Rf= 0.36 (18:1 chloroform-ethanol). []D = +5.8 (c=0.5, CHC13). [a]D = +53.2 (c=0.73, MeOH). MS(CI) m/e 631(m+H) , 518, 458, 446, 368.
lH NMR(CDCl3,300MHz) ~ 0.88-0.94(m,6H), 1.22-1.91(m,10H), 1.50-1.59(m,2H), 2.96-3.30(m,5H), 3.52-3.62(m,lH), 5.33-5.92(m,lH), 7.22(d,J=8Hz,lH), 7.30(d,J=8Hz,lH), 7.37(d,J=8Hz,2H), 7.63(dt,J=1,7Hz,lH), 7.68(dt,J=1,7Hz,lH), 7.79-7.93(m,3H), 8.0(dd,J=1,8Hz,lH), 8.16(d,J=3Hz,lH), 8.22(d,J=8Hz,lH), 8.56~d,J=2Hz,lH), 9.02(d,J=2Hz,lH), 9.32(d,J=2Hz,lH), 9.54(d,J=2Hz,lH).
C,H,N analysis calculated for C39H42N4O4, H2O: C 72-20, H
6.84, N 8.64; found: C 72.38, H 6.62, N 8.50.
Exam~le 74 N-(2'-In~olyl~carbonyl)-R-Tyrosine-d~-n-pentylamide The product of example 72 (200 mg, 0.56 mmol), indole-2-carboxylic acid (97 mg, 0.6 mmol) and TEA (84 ~L, 0.6 mmol) were dissolved in 5 mL methylene chloride and treated with EDCI (115 mg, 0.6 mmol) at room temperature.
After 3 days, the solvent was evaporated and the residue was extracted as in example 71. Column chromatography on silica gel eluted with 1% ethanol in methylene chloride provided product. Rf= 0.38 (18:1 methylene chloride-ethanol). mp= 124-7 C.l [~]D = +21.4 (c=1.17, MeOH).
MS(CI) m/e 964(m+H) . H NMR(CDCl3,300MHz) ~
0.88(apparent q,J=8Hz,6H), 1.15-1.56(m,12H), 2.46-3.22~m,5H~, 3.48-3.54(m,lH), 5.23-5.32(m,lH), 6.12(s,lH), : :, -.
WO 91tO0725 PCTtUS90/03630 SS
6.70(d,J=8Hz,2H), 6.95(d,J=lHz,lH), 7.05(d,J=8Hz,2H), 7.13(dt,J=1,7Hz,lH), 7.18(d,J=8Hz,lH), 7.27(dt,J=1,7Hz,lH), 7.90(d,J=8Hz,lH), 7.64(d,J=8Hz,lH), 9~22(s,lH). C,H,N analysis calculated for C28H37N3O3: C
72.54, H 8.05, N 9.06; found: C 72.37, H 8.10, N 8.80.
Example 75 N-(3',4'-Dichlorobenzoyl)-R-Tyrosine-di-n-pentylamide The product of example 72 (103 mg, 0.29 mmol) was dissolved in 5 mL methylene chloride and treated with 3,4-dichlorobenzoylchloride (126 mg, 0.6 mmol) and TEA (84 ~L, 0.6 mmol) at room temperature. After 2 hours, additional acid chloride (13 mg) and TEA (8 ~L) were added and the reaction was stirred overnight. The volatiles were evaporated and the residue, in EtOAc, was extracted with 0.1% citric acid, H2O; then dried over MgSO4, filtered and concentrated in vacuo. The resulting diacylated product residue was dissolved in 10 mL of 1:1 THF-methanol and treated with 1 N NaOH (290 mL, 0.29 mmol). After 1 hour, tlc revealed complete reaction and the solvent was evaporated in vacuo. The residue was dissolved in EtOAc and acidified with 0.1 M citric acid. The EtOAc layer was then washed until neutral, dried over MgSO4, filtered and concentrated in vacuo. The residue was warmed with 80%
aqueous ethanol and cooled overnight to provide a solid, 64 mg, 0.13 mmol (45% yield). mp= 148-52 C. [a]D =
+15.6 (c=1.0, MeOH). MS(CI) m/e 493(m+H) . H
NMRtCDCl3,300MHZ) ~ 0.88-0.92~m,6H), 1.2-1.6(m,12H), 2.93-3.22(m,5H), 3.50-3.60(m,lH), 5.21-5.28(m,lH), 6.29(s,lH), 6.68(d,J=8Hz,2H), 7.02(d,J=8Hz,2H), 7.15(d,J=8Hz,lH), - .
- , . .
'' ~ ., - -, .
W091/00725 PCT~US90/03630 2~ 55 7.47(d,J=8Hz,lH), 7.59(dd,J=2,8Hz,lH), 7.91(d,J=2Hz,lH).
C,H,N analysis calculated ~or C26H34Cl2N2O3: C 63.28, H
6. 94, N 5.68; found: C 63.39, H 7.00, N 5.54.
Example 76 N-(2'-Naphthoyl)-R-Tyrosine-di-n-pentylamide The product of example 72 (100 mg, 0.28 mmol) was acylated with 2-naphthoic acid (52 mg, 0.30 mmol) in the presence of TEA (39 ~L, 0.28 mmol) and EDCI ~57 mg, 0.30 mmol) in 5 mL methylene chloride. The reaction and extractive workup were performed as in example 71 to yield 120 mg, 0.25 mmol (89%). mp= 128-133C. [a]D = +11.8 (c=0.68, MeOH). MS(CI) m/e 975(m+H) , 303, 290. H
NMR(CD30D,300MHz) ~ 0.88-0.93(m,6H), 1.19-1.38(m,9H), 1.44-1 62(m,3H), 2.99(dd,J=7,13Hz,lH), 3.08-3.29(m,4H), 3.37-3.47(m,lH), 5.22(dd,J=7,9Hz,lH), 6.72(d,J=8Hz,2H), 7.13(d,J=8Hz,2H), 7.53-7.62(m,2H), 7.84(dd,J=2,9Hz,lH), 7.90-7.99(m,3H), 8.37(s,lH). C,H,N analysis calculated for C30H38N2O3: C 75.91, H 8.07, N 5.90; ound: C 75.57, H 7.97, N 5.83.
Example N-t-Butyloxycarbonyl-(O-benzyl)-R-Tyrosine-di-n-pentylamide N-t-Butyloxycarbonyl-(O-benzyl)-R-Tyrosine (3.71 g, 10 mmol) was stirred with di-n-pentylamine (5.1 mL, 25 mmol), HOBt (1.4 g, 10 mmol) and TEA (1.4 mL, 10 mmol) in 150 mL methylene chloride at 4C and then BOPCl (2.6 g, 10 mmol) was added. The reaction was allowed to reach room temperature overnight. After one day, additional BOPCl ,~
~: : `: . : - -WO91~00725 PCT/US90/03630 _~, 1' ~` .
;~?~ S5 (260 mg) and TEA (140 ~L) were added. After 2 days, the volatiles were evaporated and the residue (in EtOAc) was extracted with 0.1 M H3PO4, 0.1 M Na2CO3, H2O; then dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluted with 2:1 hexanes-EtOAc to yield an oil, 1.3 g, 2.55 mmol (25%).
[a]D = +5.8 (c=1.5, MeOH). MS(CI) m/e 511(m+H) , 456, 393. H NMR~CDC13,300MHz) ~ 0.84-0.93(m,6H), 1.1-1.35(m,12H), 1.41(s,9H), 2.81-3.04(m,5H), 3.36-3.46(m,1H), 4.15-4.23(m,1H), 5.03(s,2H), 5.32(d,J=8Hz,lH), 6.87(d,J=8Hz,2H), 7.11(d,J=8Hz,2H), 7.32-7.43(m,5H).
~xam~ 78 (O-Benzyl)-R-Tyr~sine-di-n-pentylamide hydrochloride The product of example 77 (1.3 g, 2.55 mmol) was treated with 5 mL of 4 N HCl in dioxane, precooled to 4C.
The reaction mixture was then allowed to reach room temperature. After 1 hour tlc revealed complete reaction and the excess reagent was evaporate. The residue was placed under high vacuum overnight to yield an oil, 1.2 g.
Rf= 0.59 (80:20:1 chloroform-methanol-ammonium hydroxide).
[~]D = -32.5 (c=2.2, MeOH). MS(CI) m/e 411(m+H) . H
NMR(DMSOd6,300MHz) ~ 0.85(apparent q,J=7Hz,6H), 1.07-1.38(m,12H), 2.68-2.97(m,4H), 3.05(dd,J=5,13Hz,lH), 3.32-3.92(m,2H), 4.27(dd,J=5,8Hz,lH), 5.09(s,2H), 6.93(d,J=8Hz,2H), 7.12(d,J=8Hz,2H), 7.32-7.43(m,5H), 8.37~s,3H).
... . .
WO91/00725 PCT/US90/0363~
, 21?~755 E~m~l~ 79-(3'-Ouinolylcarbonyl;-(O-benzyl)-R-Tyrosine-di-n-pentylamide EDCI (290 mg, 1.5 mmol) was added to a cooled (4C) solution of quinoline-3-carboxylic acid (260 mg, 1.5 mmol), the product of example 78 (650 mg, 1.35 mmol), and TEA (418 ~L, 3.0 mmol) in 5 mL methylene chloride. The stirred reaction mixture was allowed to warm to room temperature overnight. After evaporation of the volatiles, the residue was dissolved in EtOAc and extracted with 0.1 M H3PO9 (3x), 0.1 M Na2CO3 (3x), brine (3x); then dried over MgSO4, filtered and concentrated in vacuo to yield an oil, 650 mg, 1 15 mmol ~85%). Rf- 0.77 ~18:1 chloroform-ethanol), 0.40 ~1:1 hexanes-EtOAc). [~]D
~0.21 ~c=0.47, CHC13). MS~FAB) m/e 566(m+H) , 393, 381. H NMR(CDC13,300MHz) ~ 0.91(apparent q,J=7Hz,6H), 1.17-1.38(m,10H), 1.43-1.6(m,2H), 2.86-3.17(m,SH), 3.49-3.59(m,lH), 5.03(s,2H), 5.26-5.33~m,lH), 6.90(d,J-8Hz,2H), 7.16~d,J=8Hz,2H), 7.28-7.43(m,6H), 7.62(dt,J=1,7Hz,lH), 7.82(dt,J=1,8Hz,lH), 7.90(d,J=8Hz,lH), 8.18(d,J=8Hz,lH), 8.54(d,J=2Hz,lH), 9.32(d,J=2Hz,lH). C,H,N analysis calculated for C36H43N3O3: C 76.55, H 7.88, N 7.29;
found: C 76.43, H 7.66, N 7.43.
Example 80 N-(3~-ouinolylcarbonyl)-p-T~rosin~-c~-n-~entylamide The product of example 79 (614 mg, .09 mmol) was dissolved in 30 mL methanol and treated ~Jith 10% Pd/C (200 mg, pre-wetted with solvent under nitroa~n) under 1 : : , - ~ 1, ' . . ..
: . ~
: . - , , . :
:, , .' ' ~ :,. ~ ... . .
,. . . ... .. . . .. . . . .. .. . . . .. .
atmosphere hydrogen gas. Another 200 mg of catalyst was added after 4 hours and the reaction mixture was stirred overnight. The mixture was then filtered and the filtrate concentrated in vacuo. Silica gel column chromatography of the residue (eluted with a 2:1 to 1:1 hexane-EtOAc step gradient) provided 270 mg, 0.57 mmol (52% yield). mp=
135-37 C. [~]D = +12.6 (c=0.5, MeOH). MS(CI) m/e 476(m+H) , 347, 321, 291. H NMR(CDC13,300MHz) ~
0.91(t,J-7Hz,6H), 1.29-1.38(m,8H), 1.48-1.62(m,9H), 3.0-3.28(m,5H), 3.51-3.61(m,lH), 5.30-5.38(m,lH), 6.72(d,J=8Hz,2H), 6.78(s,lH), 7.06(d,J=8Hz,2H), 7.38(d,Jz8Hz,lH), 7.60(t,J=7Hz,lH), 7 80(dt,J=1,7Hz,lH), 7.88(d,J=8Hz,lH), 8 15~d,J-9Hz,lH), 8.58(d,J=2Hz,lH), 9.27(d,J=2Hz,lH). C,H,N analysis calculated for C29H37N3O3: C 73.23, H 7.84, N 8.83; found: C 73.23, H
7.89, N 8.76.
Example ~1 N-(3'-Ouinolylcarbonyl)-(O-bisulfat~l)-R-Tyrosine di-n-pentylamide ammonium salt The product of example 80 (59 mg, 0.12 mmol) was dissolved in 2 mL DMF and treated with rreshly prepared pyridine-sulfur trioxide complex (H.C.Reitz et al J. Amer.
Chem. ~QÇ~ 68, 1031-5, 1946) overnight at room temperature. The pyridine was evaporated in vacuo and the DMF solution was poured into water and t:~e pH adjusted to 7 with 1 N NaOH. The homogeneous solution was then frozen and lyophilized. Preparative C-18 chrom~tography of the residue eluted with a gradient from 100~ aqueous buffer (0.05 M ammonium acetate, pH 6.2) to 50~
.
W09t/00725 PCT/US90/03630 I
2~ SS
.', , ~ "5 acetonitrile/aqueous buffer over 10 minutes provided product fractions which were pooled, frozen and lyophilized to yield 48 mg, 0.08 mmol (67%). mp= 113-6C.
[a]D = +12.2 ~c=0.88, MeOH). MS(FAB) m/e 559~m-H) , 368, 302, 298. H NMR(D20,300MHz) ~ 0.68-0.75(m,6H), 0.98-1.43(m,12H), 2.98-3.28(m,6H), 5.22(t,J=7Hz,lH), 7.24~d,J=8Hz,2H), 7.30(d,J=8Hz,2H), 7.44(t,J=8Hz,lH), 7.62(d,J=8Hz,lH), 7.69(t,J=8Hz,lH), 7.82(d,J=8Hz,lH), 8.36(s,1H), 8.78(s,lH). C,H,N analysis calculated for C29H40N4O6S, 0.50 H2O: C 59.88, H 7.10, N 9.63; found:
C 59.77, H 6.82, N 9.11.
~xample ~L
3~5-Di-iodo-N-(3'-quinolylcarbonyl)-R-Tvr-di-n-pentylamide (b) 3-Iodo-N-(3'-quinolylcarbonyl)-R-T~r-di-n-pentylamide Iodine (27 mg, 0.11 mmol) was mixed with morpholine (40 ~L, 0.46 mmol) in 5 mL methanol and added to the product of example 80 (50 mg, 0.11 mmol) in 15 mL methanol at room temperature. The reaction was stirred until tlc indicated complete reaction. After evaporation of the solvent, chromatography of the residue on silica gel eluted with a step gradient of chloroform to 1~ ethanol in chloroform provided first the diiodo product followed by the monoiodo compound. Diiodo product (a): [a~ D = +18 (c=0.11, MeOH). MS~CI) m/e 728(m+H) , 602. H
NMR(CDCl3,300MHz) ~ 0.92(apparent q,J=7Hz,6H), 1.2-1.45(m,12H), 2.92-3.13~m,SH), 3.53-3.67(m,lH), 5.22-.
:: .: -: , .. . . .. . .. ....
.
WO91/00725 PCT/US90~3630 ~ ....
, Z~
5.28(m,1H), 5.72(s,1H), 7.27(d,J=7Hz,lH), 7.56(s,2H), 7.63(dt,J=1,8Hz,lH), 7.83(dt,J=1,8Hz,lH), 7.93(d,J=8Hz,lH), 8.18(d,J=8Hz,lH), 8.55(d,J=2Hz,lH), 9.33(d,J=2Hz,lH). C,H,N analysis calculated for C29H35I2N3O3, 0.4 EtOAc: C 48.19, H 5.05, N 5.51; found:
C 48.43, H 5.03, N 5.79. Monoiodo product (b): mp= 75-85 C. MS(CI) m/e 602(m~H) . H NMR(CDCl3,500MHz) 0.84(apparent q,J=7Hz,6H), 1.13-1.35(m,9H), 1.37-l.S3(m,3H), 2.90-2.98(m,3H), 3.02-3.08(m,2H), 3.48-3.5S(m,lH), 5.18-S.23(m,lH), 6.83(d,J=8Hz,lH), 7.05(dd,J=1,8Hz,lH), 7.22(d,J=8Hz,lH), 7.46(d,J=2Hz,lH), 7.57(dt,J=1,8Hz,lH), 7.76(dt,J=1,8Hz,lH), 7 84(d,J=8Hz,lH), 8.10~d,J=8Hz,lH), 8.98~d,J=2Hz,lH), 9.24~d,J~2Hz,lH). C,H,N analysis calculated for C29H36IN3O3, 1.5 H20: C 55.42, H 6.25, N 6.69; found: C
55.19, H 5.95, N ~.17.
Example 83 N-(3'-Ouinolylcarbonyl)-(O-methyll-R-T~roslne-di-n-pentylamide The product of example 80 (25 mg, 0.053 mmol) was dissolved in 1 mL acetone and K2CO3 ~8 mg, 0.058 mmol) and methyl iodide (5 ~L, 0.08 mmol) were added. After 3 hours at reflux, additional methyl iodide (5 mL) and acetone (2 mL) were added. After 2 days, the volatiles were evaporated and the residue, in EtOAc, was extracted with 0.1% aqueous citric acid, water; then dried over MgSO4, filtered and concentrated in vacuo. MS~CI) m/e 490~m+H) , 476, 361, 347, 317. H NMR~CDC13,300MHz) ~ 0.86-0.93(m,6H), 1.2-1.56~m,12H), 2.42-3.15(m,5H), 3.49-, .. .. .
, - : . ~: . . .
.. - . . - :
WO91/00725 PCT/USgO/03~30 ;~'5~7S5 .. V
3.59(m,1H), 3.78(s,3H), 5.27-5.39(m,1H), 6.77(d,J=8Hz,lH), 6.82(d,J=8Hz,lH), 7.08(d,J=8Hz,lH), 7.16(d,J=8Hz,lH), 7.41-7.46(m,1H), 7.56-7.63(m,1H), 7.76-7.82(m,1H), 7.83-7.88(m,lH), 8.14(d,J=8Hz,lH), 8.53(d,J=2Y.z,lH), 9.29(t,J=2Hz,lH).
Example 8Methyl N-t-Butyloxycarbonyl-(O-benzyl)-R-Tyrosyl-S-phenylglycinate N-t-Butyloxycarbonyl-(O-benzyl)-R-Tyrosine (1.0 g, 2.7 mmol), methyl S-phenylglycinate hydrochloride (540 mg, 2.7 mmol), HOBt (362 mg, 2.7 mmol) and TEA (374 ~L, 2.7 mmol) were dissolved in 20 mL THF and treated with BOPCl (682 mg, 2.7 mmol). The reaction was followed by tlc (18:1 chloroform-ethanol) and additional BOPCl ~200 mg) and TEA (374 ~L) were added after 1,2 and 4 days.
Methylene chloride (20 mL) also was added after 2 days.
After 1 week, the volatiles were evaporated in vacuo and the residue, in EtOAc, was extracted as in example 71.
Chromatography of the residue on silica gel eluted with a step gradient from 9:1 to 2:1 hexanes-EtOAc yielded 485 mg, 1.13 mmol (42%). mp= 138-39C. [a]D = +48.7 (c=1.0, MeOH). MS(CI) m/e 519(m+H) , 463, 419. lH
NMR~CDC13,300MHz) ~ 1.41(s,9H), 2.92-3.04~m,2H), 3.71(s,3H), 4.35~bs,lH), 5.01(s,3H), 5.43-5.46(m,lH), 6.78(d,J=7Hz,lH), 6.82(d,J=8Hz,2H), 7.02(d,J=8Hz,2H), 7.19-7.23(m,lH), 7.30-7.45(m,10H).
:
- .: - ~ .. .~.. ..
.~
W091~00725 PCT/US9OJ03630 ~, ;~(?~i~755 ExamDle ~ethyl (O-Benzyl)-R-Tyrosyl-S-phenylglycinate hydrochloride The product of example 84 (450 mg, 1.05 mmol) was dissolved in 4 N HCl in dioxane (5 mL, 20 mmol) precooled to 4C. After 1 hour, the excess reagent was evaporated in vacuo and the product used directly in the next step.
mp= 153-6C. [a]D = +43-7 (c=0.76, MeOH). MS(FAB) m/e 419~m+H) , 403, 226. H NMR(DMSOd6,300MHZ) ~ 2-86-3.00(m,2H), 3.67(s,3H), 4.13(bt,J=5Hz,lH), 5.03(s,2H), 5.45(d,J=7Hz,lH), 6.88(d,J=8Hz,2H), 7.05(d,J=8Hz,2H), 7.22-7.25(m,2H), 7.33-7.46(m,8H), 8.28~s,3H), 9.35(d,J=7Hz,lH).
Example 86 Methyl N-t3'-Ouinolvl~arbonyl~-(O-benzyl)R-Tyrosyl-S-phenylalycinate Quinoline-3-carboxylic acid (182 mg, 1.05 mmol), TEA
(146 ~L, 1.05 mmol) and the product of example 85 (1.05 mmol) were dissolved in 20 mL methylene chloride and EDCI
(201 mg, 1.05 mmol) was added at ambient temperature.
After 4 days, the volatiles were evaporated and the residue was extracted as in example 71. The solvents were evaporated in vacuo to provide 407 mg, 0.71 mmol (68%
yield). mp= 153-8 C. [a]D = +73.0 (c=1.2, CHC13-MeOH/l:l). MS(FAB) m/e 574(m+H) , 419, 381. H
NMR(CDC13,300MHz) ~ 3.06(dd,J=8,14Hz,lH), 3.20(dd,J-5,14Hz,lH), 3.70(s,3H), 4.94-5.02(m,3H), 5.53(d,J=7Hz,lH), 6.78(d,J=8Hz,2H), 6.83(d,J=7Hz,lH), -' -: :
: .. .': '. : : ~ :
W O 91/00725 PC~rtUS90/03630.`
2(?5i~55 ~;
7.01(d,J=8Hz,2~), 7.14~d,J=7Hz,lH), 7.20-7.23(m,2H), 7.33-7.36~m,4H), 7.39-7.49(m,4H), 7.62(dt,J=1,7Hz,lH), 7.82(dt,J=1,7Hz,lH), 7.88(d,J=8Hz,lH), 8.15(d,J=8Hz,lH), 8.54(d,J=2Hz,lH), 9.28(d,J=2Hz,lH). C,H,N analysis calculated for C35H3lN3Os~ 0-5 H2O C 72.15~ H 5-54~ N
7.21; found: C 72.05, H 5.63, N 6.88.
Exa~L~ 87 Methyl N-(3'-OuinolylcarbQnyl)-R-Tyrosyl-S-phenylglycinate The product of example 86 (200 mg, 0.35 mmol) was dissolved in 10 mL methylene chloride and treated with trimethylsilyliodide (TMSI, 198 ~L, 1.39 mmol) at room temperature. Additional TMSI (198 ~L) was added after 1 day After 3 days, the reaction was quenched with methanol for 5 minutes and then poured into 0.1 M citric acid and extracted with ethylacetate (3x). The combined ethylacetate solution was washed with water; then dried over MgSO4, filtered and concentrated in vacuo. The crude solid was purified by chromatography on silica gel eluted with a s~ep gradient of 1 to 5% ethanol in methylene chloride and then crystallized from EtOAc and hexane to yield 51 mg (30%). mp= 238-40 C. [a~D = +72.6 (c=0.23, MeOH). MS(CI) m/e 484(m+H) , 319. H NMR(CDCl3-CD3OD,300MXz) ~ 3.0-3.16~m,2H), 3.72(s,3H), 4.92-5.01(m,lH), 5.50(d,J=7Hz,lH), 6.67(d,J=8Hz,2H), 6.99(d,J=8Hz,2H), 7.21-7.24(m,2H), 7.35-7.38(m,3H), 7.40(s,1H), 7.68(dt,J=1,7Hz,lH), 7.86(dt,J=1,7Hz,lH), 7.98(d,J=8Hz,lH), 8.12(d,J=8Hz,lH), 8.14(d,J=6Hz,lH), 8.22~d,J=8Hz,lH), 8.68(d,J=2Hz,lH), 9.21(d,J=2Hz,lH).
:. : ..
, , , , -.: . . . . .
.- , . - . . ~ ., .
: . . .: : .. . , ~ ~ , ~ : . , . . ~ , ~ , . , . -W091/0072~ PCT/US90/03630 2~ ' . 55 C,H,N analysis calculated for C28H25N3O5: C 69.55, H 5.21, N 8.69; found: C 69.20, H 5.29, N 8.60.
.Example 88 N'-Benzyloxycarbonyl-(2 R)-aminobutyrolactone N-Benzyloxycarbonyl-R-methionine (283 mg, 1.0 mmol) and a-iodo acetamide (555 mg, 3.0 mmol) were dissolved in 6 mL of 50% aqueous ethanol and warmed to 4C for 4 days.
Citric acid was added (3 mL of a 0.1 M solution) and the mixture was refluxed for 4 hours. After evaporation of the volatiles, the residue was poured into water and extracted with ethyl acetate (3x). The combined ethylacetate solution was extracted with 0.5 N HCl, water;
then dried and concentrated in vacuo. The resulting residue was chromatographed on silica gel eluted with 1:1 hexanes-ethylacetate to yield 106 mg, 0.52 mmol (52%).
(cf: Ozinskas, A.J., Rosenthal, G.A., ~. Oraanic Chem. 51, 5047, 1986). mp= 124-5 C. [a]D z +31.3 (c=1.2, MeOH).
H NMR(CDC13,300MHz) ~ 2.16-2.28(m,lH), 2.76~2.86(m,lH), 4.2-9.31(m,1H), 4.37-4.50(m,2H), 5.13(s,2H), 5.32(bs,1H), 7.32-7.38(m,5H).
.
Example 89 N-Benzyloxycarbonyl-Homoserine-di-n-pentylamide The product of example 88 (620 mg, 2.8 mmol) and dipentylamine (1.4 mL, 7 mmol) were dissolved in 60 mL
acetonitrile and then heated to reflux overnight. After evaporation of the volatiles, the residue was chromato~raphed on silica gel eluted with a step gradient from chloroform to 1% ethanol in chloroform to yield an , . . . - .
:
. . . . ... . . .
: :
, .
oil, 580 mg, 1.6 mmol (56~). [a]D = +0.31 (c=0-96, MeOH). MS(CI) m/e 393(m+H) , 253, 236, 192. lH
NMR(CDC13,300MHz) ~ 0.87-0.93(m,6H), 1.22-1.38(m,8H), 1.47-1.63(m,4H), 1.86-1.97(m,lH), 3.01-3.20(m,2H), 3.34-3.43(m,2H), 3.52-3.72(m,4H), 4.76(dt,J=3,11Hz,lH), 5.1(d,J=12Hz,lH), 5.13(d,J=12Hz,lH), 5.93(d,J=8Hz,lH), 7.31-7.38(m,5H).
Example 90 N'-(2'-Indolylcarbonyl)-(2,RS)-aminobutyrolactone EDCI (191 mg, 1.0 mmol) was added to a solution of indole-2-carboxylic acid (161 mg, 1.0 mmol), a-aminobutyrolactone hydrobromide (182 mg, 1.0 mmol), HOBt ~135 mg, 1.0 mmol), and TEA (279 ~L, 2.0 mmol) irl 15 mL
methylene chloride at room temperature. Additional EDCI
(120 mg) and TEA (56 ~L) were added after 1 day. After 5 days, the volatiles were evaporated and the residue, in EtOAc, was extracted with 1 M H3PO4, 0.1 M Na2CO3, and brine. The solution was dried over MgSO4, filtered and concentrated in vacuo. The product was crystallized from EtOAc to yield 147 mg, 0.6 mmol, 60%. Rf= 0.17 (1:1 hexanes-EtOAc). mp= 235-6C. MS(CI) m/e 245(m+H) , 144.
H NMR(CDC13-CD3OD,300MHZ) ~ 1.86-2.51(m,lH), 2-19-2.79(m,lH), 4.32-4.42(m,lH), 4.56(dt,J=2,11Hz,lH), 4.82(dd,J=8,11Hz,lH), 7.1-7.15(m,2H), 7.28(dt,J=1,8Hz,lH), 7.40(s,0.5 H), 7.46(d,J=8Hz,lH), 7.66(d,J=8Hz,lH).
.
. . :- . . . ~ :
- . . ; ., . : , ' ~ ' , ., :: .
:.
--.
WO91/0072~ PCT/US90103630 . .
Z ~
E~ample ~1 ~-~2'-Indolylcarbonyl)-R,S-Homoserine-di-n-pentylamide The product of example 90 (25 mg, 0.1 mmol) and dipentylamine ~50 ~L, 0.25 mmol) were dissolved in 2 mL
THF and warmed to 50C. Additional dipentylamine (250 ~L) was added after several hours. After 4 days, the volatiles were evaporated and the residue was chromatographed on silica eluted with 2:1 hexanes-EtOAc.
Yield: 26 mg, 0.06 mmol, 60%. mp= 128-139 C. MS(CI) m/e 402(m+H) , 158. H NMR(CDCl3,300MHz) ~ 0.92(t,J=7Hz,6H), 1.26-1.42(m,10H), 1.52-1.72(m,3H), 1.98-2.11(m,lH), 2.69~t,J=8Hz,lH), 3.06-3.26(m,2H), 3.42-3.52(m,lH), 3.60-3.77(m,3H), 5.12-5.20(m,lH)~ 7.03~d,J=lHz,lH), 7.16(dt,J-1,8Hz,lH), 7.31~dt,J=1,7Hz,lH), 7.42(dd,J=1,8Hz,lH), 7.48~d,J=8Hz,lH), 7.67(d,J=8Hz,lH), 9.13(s,1H). C,H,N analysis calculated for C23H35N3O3, 0.5 H2O: C 67.28, H 8.84, N 10.24; found: C 67.42, H 8.64, N
10 . 10 .
E~mple 92 N'-(3'-Ouinolylcarbonyl)-(2,RS)-aminobutyrolactone Quinoline-3-carboxylic acid (5.2 g, 30 mmol) was coupled to a-aminobutyrolactone (5.5 g, 30 mmol) in a manner similar to that in example 90 to provide 2.62 g, 10.2 mmol (34~ yield). Additional extraction of the aqueous layer with EtOAc yielded another 820 mg, 3.2 mmol (10.7~). R~= 0.26 (18:1 chloroform-ethanol). mp= 160-63 C. MS(CI) m/e 257(m+H) . H ~MR(CDC13,300MHz) ~ 2.32-2.46(m,lH~, 2.91-3.01(m,lH), 4.35-4.43(m,lH), ,, :: :: : . : ~. :
.. . . .
.
, :. . ': ~ ~, ' WO91/0072S PCT/US90~03630 , ?5-'755 4.56~dt,J=2,10Hz,lH), 4.83-4.92(m,lH), 7.36(d,J=6Hz,lH), 7.60(dt,J=1,8Hz,lH), 7.81(dt,J=2,8Hz,lH), 7.86(d,Js8Hz,lH), 8.12(dd,J=1,8Hz,lH), 8.59(dd,J=1,2Hz,lH), 9.28(d,J=2Hz,lH). C,H,N analysis found: C 65.42, H 4.82, N 10.82.
Example N-(3'-Ouinolylcarbonyl)-R.S-Homoserlne-di-n-pentylamid~
The product of example 92 (500 mg, 2.0 mmol) was treated with dipentylamine (1.5 mL, 7.4 mmol) in 25 mL of toluene and refluxed. After 2 days, an additional 1 mL of dipentylamine was added and the heating was continued.
After 1 week, the volatiles wer~ evaporated in vacuo and the excess amine was removed by Kugelrohr distillation.
The residue was then chromatographed on silica gel eluted with a step gradient of chloroform to 4% ethanol in chloroform to yield an oil, 611 mg, 1.48 mmol (79%).
MS(CI) m/e 419(m+H) . 1H NMR(CDCl3,300MHz) ~ 0.88-0.95(m,6H), 1.25-1.42(m,7H), 1.52-1.75(m,5H), 2.04-2.15(m,lH), 3.06-3.28(m,2H), 3.46-3.57(m,2H), 3.62-3.81(m,3H), 4.01(dd,J=5,9Hz,lH), 5.21-5.28(m,lH), 7.63(dt,J=1,8Hz,lH), 7.72(d,J=7Hz,lH), 7.83(dt,J=1,8Hz,lH), 7.93(dd,J=1,7Hz,lH), 8.18(d,J=8Hz,lH), 8.62(d,J=2Hz,lH), 9.37(d,J=3Hz,lH).
C,H,N analysis calculated for C24H35N3O3, 0.25 H2O: C
68.95, H 8.56, N 10.05; found: C 69.26, H 8.45, N 10.06.
:~ . , , . ...... ,.,:,,.. : : .: : ,. -;, . ,. . , , :
WO91/0072~ PCT/US90/~3630 . ~ ~
2~C > ~ 55 --so--Example 94 N-(3'-Ouinolvlcarbonyl)-R,S-Ho~oserine-n-pentylamide The product of example 92 ~200 mg, 0.8 mmol) and n-pentylamine (232 ~L, 2.0 mmol) were dissolved in 20 mL of 1:1 THF-acetonitrile and stirred at room temperature until starting material was consumed (tlc: Rf= 0.15, 18:1 chloroform-ethanol). The volatiles were evaporated in vacuo. The residue was mixed with hexanes and the product filtered away to yield 273 mg, 0.79 mmol (99%). mp= 181-3 C. MS(CI) m/e 344(m+H) . H NMR~CDC13,300MHz) ~
0.91(t,J-7Hz,3H), 1.30-1.38(m,4H), 1.51-1.58(m,2H), 1.95-2.04(m,1H), 2.12-2.21(m,1H), 3.25-3.36(m,2H), 3.80(bs,2H), 4.26(bs,lH), ~.83-4.90(m,lH), 7.37(bt,J=3Hz,lH), 7.69(dt,J-1,5Hz,lH), 7.83(dt,J=1,6Hz,lH), 7.93(d,J=6Hz,lH), 8.10(d,J-6Hz,lH), 8.15(d,J-7Hz,lH), 8.68(d,J-2Hz,lH), 9.37(d,J-lHz,lH)~ C,H,N analysis calculated for ClgH25N3O3, 0.25 CHC13: C 61.13, H 6.82, N
11.26; found: C 60.82, H 6.88, N 11.16.
Example 95 N-t-Butyloxycarbonyl-R-Methionine-di-n-~entylamide BOPCl (5.1 g, 20 mmol) was added to a cooled solution (4 C) of N-t-Butyloxycarbonyl-R-Methionine (5.0 g, 20 mmol), dipentylamine (8.0 mL, 40 mmol), in 60 mL of dry THF and the stirred reaction was allowed to attain room temperature overnight. The volatiles were evaporated in vacuo. The residue was dissolved in EtOAc and extracted successively with 1 M H3PO9 (3x), 1 M Na2CO3 (3x), brine (3~.); then dried over MgSO4, filtered and concentrated in ~. . , : : .
~ , .
, xr~7ss vacuo to yield an oil: 4.6 g, 11.7 mmol ~59%). Rf= 0.81 (1:1 hexanes-EtOAc). [a]D = +27.5 (c=2.7, MeOH). MS(CI) m/e 389(m+H) , 333, 311, 258, 219, 202, 158. H
NMR(CDC13,300MHz) ~ O.86-0.93~m,6H), 1.21-1.37~m,9H), 1.42~s,9H), 1.43-1.66~m,3H), 1.76-1.96~m,2H), 2.11(s,3H), 2.54(t,J=7Hz,2H), 3.06-3.15~m,lH), 3.19-3.29~m,lH), 3.32-3.42~m,lH), 3.46-3.56~m,lH), 4.68-4.75~m,lH), 5.37~d,J=9Hz,lH).
E~mple 96 N-(3'-Ouinolylcarbonyl)-tO-methyl)-R,S-Homoserine-di-n-pentylamide The product of example 93 was methylated in a similar manner to that in example 34 to provide the title compound after purification by chromatography.
Example 97 N-(3'-Ouinolylcarbonyl!-(O-benzyl)-R,S-Homoserine-di-n-~entylamide The product of example 93 was benzylated in a manner similar to that in example 34 utilizing benzyl bromide as the alkylating agent. The title compound was provided after purification by chromatography.
Example 98 R-M~thionine-di-n-~entylamide trifluoroacetate sal~
The product of example 95 ~4 g, 10.3 mmol) was dissolved in 30 mL trifluoroacetic acid precooled to 4C.
After 2 hours, the excess reagent was evaporated and the residue was placed under high vacuum overnight. [a]D =
. . - : , . -. ,, :
.: . . . . :
' " - ~' ' W09l/00725 P~T/US90/036~0 +5.1 (c-1.4, MeOH). MS(CI) m/e 289(m+H) . H
NMR~DMSOd6,300MHz) ~ O.88(apparent q,J=8Hz,6H), 1.18-1.35(m,8H), 1.42-1.58(m,4H), 1.89-1.96(bm,2H), 2.08(s,3H), 2.43-2.67(m,2H), 3.00-3.09(m,lH), 3.13-3.23(m,lH), 3.28-3.38(m,1H), 3.q8-3.57(m,1H), 4.2-4.28(m,1H), 8.17~s,3H).
Exam~le 99 N-(3'-Ouinolylcarbonyl)-R-Methionine-di-n-pentylamide Quinoline-3-carboxylic acid (0.43 g, 2.5 mmol), the product of example 98 (1.0 g, 2.5 mmol), and TEA (697 ~L, 5 mmol) were dissolved in 15 mL of methylene chloride cooled to 4 C and EDCI (0.48 mg, 2.5 mmol) was added. The stirred reaction mixture was allowed to attain room temperature overnight. The volatiles were evaporated and the resi~ue in EtOAc was extracted with 0.1 M citric acid, 0.1 M Na2CO3, water; then dried over MgSO4, filtered and concentrated in vacuo. Silica gel chromatography of the residue eluted with a step gradient of chloroform to 0.5%
ethanol in chloroform yielded an oil, 572 mg, 1.29 mmol (52%). Rf= 0.19 (1:1 hexanes-ethylacetate). [a]D = +8.0 (c=0.85, MeOH). MS(CI) m/e 444(m+H) . H
NMR(CDCl3,300MHz) ~ 0.91(t,J=7Hz,3H), 0.93(t,J=7Hz,3H), 1.23-1.42(m,8H), 1.52-1.62~m,2H), 1.63-1.75(m,2H), 2.02-2.17~m,5H), 2.56-2.72(m,2H), 3.10(t,J=8Hz,0.5H), 3.14(t,J=8Hz,0.5H), 3.25-3.35(m,lH), 3.46-3.55(m,lH), 3.59(t,J=8Hz,0.SH), 3.63(t,J=8Hz,0.SH), 5.28-5.36(m,lH), 7.55(d,J=8Hz,lH), 7.12(dt,J=1,7Hz,lH), 7.81(dt,J=1,8Hz,lH), 7.88(dd,J=1,8Hz,lH), 8.15(d,J=8Hz,lH), 8.54(d,J=2Hz,lH), 9.33(d,J=2Hz,lH).
: ~ .
.
WO91t00725 PCT/US90/03630 f~
2~?755 C, H:, N analysis calculated for C25H37N3O2S, 0.5 H20: C
66.33, H 8.46, N 9.28; found: C 66.33, H 8.19, N 9.25.
Example 100 ouinolylc~~ ylL~-~e~ ioninesulfoxide-di-n pentylamide The product of example 99 (100 mg, 0.23 mmol) was dissolved in 5 mL THF and m-chloroperbenzoic acid (47 mg, 0.23 mmol) was added at room temperature. The reaction was stirred overnight. The volatiles were evaporated and the residue, in EtOAc, was extracted with water until the aqueous extract was neutral (pH=7); then the solution was dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel eluted with methylene chloride and ethanol to provide the product as an oil- t~]D = 8i8 (c=0.73, MeOH). MS(CI) m/e 460(mlH) , 396. H NMR(CDC13,300MHz) ~ 0.92(apparent q,J=7Hz,6H), 1.26-1.40(m,10H), 1.52-1.73(m,3H), 2.14-2.26(m,lH), 2.39-2.52(m,lH), 2.71-3.02(m,3H), 3.08-3 18(m,lH), 3.23-3.35(m,lH), 3.38-3.52(m,lH), 3.58-3.68(m,1H), 5.20-5.34(m,1H), 7.62(tt,J=1,8Hz,2H), 7.72(d,J=7Hz,lH), 7.83(tt,J=1,8Hz,lH), 7.92(d,J=8Hz,lH), 8.17(d,J=8Hz,lH), 8.62~dd,J=2,5Hz,lH), 9.35(dd,J=2,3Hz,lH). C,H,N analysis calculated for C25H37N3O3S, 0.1 EtOAc: C 65.13, H 8.13, N 8.97; found: C
65.31, H 8.30, N 8.73.
.......... . .
"::; ' :. . : . , :
-: -~, . .- ~:
.: .: , ............. , - .: :. . .:
. - ~ .
. . :: , . , , . :, .: : , - . - . . -.
,, . . .
~?~;~5 E~ample lQl N-t-Butyloxycarbonyl-R-Proline-di-n-pentylamide BOPCl (1.18 g, 9.69 mmol) was added to a cooled solution (4C) of N-t-Butyloxycarbonyl-R-Proline (1.0 g, 9.64 mmol), dipentylamine (2.5 mL, 12.5 mmol), in 50 mL of dry THF. The cooling bath was removed and the stirred reaction mixture was allowed to warm to ambient temperature gradually. After 5 hours, the volatiles were evaporated in vacuo. The residue was dissolved in EtOAc and extracted successively with 1 M H3PO4 (3x), 1 M Na2CO3 (3x), brine (3x); then dried over MgSOg, filtered and concentrated in vacuo to yield an oil, 880 mg, 2.48 mmol (54%). Rf= 0.28 (2:1 hexanes-EtOAc). [a]D = +28i7 (c=1.0, MeOH) MS(CI) m/e 355(m+H) , 299, 255. H
NMR(CDC13,300MHz) ~ 0.84-0 94(m,6H), 1 23-1.38(m,8H), 1.41(s,6H), 1.45(s,3H), 1.49-1.58(m,6H), 1.80-1.90(m,lH), 2.0-2.23(m,lH), 3.12-3.33(m,4H), 3.4-3.52(m,lH), 3.56-3.67(m,lH), 4.44(dd,J=4,8Hz,0.6H), 4.58(dd,J=2,8Hz,0.4H).
Example 102 R-Proline-di-n-pentylamide hydrochloride The product of example 101 (800 mg, 2.3 mmol) was mixed with HCl-Dioxane (12.5 mL, 50 mmol, pre-cooled to 4C) under an N2 atmosphere at ambient temperature. After 1 hour, the volatiles were evaporated in vacuo and the residue was mixed with toluene and concentrated (twice) then placed under high vacuum overnight. The residue was utilized directly.
` `' ,:~` . : .
.
...
: - , , . ,, ~ :
WO9l/00725 PCT~US90/03630 2~ 55 ~; ,,~
~a~le 103 N-(2'-IndQlvlcarbonvl)-R-Proline-di-n-~entylamide EDCI (440 mg, 2.3 mmol) was added to a cooled (9C) solution of indole-2-carboxylic acid (371 mg, 2.3 mmol), the product of example 102 (2.3 mmol assumed), HOBt (311 mg, 2.3 mmol), and TEA (321 ~L, 2.3 mmol) in 10 mL
methylene chloride. The stirred reaction was allowed to attain ambient temperature overnight. The volatiles were evaporated and the residue was dissolved in EtOAc and extracted with 1 M H3PO4 (3x), 1 M Na2CO3 (3x), brine (3x); then dried over MgSO4, filtered and concentrated to an orange oil. The crude product was purified by chromatography on silica eluted with 2:1 hexanes-EtOAc to yield 0.92 g, 2.4 mmol (92%) as a slightly yellow glass Rf- 0.22 (2:1 hexanes-EtOAc). The glass was dissolved in hot hexanes-EtOAc, then cooled slowly to -20C. An oil separated out and o~er 24 hours solidified. The solution was decanted and the solid was collected using hexanes to yield 769 mg (84%). mp= 63-7C. [a]D= -20.4 (c=1.0, MeOH). MS(CI) m/e 398(m+H) , 241, 213. 1H
NMR(CDCl3,300MHz) ~ O.88(t,J=7Hz,3H), 0.93(t,J=6Hz,3H), 1.24-1.43(m,8H), 1.51-1.75(m,3H), 1.80-1.90(m,lH), 1.94-2.28~m,3H), 2.32-2.45(m,lH), 3.16-3.37(m,2H), 3~43-3.54(m,2H), 4.0-4.08(m,lH), 4,12-4.2(m,lH), 5.02~dd,J=4,8Hz,lH), 6.96(bs,1H), 7.12(dt,J=1,8Hz,lH), 7.28(dt,J=1,7Hz,lH), 7.48~dd,J=1,8Hz,lH), 7.67(d,J=8Hz,lH), 9.30(s,1H) C,H,N analysis calculated for C24H35N3O2: C 72.50, H 8.87, N 10.57; found: C 72.55, H 8.91, N 10.49.
,. ~ . . .. . . .. . . . . . .
- -.: .. :- :: - .. -.: . : - :: . . . - -:: : : :--:. -: .: ., : .... , .: : . .. :.
WO 91tO0725 PCT/US90/03630 . . . ~
~m~ lQ~
Methyl 2-(3'-Ouinolylcarbonylamino)-2-methylpro~ionate Quinoline-3-carboxylic acid (1.12g, 6.5 mmol~, methyl a-aminoisobutyrate (l.Og, 6.5 mmol) and TEA (1.8 mL, 1.3 mmol) were dissolved in 50 mL methylene chloride and treated with EDCI (1.2g, 6.5 mmol) overnight. The solvent was evaporated and the residue was extracted as in example 71 to give a white solid, 660 mg, 2.58 mmol (40%). mp=
138-140 C. MS(CI) m/e 273(m+H) . H NMR(CDCl3,300MHz) 1.75~s,6H), 3.82(s,3H), 7.06(s,lH), 7.62(d,J=1,7Hz,lH), 7.81(dt,J=1,7Hz,lH), 7.91(dd,J=1,8Hz,lH), 8.15(d,J=8Hz,lH), 8.58(d,J=2Hz,lH), 9.28(d,J=2Hz,lH).
E~ 105 2-(3'-Ouinolvlcarbonvlamino)-2-methvlpropionic acid The product of example 104 (620 mg, 2.42 mmol) was dissolved in 50 mL methanol and treated with 1 N NaOH (2.5 mL, 2.5 mmol). An additional 2.5 mL was added after 1 day. After 2 days, the solvent was evaporated and the residue was dissolved in water and extracted with ethylacetate. The aqueous phase was then acidified and re-extracted with ethylacetate. This second EtOAc layer was dried over MgSO4, filtered and evaporated to yield 406 mg, 1.67 mmol (69%). Rf= 0.3 (80:20:~ CHCl3-CH30H-NH40H).
Example 1062-(3'-Ouinolylcarbo~ylamino)-2-m~thylpropion-di-n-pent~ zmide The product of example 105 (100 mg, 0.413 mmol), dipentylamine (202 ~L, 1.0 mmol) and TEA (59 ~L, 0.42 ' ' . ' ' . ' ' ' ` ' ': ' WO 91~0072~ PCT/US90tO3630 2~ 55 .
- .
mmol) were dissolved in 15 mL methylene chloride, treated with EDCI (80 mg, 0.42 mmol) and stirred at room temperature overnight. The solvent was evaporated and the residue was dissolved in ethylacetate and extracted as in example 71. NMR indicated the presence of undesired dehydrated product (oxazolone). MS(CI) m/e 241(m+H) . lH
NMR(CDCl3,300MHz) ~ 1.61(s,6H), 7.66(dt,J=l,'Hz,lH), 7.86(dt,J=1,7Hz,lH), 7.94(dd,J=1,8Hz,lH), 8.20(d,J=8Hz,lH), 8.74(d,J=2Hz,lH), 8.98(d,J=2Hz,lH). The crude dehydrated product was redissolved in 25 mL THF and treated with dipentylamine (202 ~L, 1.0 mmol). Another 400 mL of dipentylamine was added at 2 and 4 days. After evaporation of the solvent, the residue was purified by chromatography on silica gel eluted with a 4:1 to 1:1 hexane-ethylacetate step gradient to yield 51 mg, 0.13 mmol ~32~). mp= 139-5C. MS(CI) m/e 398(m+H) , 158. lH
NMR(CDC13,300MHz) ~ 0.92~t,J=7Hz,6H), 1.25-1.49(m,12H), 1.90(s,6H), 3.40(bs,4H), 7.61(dt,J=1,7Hz,lH), 7.80(dt,J=1,7Hz,lH), 7.91(dd,J=1,8Hz,lH) 8.15(d,J=8Hz,lH), 8.58(d,J=2Hz,lH), 8.69(s,lH), 9.37(d,J=2Hz,lH). C,H,N
analysis calculated for C24H35N3O2, 0.25 H2O: C 71.69, H
8.90, N 10.45; found: C 71.65, H 8.74, N 10.39.
~xample 107 N-(3'-Ouinolvlcarbonyl)-R-L~rsine-d--n-pentylamide hydrobromide The product of example 62 (1.61 g, 2.64 mmol) was treated with 15 mL of HBr in HOAc (1.1 N, 16.5 mmol) for 2 hours under an inert atmosphere. The solvent was evaporated and the residue was purified by chromatography :: . : .- - - : .
-:
, .: : .
':'.': ' ' ' ' WO9l/00725 PCT~US90/03630 . j, .
2~ 755 on silica gel eluted with a methylene chloride to 1%
ethanol in CH2Cl2 step gradient to yield 1.25 g, 2.39 mmol (91%) as a yellow glass. mp= 85-95 C. H
NMR~DMSOd6,300MHz) ~ 0.85(t,J=7Hz,6H), 1.23-1.83(m,18H), 2.78(t,J=7Hz,2H), 3.06-3.17(m,1H), 3.28-3.44(m,3H), 4.86-4.93(m,lH), 7.57(bs,2H), 7.72(dt,J=1,7Hz,lH), 7.88(dt,J=1,7Hz,lH), 8.10(d,J=8Hz,2H), 8.92(a,J=2Hz,lH), 9.02(d,J=8Hz,lH), 9.32(d,J=2Hz,lH).
ExampLe 108 Na-t3'-Ouinolylcarbonyl)-~-~henylthiolcarbonyl-R-Lysine dipentylamide The product of example 107 (20 mg, 0.045 mmol) was treated with carbonyldiimidazole (8.1 mg, 0.05 mmol) in 10 mL methylene chloride at room temperature overnight.
Thiophenol ~10.3 ~L, 0.10 mmol) and 10 mL THF were added and the mixture was heated to 60C. After 1 day, the reaction was eluted on silica gel with 1% ethanol in methylene chloride to yield an oil. MS(CI) m/e 577(m+H) , 467, 420. H NMR(CDCl3,300MHz) ~ 0.88-0.96(m,6H), 1.23-1.86(m,18H), 3.12(dt,J=7,13Hz,lH), 3.22-3.44(m,4H), 3.59(dt,J=7,13Hz,lH), 5.0-5.17(m,lH), 5.70(t,J=SHz,lH), 7.32-7.37(m,3H), 7.47-7.51(m,3H), 7.62(dt,J=1,8Hz,lH), 7.82(dt,J=1,7Hz,lH), 7.91(dd,J=1,8Hz,lH), 8.16(d,J=8Hz,lH), 8.63(d,J=2Hz,lH), 9.37(s,J=2Hz,lH).
.
, . .
. ~ , ; - :
, i"755 .,, .~, . . .
_99_ ~ample l N-Benzyloxycarbonyl-R-Phenylalycine-(2'-~ropylpiperidinyl)amide N-Benzyloxycarbonyl-R-phenylglycine (1.0 g, 3.5 mmol), 2-propylpiperidine (1 mL, 6.64 mmol), HOBt (475 mg, 3.5 mmol) and TEA (490 ~L, 3.5 mmol) were dissolved in 25 mL of CH2C12 and treated with BOPCl (890 mg, 3.5 mmol).
Additional TEA (490 ~L) and BOPC1(890 mg) were added after 2 days. After 6 days, the solvent was evaporated and the crude reaction was purified by chromatography on silica gel eluted with a 9:1 to 4:1 hexane-ethylacetate step gradient to yield 179 mg, 0.454 mmol (13%). mp= 100-115C. ~a]D= -13.5 (c=1.0, MeOH). MS(CI) m/e 395(m+H) , 261. H ~MR(CDC13,300MHz) ~ 0.52(t,J=7Hz,lH), 0.92(t,J=7Hz,2H), 1.18-1.70(m,10H), 2.56-2.67(m,0.33H), 3.01(dd,J=2,13Hz,0.67H), 3.57(bd,J-12Hz,0.67H), 3.80(bs,0.33H), 4.51(bd,J=13Hz,0.33H), 4.78(bs,0.67H), 4.98(d,J=llHz,lH), 5.12(d,J=llHz,lH), 5.54(d,J=7Hz,0.67H), 5.58(d,J=7Hz,0.33H), 6.46-6.55(m,1H), 7.28-7.43(m,10H).
~ 0 R-Phenylalycine-(2'-propylpiperidinyl)amide The product of example 109 (150 mg, 0.38 mmol) was treated with 25 mg of 10% Pd on carbon ln 5 mL of methanol under one atmosphere of hydrogen for 24 hours. The catalyst was filtered away and the filtrate was evaporated to yield product.
,: . . . . .
:: . . : ' . . :
:: , ' W09l/0072~ PCT/US90/03630 - 1 o o--~L~ 1 1 1 N-(3'-Ouinolylcarhonyl)-R-Dhenylalyc~ne-(2'-propylpi~eridinyl)amide Quinoline-3-carboxylic acid (38.1 mg, 0.22 mmol), the product of example 110 ~31 mg, 0.22 mmol) and TEA ~31 ~L, 0.22 mmol) were dissolved in 4 mL of 1:1 DMF-CH2Cl2 and treated with EDCI ~42.1 mg, 0.22 mmol) with stirring at room temperature overnight. The solvent was evaporated and the residue was extracted as in example 71. Rf= 0.4 ~1:1 hexane-ethylacetate). MS~CI) m/e 416~m+H) , 261, 154, 128. H NMR~CDCl3,300MHz) ~ 0.55~t,Jz7Hz,lH), 0.94~t,J=7Hz,2H), 1.23-1.72(m,10H), 2 71(dt,J=2,13Hz,0;33H), 3.08~dt,J=2,13Hz,0.67H), 3.68(bd,J=13Hz,0.67H), 3.93(bs,0.33H), 4.58(bd,J=13H~,0.33H), 4.85(bs,0.67H), 6.03(d,J-7Hz,0.67H), 6.07(d,J=7Hz,0.33H), 7.3-7.42(m,3H), 7.52-7.63(m,3H), 7.80(dt,J=1,7Hz,lH), 7.90(d,J=8Hz,lH), 8.14(d,J=8Hz,lH), 8.28(t,J=6Hz,lH), 8.59(d,J=2Hz,lH), 9.34(d,J=2Hz,lH). C,H,N analysis calculated for C26H29N3O2, 0.5 H2O: C 73.56, H 7.12, N 9.90; found: C
73.60, H 7.10, N 9.61.
~xamPle 11~
N-(4',8'-Dihydroxy-2'-quinolylcarbonyl)-R-phenylglycine-(2'-propylpiperidinyl)amide 4,8-Dihydroxyquinoline-2-Carboxylic acid (45 mg, 0.22 mmol), the product of example 110 (S2 mg, 0.20 mmol) and TEA (31 ~L, 0.22 mmol) were dissolved in 4 mL of 1:1 DMF-methylene chloride and treated with EDCI (42 mg, 0.22 mmol) with stirring overnight. The reaction was then . ~
. , .. . : . .
~, .: :, :- , .. : , ::
" ,,, W091J0072~ PCT/US~0/03630 , . .
2~ 55 po~red into ethylacetate and extracted as in example 71.
The resulting residue was purified by chromatography on silica gel eluted with a 1% to 9% ethanol in methylene chloride step gradient. MStCI) m/e 448(m+H) , 293. H
NMR~DMSOd6,300MHz) ~ 0.71(t,J=7Hz,lH), 0.81-0.90(m,2H), 1.15-1.70(m,10H), 3.07(bt,J=13Hz,0.67H), 3.33(s,H2O), 3.68(bd,J=12Hz,0.67H), 4.02(bs,0.33H), 4.36(d,J=8Hz,0.33H), 4.68(bs,0.67H), 6.12-6.17(m,lH), 7.09(d,J=7Hz,lH), 7.32-7.56(m,8H), 9.89(d,J=8Hz,0.67H), 10.08(d,J=8Hz,0.33H), 10.23(s,0.67H), 10.24(s,0.33H), 11.73(bs,lH).
Example 113 -Benzyloxvcarbonyl-R-phenvlalvcine-(N-benzyl ~-2'-cyanoeth~l)am;de N-Benzyloxycarbonyl-R-phenylglycine (285 mg, 1.0 mmol), 3-(benzylamino)propionitrile (391 ~L, 2.5 mmol) and TEA (139 ~L, 1.0 mmol) were dissolved in 10 mL of CH2Cl2 and treated with BOPCl (256 mg, 1.0 mmol). After 1 day, another 139 ~L of TEA was added. After 2 days, additional BOPCl (256 mg), amine (391 ~L) and ~MF (5 mL) were added.
After 3 days, the solvents were evaporated and the residue was extracted as in example 71. The crude residue was recrystallized from hexanes-ethylacetate to yield 314 mg, 0.74 mmol (74~). Rf= 0.75 (1:1 hexanes-ethylacetate).
mp= 114-150 C. [a]D= -9. 4 (c=0.67, 1:1 DMF-MeOH).
MS(CI) m/e 428(m+H) , 445, 384, 375. H NMR(CDC13,300MHz) 2.45-2.66(m,2H), 3.33-3.42(m,lH), 3.46-3.52(m,0.5H), 3.66-3.75(m,lH), 4.38~d,J=16Hz,lH), 4.43-4.5(m,0.5H), 4.63(d,J=16Hz,lH), 4.69(s,0.5H), 5.01-5.2(m,3H), ... .. , - ~.:
.
~ ' ', : ' .
WO91/00~2~ PCT/US90/03~30 5.59~d,J=7Hz,0.5H), 5.66(d,J-7Hz,lH), 6.88(s,0.5H), 6.18-6.27(m,1.5H), 6.82(bs,0.5H), 6.95(t,J=4Hz,2H), 7.10-7.18(m,2H), 7.28-7.39(m,15H). C,H,N calculated for C26H25N3O3, 0.1 H2O: C 72.74, H 5.92, N 9.79; found: C
72.79, H 5.99, N 9.40.
Example 114 R-Phenvlglycine-(N-benzyl~N-2'-c~anoethyl)amide The product of example 113 (225 mg, 0.53 mmol) was dissolved in 25 mL of ethanol and treated with 100 mg of 10% Pd/C at room temperature. After 1.5 hours, the catalyst was filtered and the filtrate was evaporated to yield 158 mg, 0.54 mmol(quantitative). MS(CI) m/e 294(m+H) , 241.
~am~le 11~
N-(3'-Ouinolylcarbonyl)-R-phenylalycine (N-benzyl.N-2'-cyanoethyl)amide Quinoline-3~carboxylic acid (35 mg, 0.20 mmol) and the product of example 114 (53 mg, 0.18 mmol) were dissolved in 10 mL of methylene chloride and treated with EDCI (38 mg, 0.20 mmol). After 1 day, the solvent was evaporated and the residue was extracted as in example 71 to give 54 mg, 0.12 mmol (67%). [a]D= -0.42 (c-2.6, CHCl3). mp= 57-63 C. MS(CI) m/e 449(m+H) . H
NMR(CDCl3,300MHz) ~ 1.90-2.02(m,0.25H), 2.27-2.38(m,0.25H), 2.49-2.72(m,1.5H), 3.42(dt,J=7,13Hz,lH), 3.81(dt,J=7,13Hz,lH), 4.46(d,J=16Hz,lH), 4.73(d,J=16Hz,lH), 6.11(d,J=6Hz,0.25H), 6.16(d,J=7Hz,0.75H), 6.98-7.02(m,2H), 7.19-7.22(m,0.5H), .
, .. , : . ' '' :~ -: ~, - : .
WO9l/00725 PCT/US90/03630 21?5~55 7.30-7 33~m,2.5H), 7.38-7.46~m,3H), 7.53-7.64~m,3H), 7.82~dt,J=1,7H,lH), 7.85-7.94~m,2H), 8.15~d,lH,J=8Hz), 8.61~d,J=lHz,lH), 9.33~d,J=lHz,lH). C,H,N analysis calculated for C28H24N42' 0-7 H2 12.15; found: C 72.86, H 5.58, N 11.77.
Exam~le 116 N-(4'.8'-Dihvd~xy-2'-quinolylcarbonyl)-R-phenylqlycine (~-benzyl,N-2'-cyanoethyl)amide 4,8-Dihydroxyquinoline-2-carboxylic acid (41 mg, 0.20 mmol), the product of example 114 ~53 mg, 0.18 mmol), and TEA ~28 ~L, 0.20 mmol) were dissolved in 5 mL of DMF and treated with EDCI ~38 mg, 0.20 mmol). Additional TEA ~28 ~L) and EDCI ~38 mg) were added after 2 hours and 1 day.
After 2 days HOBt (27 mg, 0.20 mmol) was added to the reaction mixture. After 3 days, the solvent was evaporated and the residue was extracted with 0.1 M citric acid, and water and the organic solution was dried over MgSO4 then filtered and concentrated. The crude product was purified by silica gel chromatography eluted with 1:1 hexanes-ethylacetate to provide 22.6 mg, 0.05 mmol ~26~).
Rf= 0.4 ~1:1 hexane-ethylacetate). mp= 218-222 C. ~a]D=
-4.8 ~c=0.42, MeOH). MS~CI) m/e 481(m+H) , 428. lH
NMR~CD30D,300MHz) ~ 2.47-2.58~m,0.33H), 2.6-2.82(m,2H), 3.33-3.62~m,2.33H), 3.68-3.78~m,0.33H), 3.82-3.91~m,lH), 4.53~d,J=16Hz,lH), 4.62~d,J=14Hz,0.33H), 4.76(d,J=16Hz,lH), 4.87(s,H2O), 4.92~d,J=5H2,0.33H), 6.18(s,lH), 7.10~dd,J=1,7Hz,lH), 7.2-7.35~m,7H), 7.39-7.46(m,3H?, 7.51-7.60~m,2H), 7.67(dd,J=1,8Hz,lH).
... , .. . , , . . - - -: - ~, , WO91J00725 PCT/US90tO3630 ~, . . .
Example 111 N-(3'-Ouinolvlcarbonyl)-R-Tyrosine-di-n-pentylamide hydrochlor de hvdrochloride The product of example 80 (1.5 g, 3.0 mmol) was treated with 1.4 N HCl in dioxane (11 mL, 15 mmol) for 10 minutes. The excess reagent was evaporated and the oily residue was triturated with diethylether and filtered to yield 1.3 g, 2.6 mmol (87%) of a pale yellow solid.
MS(CI) m/e 476(m+H) , 958. H NMR(DMSOd6,300MHz) ~
0.84(t,J=7Hz,6H), 1.15-1.62(m,12H), 2.87-3.22(m,3H), 3.29-3.40(m,3H), 5.02(apparent q,J=7Hz,lH), 6.66(d,J=8Hz,2H), 7 11(d,Jz8Hz,2H), 7.78(dt,J=1,8Hz,lH), 7.96(dt,J=1,8Hz,lH), 8.17(t,J-7Hz,2H), 9.04~d,J-2Hz,lH), 9.22(d,J=8Hz,lH), 9.33(d,J-2Hz,lH). C,H,N analysis calculated for C29H37N3O3, 1.3 HCl: C 66.60, H 7.38, N
8.03; found: C 66.43, H 7.38, N 7.99.
Example 118 N-(3'-Ouinolylcarbonvl)-R-Histidine-di-n-pentylamide dihydrochloride The product of example 50 (800mg, 1.78 mmol) was dissolved in 13 mL of 1.4 N HCl in acetic acid for 10 mln and then the volatiles were evaporated to remove excess reagent. The oily residue was dissolved in a small amount of CH2Cl2 and the product was precipitated with hexanes.
The solid was collected to yield 824 mg, 1.58 mmol (89~).
MS(CI) m;e 450(mtH) . H NMR(DMSOd6,300MHZ) ~
, ~, :' . '. , . . ?
, :. ' . . ~ ~ , . . . .. .
: ' :, : - . , . ~ . :-.:
WO 91/0072~ PCT/US90/0363~
0.74(t~J=7Hz,3H), 0.85(t,J=7Hz,3H), 1.12-1.32(m,8H), 1.41-1.52(m,4H), 3.08-3.43(m,6H), 5.24-5.31(m,lH), 7.45(s,lH), 7.77(dt,J=1,7Hz,lH), 7.94(dt,J=1,7Hz,lH), 8.15~dt,J=1,9Hz,2H), 9.02(s,2H), 9.31-9.33(m,2H), 14.18(s,lH), 14.57(s,1H). C,H,N analysis calculated for C26H35N5O2, 2.6 HCl: C 57.36, H 6.96, N 12.87; found: C
57.30, H 6.96, N 12.86.
Example 119 N-(4',8'-Dihydroxy-2'-quinolylcarbonyl)-R-(4'-hydro~yphenyl)-alycine-di-n-pentylamide The reaction was performed in a similar manner to that in example 8 utilizing 0.3 g of the compound of example 64, 4',8'-dihydroxyquinoline-2-carboxylic acid ~0.2 g), EDCI ~0.21 g), HOBt ~0.13 g) and NMM ~0.22 mL).
The product was isolated in 75% yield ~0.37 g). MS~CI) m/e 494~m+H) .
H NMR(DMSOd6,300MHz) ~ 0.85(m,6H), 1.1-1.35(m,10H), 1.38-1.45(m,4H), 3.0-3.5(m,4H), 5.95(d,Jz9Hz,lH), 6.76(d,J=9Hz,2H), 7.08(d,J=9Hz,lH), 7.23(d,J=9Hz,2H), .
7.4(t,J=9Hz,lH), 7.55~m,2H), 9.5~bs,lH), 9.75(d,J=lOHz,lH). C,H,N calculated for C28H35N3O5, 0.5 H2O: C 66.91, H 7.22, N 8.36; found: C 66.76, H 7.20, N
8.18.
Example 120 N-Benzyloxycarbonyl-alycine-di-n-pentylamide The compound was prepared in a manner similar to that in example 1 utilizing N-t-butyloxycarbonylglycine.
MS~CI) m/e 349(m+1) , 305, 241, 215, 184. lH
WO91/00~2~ PCT/US90/03630 ~, 2~ S5 NMR(CDC13,300MHz) ~ 7.30-740(m,5H), 5.86(bs,1H), 5.12(bs,2H), 4.0(bd,J=4.5Hz,2H), 3.32(t,J=7.5Hz,2H~, 3.15(t,J=7.5Hz,2H), 1.50-1.70(m,4H), 1.20-1.40(m,8H), O.9(m,6H).
Example 1~1 N-(2'-Indolylcarbonyl)-~lycine-di-n-pentylamide The product of example 120 was deprotected in a manner similar to that in example 80. The free amine product was then coupled with indole-2-carboxylic acid as in example 4. mp= 98-100 C. MS(EI) m/e 3S7(m) , 287, 184. lH NMR(CDCl3,300MHz) ~ 9.27(s,lH), 7.67~d,J=6Hz,lH), 7.95(bd,J=7Hz,2H), 7.29(dt,J=1,6Hz,lH), 7.14(dt,J=1,6Hz,lH), 6.98(s,lH), 4.27(d,J=9Hz,2H), 3.~9(bt,J=7Hz,2H), 3.25(bt,Jz7Hz,2H), 1.55-1.70(m,4H), 1.25-1.40(m,8H), 0.93(t,J=6Hz,3H), O.91(t,J=6Hz,3H).
C,H,N analysis calculated for C21H31N3O2, 0.3 H2O: C
69.51, H 8.78, N 11.58; found: C 69.45, H 8.58, N 11.47.
Example 122 Ethvl N-(t-Blltyloxycarbonyl~alycinyl-lN-benzyl)alycinate N-t-Butyloxycarbonylglycine and ethyl N-benzylglycinate were coupled in a manner similar to that in example 1 to provide product.
. .
.. : : - ' : . .
.. , . ~ . . ..
, 2~ 755 . . .
~xam~le 12~
Ethyl N-(3'0uinolvlcarbonvl)glycinyl (N-benzyl)alvcinate The product of example 122 was deprotected in a manner similar to that in example 2 and then coupled in a manner similar to that in example 3 to provide product.
MS(CI) m/e 406(m+H) , 334, 194. lH NMR(CDC13,300MHz) 9.37(d,J=2Hz,0.33H), 9.35(d,J=2Hz,0.67H), 8.65(bm,1H), 8.18(bd,J=7Hz,lH), 7.94~m,lH), 7.83~m,lH), 7.63(m,lH), 7.43-7.55(m,lH), 7.30-7.40(m,3H), 7.25(m,2H), 4 73(s,0.67H), 4.67(s,1.33H), 4.51(d,J=4Hz,1.33H), 4.33(d,J=4Hz,0.33H), 4.16-4.25(m,2H), 4.13(s,1.33H), 4.00(s,0.67H), 1.28(m,3H).
., E~melQ 1~4 N-(t-Butyloxvcarbonvl)-R-homo~henvlalanine-di-n-pentylamide The product was prepared in an analogous manner to that in example 1 using t-Butyloxycarbonyl-R-homophenylalanine. MS(CI) m/e 419(m+H) , 363, 345, 319.
H NMR(CDC13,300MHz) ~ 1.85(m,lH), 7.48(m,lH), 7.18-7.32(m,5H), 5.39(bd,J=9Hz,lH), 4.56(m,lH), 3.48(dt,J=7,14Hz,lH), 3.39(t,J=7Hz,lH), 3.08(m,2H), 2.68(m,2H), 1.88(m,2H), 1.45(s,9H), 1.20-1.35(m,8HI, 1.13(m,2H), 0.88(m,6H).
:. ~. , : - .
. ., , . : . -. - , .
: ~ , : - :
:~ ,. , ", Z(.'~ ~ 5~
N-(3'-Ouinolylcarbonyl)-R-homophenylalanir.e-di-n-pentylamide The product was prepared in analogous manner to those in examples 2 and 3 utilizing the product of example 124 as the starting material. MS~CI) m/e 97q(m+H) , 369, 319, 305, 289. H NMR~CDCl3,300MHz) S 9.32~d,J=2Hz,lH), 8.53(d,J=2Hz,lH), 8.16(bd,J=8Hz,lH), 7.90(dd,J=1,8Hz,lH), 7.82(m,lH), 7.62(m,1H), 7.40(bd,J=8Hz,lH), 7.30(m,4H), 7.20(m,lH), 5.19(m,lH), 3.55-3.70(m,lH), 3.05-3.20(m,3H), 2.78(bt,J=7.5Hz,2H), 2.15(m,2H), 1.50-1.65(m,4H), 1.15-1.35(m,8H), 0.90(m,6H).
E~ ~
N-(3'-Q~innlylcarbonyl)al~cine Quinoline-3-carboxylic acid and methyl glycinate hydrochloride were coupled in a manner similar ~o that in example 3. The resulting product was subjected to saponification in methanol with 1 N NaOH. The desired product was extracted with EtOAc from the acidified solution or alternatively allowed to slowly precipitate from the acidified solution. MS(CI) m/e 231(m+H) , 187.
H NMR(DMSOd6,300MHz) S 12.72~bs,1H), 9.32(d,J=9Hz,lH), 9.11(t,J=6Hz,lH), 8.87(d,J=3Hz,lH), 8.12(t,J=7H ,2H), 7.89~t,J=7Hz,lH), ?.71(t,J=7Hz,lH), 4.03(bs,2H).
.: . :: , , . ~
-:
W09lt00725 PCT/US90/03630 2(?~?755 Example 127 N- (3'-Ouinolylcarbonyl~alycine-di-n-pentylamide The product of example 126 and di-n-pentylamine were coupled in a manner similar to that in example 1. The product was isolated by chromatography and solidifies upon concentration. mp= 36-375. MS~CI) m/e 370~m+H) . lH
NMR~CDC13,300MHz) ~ 9.38~d,J=2Hz,lH), 8.65~d,J=1.8Hz,lH), 8.18~d,J=8.5Hz,lH), 7.93~dd,J=1,8Hz,lH), 7.83~m,lH), 7.69(m,2H), 4.32(d,J=3.7Hz,2H), 3.41(bt,J=8Hz,2H), 3.27(bt,J=8Hz,2H), 1.62(m,4H), 1.30-1.45(m,8H), 0.95~t,J=7Hz,3H), 0.92~t,J=7Hz,3H). C,H,N analysis calculated for C32H31N32 C 71-49~ H 8-46~ N 11-37 found: C 71.28, H 8.42, N 11.36.
Example 1~
N-(3'-Ouinolylcarbonyl)alvcine-(~-propyl)piperidinylamide The acid from example 126 and 4-propylpiperdine were coupled as in example 1. mp= 116-117C. MS~CI) m/e 340(m+H) , 279, 254, 201. lH NMR~CDCl3,300MHz) ~
9.36~d,J=2Hz,lH), 8.63~d,J=2Hz,lH), 8.16~d,J=8.5Hz,lH), 7.93~dd,J=1,8Hz,lH), 7.82(m,lH), 7.60(bs,lH), 7.63(m,lH), 4.61(dt,J=2,13Hz,lH), 4.31(m,2H), 3.79(bd,J=lOHz,lH), 3.07(dt,J=3,13Hz,lH), 2.70(dt,J=3,13Hz,lH), 1.81(bm,2H), 1.55(m,lH), 1.05-1.40(m,6H), 0.92(t,J=7Hz,3H). C,H,N
analysis calculated for C20H25N3O2, 0.1 H2O: C 70.40, H
7.44, N 12.31; found: C 70.19, H 7.44, N 12.15.
.. ~ , :
: - , . ::, ,. ~ : -:, , - -:
,, "
WO91/00725 PCT/US90/0363~
2~ J
E~mel~ 129 N-Benzvlo~ycarbonyl-R-phenylalvcine-di-n-~entylamide The product was obtained from the coupling of N-Benzyloxycarbonyl-R-phenylglycine and di-n-pentylamine as in example 1. MS(CI) m/e 425(m+H) , 333, 317, 291. lH
NMR(CDCl3,300MHz) ~ 7.27-7.45(m,10H), 6.48(bd,J=7.5Hz,lH), 5.53(d,J=7.5Hz,lH), 5.12(d,J=12Hz,lH), 5.01(d,J=12Hz,lH), 3.48(m,lH), 3.18(m,2H), 2.97(m,lH), 1.50(m,4H), 1.10-1.35(m,8H), 0.87(t,J=7.5Hz,3H), 0.84(t,J=7.5Hz,3H).
Exam~le 130 R-Phenylalycine-dl-n-pentylamide The product resulted from the hydrogenolysis of the product of example 129. MS(CI) m/e 291(m+H) , 158. H
NMR(CDC13,300MHz) ~ 7.25-7.40(m,5H), 4.65~bs,lH), 3.52~m,lH), 3.08-3.22(m,2H), 2.92(m,lH)j 2.02~bs,2H), 1.50(m,3H), 1.10-1.35(m,9H), 0.88(t,J=7Hz,3H), 0.85(t,J=7Hz,3H).
N-(3~ouinolylcarbonyll-R-phenylalyclne-di-n-pentylamide The product of example 130 was coupled in a similar manner to that in example 3 to provide product. MS(CI) m/e 446(m+H) . H NMR(CDCl3,300MHz) ~ 9.33(d,J=2Hz,lH), 8.58(d,J=2Hz,lH), 8.13(bt,J=8Hz,2H), 7.88(bd,J=8Hz,lH), 7.79(m,lH), 7.62(m,1H), 7.55(m,2H), 7.32-7.42(m,3H), 6.03(d,J=6Hz,lH), 3.55(m,3H), 1.15-1.40(m,9H), 0.90(t,J=7Hz,3H), 0.86(t,J=7Hz,3H).
.. ~ .......... . . .
,: .- . . . :~, - ,- . . . :.:
WO91/On~25 PCT/US90/03630 `:
Z~. 5,_7155 Example 1~2 N-(4',8'-Dihydro~y-~'-~inQlylc~arbonyl)-R-Phenylglycine-di-n-~entylamide The product of example 130 was coupled in a similar manner to that in example 8 to provide the title compound.
mp= 89-91C. MS(CI) m/e 478(m+H) , 293, 190, 177. lH
NMR(DMSOd6,300MHz) ~ 9.91(bd,J=8Hz,lH), 7.55(m,2H), 7.35-7.45(m,7H), 7.08(dd,J=1,7.5Hz,lHj, 6.11(bd,J=8Hz,lH), 3.05-3.30(m,4H), 1.60(m,lH), 1.48(m,2H), 1.13-1.35(m,9H), 0.85(t,J=7Hz,3H), 0.78(t,J=7Hz,3H). C,H,N analysis calculated for C28H35N34' 0-3 H2 8.70; found: C 69.61, H 7.40, N 8.65.
Example 133 N-(3'-Chlorophenylaminocarbonyl)-R-phenylglycine-di-The product of example 13b was reacted with 3-chlorophenylisocyanate to provide the title compound.
MS(CI) m/e 444(m+H) , 425, 317, 291, 259, 242. lH
NMR(CDC13,300MHz) ~ 7.95(bs,1H), 7.42(m,1H), 7.22-7.34(m,5H), 7.13(d,J=7.5Hz,lH), 7.08(m,2H), 6.89(m,lH), 5.92(d,J=8Hz,lH), 3.50(m,lH), 3.00-3.30(m,4H), 1.43-1.63(m,3H), 1.10-1.30(m,8H), 0.84(t,J=7Hz,3H), 0.78(t,J=7Hz,3H).
,. . i, , :- , .: , : : .
. . ,. : . -- . -:
, ,~ ...
- :
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,'' ~ ~ ' " ',' ' W09l/00725 P~T/US90/03630 2~ , SS
~m~l~ 134 N-(3'-Methylphenylaminocarbonyl)-R-phenylqlYcine-di-n-pentylamide The product of example 130 was reacted with 3-methylphenylisocyanate to provide the title compound.
MS(CI) m/e 424(m+H) , 374, 317, 291, 276, 239, 228. H
NMR(CDCl3,300MHz) ~ 7.27-7.48(m,5H), 7.18~m, L H), 7.12~d,J=8Hz,lH), 7.06~m,2H), 6.82~bd,J=8Hz,lH), 6.77(bd,J=8Hz,lH), 5.87(d,J=8Hz,lH), 3.51~m,lH), 3.20~m,2H), 3.04~m,1H), 2.28~s,3H), 1.50~bm,qH), 1.10-1.30~m,8H), 0.84~t,J=7Hz,3H), 0.82~t,J=7Hz,3H).
Example 135 N-(5'-Fluoroindolylcarbonyl)-R-p:~enylalycine-di-n-pentylamide The product of example 130 was reacted with 5-fluoroindole-2-carboxylic acid in a manner similar to that in example 4 to provide the desired product. mp= 94-6C.
MS~CI) m/e 452~m+H) , 276, 267, 184. H NMR(CDCl3,300MHz) 9.36(bs,lH), 7.96(d,J=7Hz,lH), 7.50~m,2H), 7.30-7.40~m,3H), 7.36~s,lH), 7.33(m,lH), 6.98(dt,J=2.5,9Hz,lH), 6.91(m,lH), 5.94(d,J=7Hz,lH), 3.53(m,lH), 3.13-3.30(m,2H), 3.04(m,lH), 1.45-1.65~m,4H), 1.10-1.40~m,8H), 0.89(t,J=7Hz,3H), 0.85(t,J=7Hz,3H). C,H,N analysis calculated for C27H34FN3O2: C 71.81, H 7.59, N 9.31;
found: C 71.53, H 7.50, N 9.30.
.: . :
,: . . . : . . . -.. . : . ~,: - : -. . . ~, , : .
.
., :
.. , . . .. ~ . . . . .
WO91/00725 PCT/US90/0363~
2~5~isS
E~m~l~ 13~
N-(5'-Chloroindolylcarbonyl)-R-phenylalycine-di-n-pentylamide The product of example 130 was reacted with 5-Chloroindole-2-carboxylic acid in a manner similar to that in example 4 to provide the title compound. MS~CI) m/e 468(m+H) , 434, 302, 276, 212. H NMR~CDC13,300MHz) 9.36(bs,lH), 7.97~d,J=7Hz,lH), 7.59(m,lH), 7.50(m,2H), 7.35(m,3H), 7.22(m,2H), 6.89(m,lH), 5.94(d,J=7Hz,lH), 3.53(m,lH), 3.15-3.30(m,2H), 3.04~m,lH), 1.45-l.60(m,9H), 1.10-1.40~m,8H), 0,89~t,J=7Hz,3H), 0.85~t,J=7Hz,3H).
C,H,N analysis calculated for C27H34ClN3O2: C 69.29, H
7.32, N 8.98; found: C 69.49, H 7.36, N 8.95.
E~ ~
N-(2'-Ouinolylcarbonyl)-~-Phenylalycine-di-n-~entylamide The product of example 130 was coupled in a similar manner to that in example 5 to provide the desired compound. mpz 116-7 C. MS~CI) m/e 446~m+H) , 289, 277, 261, 246. H NMR~CDCl3,300MHz) ~ 9.62~d,J=8Hz,lH), 8.24(bs,2H), 8.17~d,J=8Hz,lH), 7.83~d,J=8Hz,lH), 7.74~m,lH), 7.59~m,3H), 7.30-7.40~m,3H), 6.06~d,J=8Hz,lH), 3.61~m,lH), 3.32~m,lH), 3.0-3.20~m,2H), 1.50-1.65~m,4H), 1.15-1.40~m,8H), 0.89~t,J=7Hz,3H), 0.87~t,J=7Hz,3H).
C,H,N analysis calculated for C28H35N3O2: C 75.47, H 7.92, N 9.43; found: C 75.45, H 7.91, N 9.43.
- . .
~ ',, ', ' ':' `, ~- , ' ' - :, , ; .......... : . "
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WO91/0072~PCTJUS90/0363~
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21?~755 E~
N ' - (t-Butyloxycarbonyl)-l-amino-cvclch~x~ne-(di-n-pentyl)carboxamide The product was prepared as in example 1 from di-n-pentylamine and N ' -t-Butyloxycarbonyl-l-aminocyclohexane carboxylic acid. MS(CI) m/e 383(m+H) . H
NMR~CDCl3,300MHz) ~ 4.70(bs,1H), 3.20-3.50(m,4H), 1.85-2.0(m,4H), 1.45-1.70(m,8H), 1.42(bs,9H), 1.20-1.90(m,10H), 0.92(bt,J=7Hz,6H).
~xample 139 N ' - (3'-Ouinolylcarbonyl~ amino-cyclohexane-(di-n-pentyl)carboxamide The desired product was prepared via deprotection of the product of example 138 ~in a manner similar to that in example 2) and coupling with quinoline-3-carboxylic acid as in example 3. mp= 136-137C.
Example 140 N ' - (t-Butyloxycarbonyl)-l-am~n~=ÇYclohexane(N-pentyl)carboxamide The product was prepared via coupling of N'-t-Butyloxycarbonyl-l-aminocyclohexane carboxylic acid and pentylamine as in example 1. MS(CI) m/e 313~m+H) , 257, 239, 213, 198. H NMR(CDC13,300MHz) ~ 6.70(s,lH), 4.52(bs,lH), 3.23(m,2H), 1.80-2.05(m,4H), 1.65(m,4H), 1.99(s,9H), 1.25-1.38(m,8H), 0.88(t,J=7Hz,3H).
: ~: j ,. : . . . . . : . - .
i i . , .-; - ~ : : . . .
. : ~ ; , ,: . :.
WO9l/0072~ PCT/US90/03630 . :
2(~ 7SS
. .
. . ..
E~ ~
N'-(3'-Ouinolylcarbonyl~-l-amino-cyclohexane-(N-pentyl)carboxamide The product was obtained in a similar manner to that in example 139 using the product of example 140 as the starting material. MS(CI) m/e 368~m+H) . H
NMR(CDCl3,300MHz) ~ 9.38(d,J=2Hz,lH), 8.58(d,J=2Hz,lH), 8.18(d,J=8Hz,lH), 7.94(bd,J=8Hz,lH), 7.83(m,lH), 7.65(m,lH), 7.12(bs,lH), 6.27(bs,lH), 3.38(m,2H), 2.34(m,2H), 2.03(m,2H), 1.65-1.80(m,4H), 1.50-1.60(m,4H), 1.25-1.40(m,9H), 0.88(t,J=7Hz,3H). C,H,N analysis calculated for C22H29N3O2: C 71.91, H 7.95, N 11.43;
found: C 71.73, H 7.95, N 11.33.
N-(4',8'-Dihydroxy-2'-quinolylcarbonyl)alycine-di-n-pentylamide The product of example 120 was deprotected in a manner similar to that in example 80 and the resulting amine was then coupled in a manner similar to that in example 8 to yield the title compound. mp= 158.5-159.5C.
MS~FAB) m/e 402(m+H) , 386, 245, 217. H
NMR(DMSOd6,300MHz) ~ 9.90~bs,lH), 9.80(bs,lH), 7.55(bt,J=8Hz,lH), 7.52(bs,lH), 7.42(m,lH), 7.11(bd,J=8Hz,lH), 4.20(bd,J=6Hz,2H), 3.36(bs,H20), 3.20 -3.33(m,4H), 1.58(m,2H), 1.48(m,2H), 1.20-1.33(m,8H), 0.85(m,6H). C,H,N analysis calculated for C22H31N3O4, H2O: C 62.99, H 7.93, N 10.02; found: C 53.12, H 8.02, N
10 . 01 .
.
.: . -. . : .
. .
. ~ .
Z~ . 55 Exam~le 143 N-(2'-NaDhthovl)~lycine-di-n-~entylamide The product of example 120 was deprotected in a manner similar to that in example 80 and the resulting amine was then coupled in a manner similar to that in example 17 to yield the title compound. MS~CI) m/e 369(m~H) , 200, 184, 172. H NMR(CDCl3,300MHz) S
8.38(s,lH), 7.85-7.95~m,4H), 7.50-7.60(m,3H), 9.30~d,J=4Hz,2H), 3.40(t,J=7.SHz,2H), 3.26(t,J=7.SHz,2H), 1.60(m,4H), 1.25-1.45(m,8H), 0.94(t,J=7Hz,3H), 0.92(t,J=7Hz,3H). C,H,N analysis calculated for C23H32N2O2: C 74.96, H 8.75, N 7.68; found: C 74.44, H
8.75, N 7.55.
N-(6'-Hvdroxy-2'-nanhthoyl)alycine-di-n-pentylamide The product of example 120 was deprot~cted in a manner similar to that in example 80 and the resulting amine was then coupled with 6-hydroxy-2-naphthoic acid in a manner similar to that in example 17 to yield the title compound. MS(CI~ m/e 385~m+H) , 228, 200, 184. 1H
NMR(DMSOd6,300MHz) S 8.58(bt,J=6Hz,lH), 8.36(bs,lH), 7.86(m,2H), 7.63(d,J=8Hz,lH), 7.15(m,2H), 4.14(d,J=5Hz,2H), 3.20-3.35(m,4H), 1.60(m,2H), 1.45(m,2H), 1.20-1.35(m,8H), 0.89(t,J=7Hz,3H), 0.86(t,J=7Hz,3H). C,H,N
analysis calculated for C23H32N2O3: C 71.84, H 8.39, N
7.29; found: C 71.73, H 8.36, N 7.21.
:: ., . .: :, ,, ,, , ". ::, .: : -.: . . . .. . .~ -.
WO91/00725 PCT~US90/03630 ':
~ample 145 N-~'-Methylphenylaminocarbonvl)alvcine-di-n-E~nt~lamide The product of example 120 was deprotected in a manner similar to that in example 80 and the resulting amine was then coupled with 3-methylphenylisocyanate to yield the title compound. mp= 66-7C. MS(CI) m/e 348(m+H) , 241, 215, 200, 184. H NMR(CDCl3,300MHz) 7.08-7.20(m,3H), 7.03~bs,lH), 6.86(bd,J=7Hz,lH), 6.21(bs,lH), 4.13(bs,2H), 3.32(bt,J=7.SHz,2H), 3.21(bt,J=7.5Hz,2H), 2.30(s,3H), 1.45-1.65(m,4H), 1.20-1.40(m,8H), 0.92(t,J=7Hz,3H), 0.86(t,J=7Hz,3H). C,H,N
analysis calculated for C20H33N3O2:
C 69.13, H 9.57, N 12.09; found: C 68.99, H 9.56, N 12.04.
~xample 196 N-(2'-Chloro~henylaminocarbonyl3-(2R.3S~-(O-benzvl)Threonine-di-n-pentylamide The reaction was performed in a similar manner as in the example above utilizing 0.35 g of the hydrochloride salt of example 30, 2-chlorophenylisocyanate (0.16 g), and TEA (0.135 mL). The product was purified using chloroform and methanol as the elutant mixture. The oily product was isolated in 83% yield (0.42 g). [a]D= +21.8 (c=0.11, MeOH). MS(CI) m/e 502(m+H) . H NMR(CDCl3,300MHz) ~
0.85(m,6H), 1.23(m,11H), 1.43-1.65(m,4H), 3.0-3.21(m,2H), 3.55(m,2H), 3.33(m,lH), 4.57(d,J=lSHz,lH), 4.63(d,J=15Hz,lH), 4.98(m,1H), 6.48(d,J=9Hz,lH), 6.95(t,J=7Hz,lH), 7.2(m,2H), 7.3(m,6H), 8.11(d,J=9Hz,lH).
-t . . , . , - . , , - . . . . . .
. : . ' :, . : :
,, ,,~c~j J~
C,H,N analysis calculated for C28H40ClN3O3, 0.3 CH~13: C
63.19, H 7.55, N 7.81; found: C 63.21, H 7.39, N 7.82.
~m~l~ 147 N-(4' 8'-Dihydroxy-2'-quinolylcar~onyl)-(2R 3S)-(O-benzyl)-Threonine-di-n-pentylamide The reaction was performed in a similar manner as in example 8 utilizing 0.35 g of the hydrochloride salt of example 30 4,8-dihydroxyquinoline-2-carboxylic acid (0.21 g), EDCI ~0.22 g), HOBt (0.14 g), and NMM (0.22 g). The oily product was isolated in 60% yield (0.32 g)- [~]D=
+8.0 (c=0.125, MeOH). MS(CI) m/e 536(m+H) . 1H
NMR(DMSOd6,300MHz) ~ 0.82(m,6H), 1.15-1.3(m,11H), 1.4-1.6(m,4H), 3.2-3.65(m,~H~, 4.08(m,lH), 4.52(d,J=12Hz,lH), 4.63(d,~-12Hz,lH), 4.98(t,J=9Hz,lH), 7.12(m,SH) 7.42(t,J=gHz,lH), 7.55(m,2H), 9.8(d,J=9Hz,lH), 10.4(bs,1H), 11 72(bs,2H) C,H,N analysis calculated for C31H41N3O5, H2O: C 67.25, H 7.83, N 7.59; found: C 67.19, H 7.60, N 7.38.
Example lq8 Methyl Boc-R-Methionine-S-(p-hydroxy)-phenylalycinate Boc-R-methionine (250 mg, 1 mmol) , methyl p-hydroxyphenylglycinate hydrochloride (217 mg, 1 mmol) and triethylamine (139 ~L, 1 mmol) were combined in 10 mL of dichloromethane at 0C and treated with BOPCl (254 mg, lmmol). Additional BOPCl (254 mg) and TEA (134 ~L) were added after one day. After two days, the reaction mixture was poured into EtOAc and extracted successively with 0.1%
citric acid, 0 1 M NaHCO3 and water. The solution was . . . . .
- - .. .
- . -: . , .,:: :.
W09l~00725 PCT/US90/03630 2~ ?~S
therl dried over MgSO4, filtered and evaporated to yield 288 mg, 0.7 mmol (70%). Rf = 0.56 ~1:1 hexanes - EtOAc) mp = 158C ~dec). MS~CI) m/e 413(m+H)+, 357, 313.
1HNMR~CDCl3,300MHz) d 1.43(s,9H), 3.72(s,3H), 6.73(d,J=8Hz,2H), 7.17(d,J=8Hz,2H), 7.33~bs,1H).
Example 149 Methyl R-Methionine-S-(p-hydroxy)-phenylalycinate hvdrochloride The product of the example 148 ~250 mg, 0.6 mmol) was treated with 5 mL of 4 N HCl in dioxane at room temperature under a nitrogen atmosphere. After 30 minutes, the excess reagent was evaporated to yield quantitatively the product.
~xampl~ 150 Methyl N-(3'-Ouinolylcarbonyl)-R-Methionine-S-(p-hydrox.y)-phenylalycinate The hydrochloride salt of example 149 ~50 mg, 0.14 mmol), 3-quinoline carboxylic acid ~26 mg, 0.15 mmol) and TEA ~21 ~L, 0.15 mmol) were dissolved into 5 mL
methylenechloride and treated with EDCI ~29 mg, 0.15 mmol) for 4 hours. The reaction was poured into EtOAc and extracted with 0.1% citric acid and water followed by drying over MgSO4. The resultant filtrate was concentrated and chromatographed over silica gel eluting with a 2:1 to 1:2 hexane - EtOAc gradient to yield 29 mg, 0.06 mmol (44%). MS~CI) m/e 468(m+H)+, 393, 287.
1HNMR(CDC13,300MHz) ~ 2.04~s,3H), 2.12-2.20~m,2H), 2.42-.. "
:, :.
2~ _755 2.52(m,lH), 2.57-2.67(m,lH), 3.65(s,3H), 5.05(q,J=7Hz,lH), 5.41(d,J=6Hz,lH), 6.77(d,J=8Hz,2H), 7.16(d,J=8Hz,2H), 7.59(dt,J=1,7Hz,lH), 7.73-7.82(m,3H), 7.83(d,J=8Hz,lH), 8.12(d,J=8Hz,lH), 8.61(d,J=2Hz,lH), 9.30(d,J=2Hz,lH).
C,H,N analysis calculated for C2qH25N3O5S 0.5 H2O: C
60.99, H 5.60, N 8.81; found: C 60.69, H 5.63, N 8.35.
Example 151 N-(3'-Ouinolylcarbonyl)-R-Serine-di-n-pentylamide BTFA (trifluoroacetoxyboronate) 0.154 g, 0.4 mmol was added to the product of example 27 (71 mg, 0.145 mol) dissolved in 2 mL of methylene chloride. Another mL of methylene chloride was added and the reaction was monitored by tlc. After 20 minutes of stirring at ambient temperature, the starting material was consumed and the solvents with methanul were evaporated under vacuum. This evaporation sequence using methanol was repeated several times . The residue was separated by chromatography using EtoAc-hexane ~1:1) as the elutants. An oily product was isolated in 69~ yield (40 mg). MS(CI) m/e 400 (m+H)+.
lHNMR(CD30D,300MHz) ~ 0.94 (m,6H), 1.26-1.44 (m,8H), 1.54-1.64(m,2H), 1.68-1.86(m,3H), 3.25-3.35(m,lH), 3.43-3.62(m,3H), 3.82-3.96(m,2H), 5.22(t,J=6Hz,lH), 7.73(t,J=6Hz,lH), 7.91(t,J=6Hz,lH), 8.07(d,J=9Hz,lH), 8.12(d,J=9Hz,lH), 8.9(s,lH), 9.28(s,lH).
E~ample 152 N-(8'-~ydro~.y-2-quinolylcarbonyl)-alycine-di-n-pentylamide :. . :. . . . . , ~
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Similar to example 121, the product of example 120 was deprotected and coupled to 8-hydroxy-2-quinolinic carboxylic acid in a standard fashion utilizing EDCI etc.
to provide the product. MS(CI) m/e 386 (m+H)+.
lHNMR(CDC13,300MHz) ~ 8.96(bs,lH), 8.23(s,2H), 8.02(s,lH), 7.53(t,J=7.5Hz,lH), 7.36(dd,J=1,7.5Hz,lH), 7.23(dd,J=1,7.5Hz,lH), 4.34(d,J=5Hz,2H), 3.42(bt,J=8hz,2H), 3.28(bt,J=8Hz,2H), 1.55-1.70(m,4H), 1.25-1.40(m,8H), 0.93(apparent q,6H). C,H,N analysis calculated for C22H31N3O3 0.2 H2O: C 67.91, H 8.13, N
10.80; found: C 67.90, H 8.14, N 10.69.
Example 153 N-Methyl-N-(3'Ouinolylcarbonyl)-alycine-di-n-pentylamide The product of example 127 was methylated using bistrimethylsilylamide and methyl iodide in TH~ at -78C
warming to ambient temperature to provide product after standard workup and purification. MS(DCI) m/e 384(m+H)+.
Example 154 N-(3'-Iodo-2'-indolylcarbonyl)-alycine-di-n-pentylamide The product of example 121- was iodinated with N-iodosuccinimide to provide product after chromatographic purification. MS(DCI) m/e 484(m+H)+. C,H,N analysis calculated for C21H30IN3O2: C 52.18, H 6.25, N 8.69;
found: C 52.09, H 6.21, N 8.49.
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found: C 70.76, H 9.03, N 11.17.
The ability of the compounds of Formula I to interact with CCK receptors and to antagonize CCK can be demonstrated 1~ vitro using the following protocols.
~harmacoloaical Methods CCK8 ~Asp-Tyr(SO3H)-Met-Gly-Trp-Met-Asp-Phe-NH2] was purchased from Peptide International (Louisville,XY) or Cambridge Research Biochemicals (Atlantic Beach, NY) EGTA, HEPES and BSA were purchased from Sigma Chemical Co.
(St. Louis, MO). [125I]BH-CCK8 tspecific activity, 2200 Ci/mmol) and Aquasol-2 scintillation cocktail were obtained from New England Nuclear (Boston, MA). Bestatin and phosphoramidon were purchased from Peptide International. Male guinea pigs, 250 to 325 g, were obtained from Scientific Small Animal Laboratory and Farm (Arlington Heights, IL).
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Pr~tocol fQL B~si~aL~am~ ~i~di~a Experiments 1. Guinea Pig Cerebral Cortical and Pancreatic Membrane ~reparations Cortical and pancreatic membranes were prepared as described ~Lin and Miller; J. Pharmacol. E~. Ther. 232, 775-780, 1985). In brief, cortex and pancreas were removed and rinsed with ice-cold saline. Visible fat and connective tissues were removed from the pancreas.
Tissues were weighed and homogenized separately in approximately 25 mL of ice-cold 50 mM Tris-HCl buffer, pH
7.4 at 4C, with a Brin~man Poloytron for 30 sec, setting 7 The homogenates were centrifuged for 10 min at 1075 x g and pellets discarded. The supernatants were saved and centrifuged at 38,730 x g for 20 min The resultant pellets were rehomogenized in 25 mL of 50 mM Tris-HCl buffer with Teflon-glass homogenizer, 5 up and down strokes. The homogenates were centrifuged again at 38,730 x g for 20 min. Pellets were then resuspended in 20 mM
HEPES, containing 1 mM EGTA, 118 mM NaCl, 4.7 mM KCl, 5 mM
MgC12, 100 ~M bestatin, 3 ~M phosphoramidon, pH 7.4 at 22C, with a Teflon-glass homogenizer, 15 up and down strokes. Resuspension volume was 15-18 mL per gram of original wet weight for the cortex and 60 mL per gram for the pancreas.
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,. ~ , . , W09l/00725 PCT~US90/03630 ,~--2~ ~ . 5 ~ -124-2. Incubation Conditions ~ I~Bolton-Hunter CCX8 ([1 I]BH-CCK8), and the test compounds were diluted with HEPES-EGTA-salt buffer (see above) containing 0.5% bovine serum albumin (BSA).
To 1 mL Skatron polystyrene tubes were added 25 ~L of [ I]BH-CCK8, and 200~L of membrane suspension. The final BSA concentration was 0.1%. The cortical tissues were incubated at 30C for 150 min and pancreatic tissues were incubated at 37C for 30 min. Incubations were terminated by filtration using Skatron Cell Harvester and SS32 microfiber filter mats. The specific binding of [125I]BH-CCK8, defined as the difference between binding in the absence and presence of 1 ~M CCK8, was 85-90% of total binding in cortex and 90-95% in pancreas. IC50's were determined from the Hill analysis. The results of these binding assays are shown in Table 1.
Protocol for Amylase Release This assay was performed using the modified protocol of Lin et al., J. pharmacol. E~- ~h~. 236, 729-739, 1986.
1. Guinea Pia a~ini Preparation Guinea pig ocean were prepared by the method of Bruzzone et al. (Biochem. J. 226, 621-624, 1985) as follows. The pancreas was dissected and connective tissues and blood vessels were removed. The pancreas was cut into small pieces (2 mm) by a seizure and placed in a " . ... . .
:
, , WO91/0~72~ PCT/US90/03fi30 2~?~55 15 mL conical plastic tube containing 2.5 mL of Krebs-Ringer HEPES (KRH) buffer plus 400 units per mL of collagenase. The composition of the KP~H buffer was:
HEPES, 12.5 mM; NaCl, 118 mM; KCl, 4.8 mM; CaCl2, 1 mM;
KH2PO4, 1.2 mM; MgS04, 1.2 mM; NaHC03, 5 mM; glucose, 10 mM at pH 7.4. The buffer was supplemented with 1% MEM
vitamins, 1% MEM amino acids and 0.001% aprotinin. The tube was shaken by hand until the suspension appeared homogeneous, usually 5-6 min. Five mL of the KRH, without collagenase and with 0.1% BSA, was added and the tube was centrifuged at 50 x g for 35 sec. The supernatant was discarded and 6 mL of the KRH was added to the cell pellet. Cells were triturated by a glass pipette and centrifuged at 50 x g for 35 sec. This wash procedure was repeated once. The cell pellet from the last centrifugation step was then resuspended in 15 mL of KRH
containing 0.1% BSA. The contents were filtered through a dual nylon mesh, size 275 and 75 ~M. The fil~rate, containing the acini, was centrifuged at 50 x g for 3 min.
The acini were then resuspended in 5 mL of KRH-BSA buffer for 30 min at 37C, under 100% oxygen atmosphere (2)' with a change of fresh buffer at 15 min.
2. Amylase Assay After the 30 min incubation time, the acini were resuspended in 100 volumes of KRH-BSA buffer, containing 3 ~M phosphoramidon and 100 ~M bestatin. While stirring, 400 ~L of acini were added to 1.5 mL microcentrifuge tubes .. . ~ .
WO9l/007~5 PCT/US90/03630 Z~ , 55 containing 50 ~L of CCK8, buffer, or test compounds. The final assay volume was 500 ~L. Tubes were vortexed and placed in a 37C water bath, un-ler 100% 2~ for 30 min.
Afterward, tubes were centrifuged at 10,000 g for 1 min.
Amylase activity in the supernatant and the cell pellet were separately determined after appropriate dilutions in 0.1% Triton X-100, 10 mM NaH2P04, pH 7.4 by Abbott Amylase A-gent test using the Abbott Bichromatic Analyzer 200.
The reference concentration for CCK8 in determining the IC50's of the compounds of Formula I was 3 x 10 OM. The results of this assay are shown in Table 2.
In Vitro Results The preferred compounds of Formula I are those which inhibited specific ~125I]-BH-CCK8 binding in a concentration dependent manner. Analysis of [125I]-BH-CCK8 receptor binding in the absence and presence of the compounds of formula I indicated the compounds of formula I inhibited specific [125I]-BH-CCK8 receptor binding. The IC50 values of the compounds of Formula I are presented in Table 1.
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W09l/00725 PCT/us9O/03630 [ 25I]-BH-CCK8 Binding Compound ofIC50 ~nM) Exam~le Pancreas Cortex 3 40 17,000 4 100 ~10,000 S 27 >10,000 7 290 >10,000 8 12 <10,000 13 190 1-10,000 17 200 ~100,000 23 87 ~10,000 24 170 >10,000 31 73 ~10,000 32 23 210,000 33 30 ~10,000 34 9 >10,000 37 210 ~10,000 47 320 ~10,000 19 2qO0 53 24 ~10,000 56 530 >10,000 41 <10,000 66 150 1-10,000 :~ . . ,~ . ,,- :.- ~ . . . : , WO 91/00725 PCr/US90~03630 ~ .~
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76 92>10, 000 37~10,000 82a 250>30, 000 87 29>10, 000 93 195~10,000 99 56~10,000 100 63~10,000 117 7428, 000 118 42 3, 300 119 110 6,200 125 160~10, 000 131 9.3 1600 132 3.1 1700 133 210~10,000 142 160>10, 000 147 86 2,900 150 980>10, 000 152 520>10,000 155 230<10,000 ~, .'~ ` - - ~........ -: ' ., ~, ' , ' '` ' .
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The results herein also indicate that compounds of the invention possess selectivity for the pancreatic (type A) CCK receptors.
Inhibition of CCK8-induced Compound of Amylase Release E~m~le IC~Q ~nM) 4 <100,000 8 <100,000 17 <30,000 31 <100,000 32 <1000 34 <100,000 <100,000 59 -100,000 <100,000 74 <100,000 <10,000 81 <10,000 .. . ,. . - :
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91 <10,000 99 <10,000 131 <100,000 132 <100,000 141 <30,000 151 <10,000 These results indicate that compounds of the invention are CCK antagonists.
In Vivo Results The ability of the compounds of Formula I to interact with CCK receptors and to antagonize CCK n vivo can be demonstrated using the following protocols.
Ll~inn ~ Induced ,Gastric Emptyina Three fasted mice were dosed (p.o.) with the test compound. CCK8 (80 ~g/kg s.c.) was administered within 60 minutes and charcoal meal (0.1 mL of 10% suspension) was given orally 5 minutes later. The animals were sacrificed within an additional 5 minutes.
Gastric emptying, defined as the presence of charcoal within the intestine beyond the pyloric sphincter, is inhibited by CCK8. Gastric emptyinq observed in 2 or 3 mice (greater than 1) indicates antagonism of CCK8.
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Compound Number of mice gf example Dose (p.o.) with Gastric Emptyina 118 100 mg/kg 2 Measurement of Plasma In~lin Level Followina Treatment ~l~h ~ and a Compound of Formula I
The ability of the compounds of Formula I to antagonize CCK induced hyperinsulinemia can be demonstrated in vivo using the following protocol.
Male mice, 20-30 g, were used in all experiments.
The animals were fed with laboratory lab chow and water ad libitum. The compound of Formula I (1-100 mg/kg in 0.2 mL
of 0.9% saline) was administered i.p. Ten minutes later CCK8 (0.2 to 200 nmole/kg in 0.2 mL of 0.9% saline) or saline was injected into the tail vein. Two minutes later the animals were sacrificed and blood was collected into 1.5 mL heparinized polypropylene tubes. The tubes were centrifuged at 10,000 x g for 2 minutes. Insulin levels were determined in the supernatant (plasma) by an RIA
method using kits from Radioassay Systems Laboratory (Carson, CA.) or Novo Biolabs (MA.).
Antagonism of ~ Mediated Behavioral Effect n Mice ~i~h Compounds of Formula I
Male Swiss CD-l mice (Charles River) (22-27 g) are provided ample food (Purina Lab Chow~ and water until the time of their injection with the test compounds.
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2~ 55 ICV injections were given by a free-hand method similar to that previously described ~aley and McCormick, ~L~ J- Pharmacol- Chemother. 1~, 12-15 1957). The animals were placed on a slightly elevated metal grid and restrained by the thumb and forefinger at the level of the shoulders, thus immobilizing their heads. Injections were made with a 30 gauge needle with a "stop" cor.sisting of a piece of tygon tubing to limit penetration of the needle to about 4.5 mm below the surface of the skin. The needle was inserted perpendicular to the skull at a midline point equidistant from the eye and an equal distance posterior from the level of the eyes such that the injection site and the two eyes form an equilateral triangle. The injection volume (5 ~L) was expelled smoothly over a period of approximately 1 second.
Immediately after the injections the mice were placed in their cages and allowed a 15 minute recovery period ~rior to the beginning of the behavioral observations.
For the behavioral observations, the mice were placed in clear plastic cages. Each cage measured 19 x 26 x 15 centimeters and contained a 60-tube polypropylene test tube rack (NALGENE #5970-0020) placed on end in the center of the cage to enhance exploratory activity. Observations were made every 30 seconds for a period of 30 minutes.
sehavior was compared between drug and CCK8 treated micei CCK8 treated mice; and mice treated with an equal volume of carrier (usually 0.9~ saline or 5% dimethylsulfoxide in water). Locomotion as reported here consisted of either floor locomotion or active climbing on the rack.
Differences among groups were analyzed by Newman-Kewels -. ':
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analysis and a probability level of p< 0.05 was accepted as significant. Each group tested consisted of 10 animals. The results of this test indicate that compounds of Formula I are antagonists of CCK in vivo. Minimally effective doses ~MED) are defined as that dose at which a statistically significant reversal of CCK-induced inactivity was observed when the test compound of formula I and CCK8 were coadministered.
Compound of Dose of 43 3 nmol 3 nmol The compounds of Formula I antagonize CCK which makes the compounds useful in the treatment and prevention of disease states in mammals ~especially humans) wherein CCX
or gastrin may be involved, for example, gastrointestinal disorders such as irritable bowel syndrome, ulcers, excess pancreatic or gastric secretion, hyperinsulinemia, acute pancreatitis, GI cancers ~especially cancers of the gall bladder and pancreas), motility disorders, pain ~potentiation of opiate analgesia), central nervous system disorders caused by CCK's interaction with dopamine such as neuroleptic disorders, tardive dyskinesia, Parkinson's disease, psychosis, including schizophrenia, or Gilles de la Tourette Syndrome; disorders of the appetite regulatory ' ' ' ,., .' , '', ' . ', ; " , . .
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systems, bulimia, Zollinger-Ellison syndrome, and central G cell hyperplasia, and the treatment of substance abuse.
The compounds of the present invention can be used in the form of salts derived from inorganic or organic acids.
These salts include but are not limited to the following:
acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptonate, glycerphosphate, hemisulfate, heptonate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproplonate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate Also, the basic nitrogen-containing groups can be quaternized with such agents as loweralkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates, long chain halides such as decyl, lauryl, myristyl, and stearyl chlorides, bromides and iodides, arylalkyl halides like benzyl and phenethyl bromides, and others. Water or oil-soluble or dispersible products are thereby obtained.
The pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of Formula I which contain a basic or acidic moiety Dy conventional methods. Generally, the salts are prepared by reacting the free base or acid with stoichiometric amounts or with an excess of the desired salt forming inorganic or organic - - .. : .
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acid or base in a suitable solvent or various combinations of solvents.
Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid and phosphoric acid and such organic acids such as oxalic acid, maleic acid, succinic acid and citric acid. Other salts include salts with alkali metals or alkaline earth metals, such as -sodium, potassium, calcium, or magnesium or with organic ~ases.
The pharmaceutically acceptable salts of the acid of Formula I are also readily prepared by conventional procedures such as treating an acid of Formula I with an appropriate amount of base, such as an alkali or alkaline earth metal hydroxide e.g. sodium, potassium, lithium, calcium, or magnesium, or an organic base such as an amine, e.g., dibenzylethylenediamine, cyclohexylamine, dicyclohexylamine, triethylamine, piperidine, pyrrolidine, benzylamine, and the like, or a quaterary ammonium hydroxide such as tetramethylammonium hydroxide and the like.
When a compound of Formula I is used as an antagonist of CCK or gastrin in a human subject, the total daily dose administered in single or divided doses may be in amounts, for example, from 0.001 to 1000 mg a day and more usually 1 to 1000 mg. Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose.
The amount of active ingredient thzt may be combined with the carrier materials to produce a single dosage form :.: . . .: ::
WO91/00725 PCT/US90~03630 Z~75~;
will vary depending upon the host treated, the particular treatment and the particular mode of administration.
It will be understood, however, that the specific -dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the severity of the particular disease undergoing therapy.
The compounds of the present invention may be administered orally, parenterally, by inhalation spray, rectally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired.
The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques.
Injectable preparations, for example, sterile injectable aqueous or oleagenous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butandiol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. ~or t~is purpose any bland fixed oil may be employed includinc synthetic mono-:: , .:. : : :- :.
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or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules.
In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents.
Tablets and pills can additionally be prepared with enteric coatings.
Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsion, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
The present agents can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-. ~ . . . . .
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lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposo~es can be used. The present compositions in liposome form can contain, in addition to the compounds of the present invention, stabilizers, preservatives, excipients, and the like. The preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic.
Methods to form liposomes are known in the art. See, for example, Prescott, Ed., ~ethods 1~ Cell Bioloay Vol.
XIV, Academic Press, New York, N. Y. 1976, p.33 et seq.
The foregoing is merely illustrative of the invention and is not intended to limit the invention to the disclosed compounds. Variations and changes which are obvious to one skilled in the art are intended to be within the scope and nature of the invention which are defined in the appended claims.
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Claims (10)
1. A compound of the formula wherein G is (1) NH2 or (2) substituted amino;
Rg is (1) hydrogen, (2) loweralkyl, (3) carboxy-substituted alkyl or (4) carboxyester-substituted alkyl;
R10 is (1) hydrogen, (2) loweralkyl, (3) functionalized alkyl or (4) cycloalkyl;
D is (1) hydrogen, (2) loweralkyl, (3) functionalized alkyl, (4) cycloalkyl, (5) aryl, (6) functionalized oxyalkyl or (7) heterocyclic;
with the proviso that D is other than indolylmethyl, indolinylmethyl or oxindolylmethyl;
or R10 taken together with D is (1) C4 to C6 alkylene, (2) - (CH2)q-V-(CH2)r- wherein q is 1 to 3, r is 1 to 3 and V is (i) -O-, (ii) -S-, (iii) -CH2- or (iv) -N(R25)- wherein R25 is hydrogen, loweralkyl, haloalkyl, alkoxyalkyl, arylalkyl, aryl or an N-protecting group;
or R9 taken together with D is (1) C3 to C5 alkylene or (2) -(CH2)p-V-(CH2)t- wherein p is 1 to 3, t is 1 to 3 and V is defined as above;
Z is (1) -C(O)-, (2) -C(S)- or (3) -S(O)2-;
B is (1) absent, (2) alkylene, (3) alkenylene, (4) substituted alkenylene, (5) -R26-R27- wherein R26 is absent or -CH2- and R27 is -O-, -S-, -NH- or -N(loweralkyl)- or (6) -R27-CH2- wherein R27 is defined as above; and Ar is (1) aryl or (2) a heterocyclic group.
Rg is (1) hydrogen, (2) loweralkyl, (3) carboxy-substituted alkyl or (4) carboxyester-substituted alkyl;
R10 is (1) hydrogen, (2) loweralkyl, (3) functionalized alkyl or (4) cycloalkyl;
D is (1) hydrogen, (2) loweralkyl, (3) functionalized alkyl, (4) cycloalkyl, (5) aryl, (6) functionalized oxyalkyl or (7) heterocyclic;
with the proviso that D is other than indolylmethyl, indolinylmethyl or oxindolylmethyl;
or R10 taken together with D is (1) C4 to C6 alkylene, (2) - (CH2)q-V-(CH2)r- wherein q is 1 to 3, r is 1 to 3 and V is (i) -O-, (ii) -S-, (iii) -CH2- or (iv) -N(R25)- wherein R25 is hydrogen, loweralkyl, haloalkyl, alkoxyalkyl, arylalkyl, aryl or an N-protecting group;
or R9 taken together with D is (1) C3 to C5 alkylene or (2) -(CH2)p-V-(CH2)t- wherein p is 1 to 3, t is 1 to 3 and V is defined as above;
Z is (1) -C(O)-, (2) -C(S)- or (3) -S(O)2-;
B is (1) absent, (2) alkylene, (3) alkenylene, (4) substituted alkenylene, (5) -R26-R27- wherein R26 is absent or -CH2- and R27 is -O-, -S-, -NH- or -N(loweralkyl)- or (6) -R27-CH2- wherein R27 is defined as above; and Ar is (1) aryl or (2) a heterocyclic group.
2. The compound of Claim 1 wherein D is (1) aryl, (2) arylalkyl, (3) heterocyclic, (4) heterocyclicalkyl, (5) functionalized oxyalkyl, (6) loweralkyl substituted by -NHC(O)R4 wherein R4 is loweralkyl, alkenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl or (7) loweralkyl substituted by -S-loweralkyl, -S(O)-loweralkyl, -S(O)2-loweralkyl, -S-aryl, -S(O)-aryl or -S(O)2-aryl; and Ar is heterocyclic.
3. The compound of Claim 1 wherein Ar is heterocyclic; B is absent; Z is -C(O)-; R9 and R10 are hydrogen; D is loweralkyl, functionalized oxyalkyl, aryl or heterocyclic; and G is substituted amino
4. The compound of Claim 3 wherein Ar is quinolyl, hydroxyquinolyl or dihydroxyquinolyl; D is phenyl, heterocyclic, hydroxyalkyl or alkoxyalkyl; and G is dialkylamino.
5. A compound selected from the group consisting of:
N-(3'-Quinolylcarbonyl)-(2R,3S)-(O-methyl)Threonine-di-n-pentylamide;
N-(3'-Quinolylcarbonyl)-(2R,3S)-Threonine-di-n-pentylamide;
N-(3'-Quinolylcarbonyl)-R-Histidine-di-n-pentylamide dihydrochloride;
N-(3'-Quinolylcarbonyl)-R-Phenylglycine-di-n-pentylamide;
and N-(4',8'-Dihydroxy-2'quinolylcarbonyl)-R-Phenylglycine-di-n-pentylamide.
N-(3'-Quinolylcarbonyl)-(2R,3S)-(O-methyl)Threonine-di-n-pentylamide;
N-(3'-Quinolylcarbonyl)-(2R,3S)-Threonine-di-n-pentylamide;
N-(3'-Quinolylcarbonyl)-R-Histidine-di-n-pentylamide dihydrochloride;
N-(3'-Quinolylcarbonyl)-R-Phenylglycine-di-n-pentylamide;
and N-(4',8'-Dihydroxy-2'quinolylcarbonyl)-R-Phenylglycine-di-n-pentylamide.
6. A method for antagonizing CCK comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Claim 1.
7. A method for treatment or prevention of hyperinsulinemia or disorders of the gastrointestinal, central nervous, appetite regulating or pain regulating systems comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Claim 1.
8. A pharmaceutical composition for antagonizing CCK
comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of Claim 1.
comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of Claim 1.
9. A pharmaceutical composition for treatment or prevention of hyperinsulinemia or disorders of the gastrointestinal, central nervous, appetite regulating or pain regulating systems comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of Claim 1.
10. A process for the preparation of a compound of the formula:
wherein G is (1) NH2 or (2) substituted amino;
R9 is (1) hydrogen, (2) loweralkyl, (3) carboxy-substituted alkyl or (4) carboxyester-substituted alkyl;
R10 is (1) hydrogen, (2) loweralkyl, (3) functionalized alkyl or (4) cycloalkyl;
D is (1) hydrogen, (2) loweralkyl, (3) functionalized alkyl, (4) cycloalkyl, (5) aryl, (6) functionalized oxyalkyl or (7) heterocyclic;
with the proviso that D is other than indolylmethyl, indolinylmethyl or oxindolylmethyl;
or R10 taken together with D is (1) C4 to C6 alkylene, (2) -(CH2)q-V-(CH2)r- wherein q is 1 to 3, r is 1 to 3 and V is (i) -O-, (ii) -s-, (iii) -CH2- or (iv) -N(R25)- wherein R25 is hydrogen, loweralkyl, haloalkyl, alkoxyalkyl, arylalkyl, aryl or an N-protecting group;
or R9 taken together with D is (1) C3 to C5 alkylene or (2) -(CH2)p-V-(CH2)t- wherein p is 1 to 3, t is 1 to 3 and V is defined as above;
Z is (1) -C(O)-, (2) -C(S)- or -S(O)2-;
B is (1) absent, (2) alkylene, (3) alkenylene, (4) substituted alkenylene, (5) -R26-R27- wherein R26 is absent or -CH2- and R27 is -O-, -S-, -NH- or -N(loweralkyl)- or (6) -R27-CH2- wherein R27 is defined as above; and Ar is (1) aryl or (2) a heterocyclic group;
comprising coupling an amine of the formula wherein P1 is hydrogen with a compound of the formula wherein Z' is an activating group; or B-Z-Z' taken together represent -N=C=O, -N=C=S, -CH2-N=C=O or -CH2-N=C=S.
wherein G is (1) NH2 or (2) substituted amino;
R9 is (1) hydrogen, (2) loweralkyl, (3) carboxy-substituted alkyl or (4) carboxyester-substituted alkyl;
R10 is (1) hydrogen, (2) loweralkyl, (3) functionalized alkyl or (4) cycloalkyl;
D is (1) hydrogen, (2) loweralkyl, (3) functionalized alkyl, (4) cycloalkyl, (5) aryl, (6) functionalized oxyalkyl or (7) heterocyclic;
with the proviso that D is other than indolylmethyl, indolinylmethyl or oxindolylmethyl;
or R10 taken together with D is (1) C4 to C6 alkylene, (2) -(CH2)q-V-(CH2)r- wherein q is 1 to 3, r is 1 to 3 and V is (i) -O-, (ii) -s-, (iii) -CH2- or (iv) -N(R25)- wherein R25 is hydrogen, loweralkyl, haloalkyl, alkoxyalkyl, arylalkyl, aryl or an N-protecting group;
or R9 taken together with D is (1) C3 to C5 alkylene or (2) -(CH2)p-V-(CH2)t- wherein p is 1 to 3, t is 1 to 3 and V is defined as above;
Z is (1) -C(O)-, (2) -C(S)- or -S(O)2-;
B is (1) absent, (2) alkylene, (3) alkenylene, (4) substituted alkenylene, (5) -R26-R27- wherein R26 is absent or -CH2- and R27 is -O-, -S-, -NH- or -N(loweralkyl)- or (6) -R27-CH2- wherein R27 is defined as above; and Ar is (1) aryl or (2) a heterocyclic group;
comprising coupling an amine of the formula wherein P1 is hydrogen with a compound of the formula wherein Z' is an activating group; or B-Z-Z' taken together represent -N=C=O, -N=C=S, -CH2-N=C=O or -CH2-N=C=S.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US37677889A | 1989-07-07 | 1989-07-07 | |
| US376,778 | 1989-07-07 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2062755A1 true CA2062755A1 (en) | 1991-01-08 |
Family
ID=23486446
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002062755A Abandoned CA2062755A1 (en) | 1989-07-07 | 1990-06-26 | Amino acid analog cck antagonists |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0480969A4 (en) |
| JP (1) | JPH04506660A (en) |
| CA (1) | CA2062755A1 (en) |
| GR (1) | GR1001129B (en) |
| IE (1) | IE902295A1 (en) |
| PT (1) | PT94623A (en) |
| WO (1) | WO1991000725A2 (en) |
Families Citing this family (25)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040122000A1 (en) | 1981-01-07 | 2004-06-24 | Vertex Pharmaceuticals Incorporated. | Inhibitors of aspartyl protease |
| US6878728B1 (en) | 1999-06-11 | 2005-04-12 | Vertex Pharmaceutical Incorporated | Inhibitors of aspartyl protease |
| WO1993003011A1 (en) * | 1991-08-08 | 1993-02-18 | Yamanouchi Pharmaceutical Co., Ltd. | Urea derivative |
| GB9200245D0 (en) * | 1992-01-07 | 1992-02-26 | British Bio Technology | Compounds |
| US5783701A (en) | 1992-09-08 | 1998-07-21 | Vertex Pharmaceuticals, Incorporated | Sulfonamide inhibitors of aspartyl protease |
| IS2334B (en) | 1992-09-08 | 2008-02-15 | Vertex Pharmaceuticals Inc., (A Massachusetts Corporation) | Aspartyl protease inhibitor of a new class of sulfonamides |
| US5723490A (en) * | 1992-09-08 | 1998-03-03 | Vertex Pharmaceuticals Incorporated | THF-containing sulfonamide inhibitors of aspartyl protease |
| EP0749421B1 (en) * | 1994-03-07 | 1999-09-15 | Vertex Pharmaceuticals Incorporated | Sulphonamide derivatives as aspartyl protease inhibitors |
| US5691372A (en) * | 1995-04-19 | 1997-11-25 | Vertex Pharmaceuticals Incorporated | Oxygenated-Heterocycle containing sulfonamide inhibitors of aspartyl protease |
| JPH08325263A (en) * | 1995-05-31 | 1996-12-10 | Sumitomo Metal Ind Ltd | New 2-amino-3-phenylpropionic acid derivative |
| CA2342471C (en) * | 1995-06-06 | 2002-10-29 | Judith L. Treadway | Heterocyclecarbonylmethyl amine intermediates |
| US6297269B1 (en) | 1995-06-06 | 2001-10-02 | Pfizer Inc. | Substituted n-(indole-2-carbonyl-) amides and derivatives as glycogen phosphorylase inhibitors |
| MY114711A (en) | 1995-06-06 | 2002-12-31 | Pfizer | Substituted n-(indole-2-carbonyl)-b-alanmamides and derivatives as antidiabetic agents |
| US6004957A (en) * | 1995-06-07 | 1999-12-21 | Vertex Pharmaceuticals, Incorporated | Sulfonamide inhibitors of aspartyl protease |
| AU8875398A (en) | 1997-08-29 | 1999-03-22 | Proteus Molecular Design Ltd | 1-amino-7-isoquinoline derivatives as serine protease inhibitors |
| WO1999026927A2 (en) * | 1997-11-21 | 1999-06-03 | Nps Pharmaceuticals, Inc. | Metabotropic glutamate receptor antagonists for treating central nervous system diseases |
| US6436989B1 (en) | 1997-12-24 | 2002-08-20 | Vertex Pharmaceuticals, Incorporated | Prodrugs of aspartyl protease inhibitors |
| WO1999065870A2 (en) | 1998-06-19 | 1999-12-23 | Vertex Pharmaceuticals Incorporated | Sulfonamide inhibitors of aspartyl protease |
| US6776990B2 (en) | 1999-04-08 | 2004-08-17 | Allergan, Inc. | Methods and compositions for the treatment of pancreatitis |
| EP1192132B1 (en) | 1999-06-14 | 2005-09-07 | Eli Lilly And Company | Serine protease inhibitors |
| GB0030306D0 (en) | 2000-12-13 | 2001-01-24 | Lilly Co Eli | Compounds |
| GB0030305D0 (en) | 2000-12-13 | 2001-01-24 | Lilly Co Eli | Compounds |
| GB0030303D0 (en) | 2000-12-13 | 2001-01-24 | Lilly Co Eli | Compounds |
| GB0030304D0 (en) | 2000-12-13 | 2001-01-24 | Lilly Co Eli | Compounds |
| US6277877B1 (en) | 2000-08-15 | 2001-08-21 | Pfizer, Inc. | Substituted n-(indole-2-carbonyl)glycinamides and derivates as glycogen phosphorylase inhibitors |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4880938A (en) * | 1986-06-16 | 1989-11-14 | Merck & Co., Inc. | Amino acid analogs |
| IT1196849B (en) * | 1986-12-16 | 1988-11-25 | Rotta Research Lab | NEW DERIVATIVES OF ACIDS 5 PENTILAMINO 5 OXO PENTAOIC AND 4 PENTILAMINO 4 OXO BUTANOIC WITH ANTAGONIST ACTIVITY OF THE CHOLECYSTOKININ AND PROCEDURE FOR THEIR PREPARATION |
| IT1217123B (en) * | 1987-02-05 | 1990-03-14 | Rotta Research Lab | OPTICALLY ACTIVE DERIVATIVES OF ACID 5 PENTILAMINE 5 OXO PENTANOIC R WITH ANTAGONIST ACTIVITY OF THE CHOLECISTOKININ AND PROCEDURE FOR THEIR PREPARATION |
| US4971978A (en) * | 1987-09-21 | 1990-11-20 | Nadzan Alex M | Derivatives of D-glutamic acid and D-aspartic acid |
| EP0336356A3 (en) * | 1988-04-05 | 1991-09-25 | Abbott Laboratories | Derivatives of tryptophan as cck antagonists |
-
1990
- 1990-06-25 IE IE229590A patent/IE902295A1/en unknown
- 1990-06-26 JP JP2509643A patent/JPH04506660A/en active Pending
- 1990-06-26 EP EP19900910218 patent/EP0480969A4/en not_active Withdrawn
- 1990-06-26 WO PCT/US1990/003630 patent/WO1991000725A2/en not_active Application Discontinuation
- 1990-06-26 CA CA002062755A patent/CA2062755A1/en not_active Abandoned
- 1990-07-05 GR GR900100516A patent/GR1001129B/en unknown
- 1990-07-06 PT PT94623A patent/PT94623A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| IE902295A1 (en) | 1991-01-16 |
| JPH04506660A (en) | 1992-11-19 |
| EP0480969A1 (en) | 1992-04-22 |
| PT94623A (en) | 1991-03-20 |
| EP0480969A4 (en) | 1993-01-07 |
| WO1991000725A2 (en) | 1991-01-24 |
| WO1991000725A3 (en) | 1991-02-21 |
| GR900100516A (en) | 1991-12-10 |
| GR1001129B (en) | 1993-04-28 |
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