Classifications

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  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
  • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
  • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
  • C07C311/18—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms, not being part of nitro or nitroso groups
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
  • A61P31/18—Antivirals for RNA viruses for HIV
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  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
  • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
  • C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
  • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
  • C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
  • C07C311/38—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton
  • C07C311/39—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
  • C07C311/41—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms, not being part of nitro or nitroso groups
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  • 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
  • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
  • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
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  • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
  • C07D305/02—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings
  • C07D305/04—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
  • C07D305/06—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
  • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
  • C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D307/12—Radicals substituted by oxygen atoms
• • 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
  • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
  • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
  • C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings 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
  • C07D307/20—Oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
  • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
  • C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings 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
  • C07D307/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
  • C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
  • C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D307/32—Oxygen atoms
  • C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/94—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom spiro-condensed with carbocyclic rings or ring systems, e.g. griseofulvins
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
  • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
  • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system

Definitions

• the present invention relates to novel carboxamide derivatives as novel compounds and compositions for inhibiting Human Immunodeficiency Virus (HIV) and process for making the compounds.
• HIV Human Immunodeficiency Virus
• HIV-1 infection remains a major medical problem, with an estimated 40 million people infected worldwide.
• the number of cases of HIV and AIDS (acquired immunodeficiency syndrome) has risen rapidly. In 2005, approximately 5.0 million new infections were reported, and 3.2 million people died from AIDS.
• HP protease inhibitors are one important class of therapeutic agents for inhibition and treatment of HIV infection.
• protease inhibitors like saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, fosamprenavir and atazanavir have been approved as drugs for treatment of HIV infection.
• novel HIV inhibitors that are very potent and effective against resistant strains of HIV. Therefore, novel anti-HrV agents exhibiting distinct resistance patterns, and favorable pharmacokinetic as well as safety profiles are needed to provide more treatment options.
• WO 02/083657 discloses broad-spectrum substituted benzisoxazole sulfonamide HIV protease inhibitors
• WO 2007/02172 and WO 2008/1 18849 disclosed HIV- 1 protease inhibitors
• WO 2008/013834 discloses bisfuranyl protease inhibitors
• WO 2008/133734 discloses method and compositions for treating HIV infections
• US 5968942, US 5578606, US 5843946 and US 6060476 disclosed alpha and beta amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors
• 00/076961 disclosed inhibitors of aspartyl protease; US 5585397, WO 95/24385, WO 99/33815, WO 99//65870 and US 5783701 disclosed sulfonamide inhibitors of aspartyl protease; WO 96/33184 and US 5723490 disclosed THF-containing sulfonamide inhibitors of aspartyl protease; WO 94/04492 and WO 95/06030 disclosed hydroxyethylamino sulfonamides useful as retroviral protease inhibitors; WO 2004/099135 discloses HIV prodrugs cleavable by CD26; WO 03/106405 and US 2004/147454 disclosed aspartyl protease inhibitors; and WO 03/78438 discloses carbamates as HIV protease inhibitors.
• the present invention relates to compounds of the formula (I)
• Bi and B 2 are independently can be selected from O, CO, C (R a ) 2 , or NR b ;
• X can be a bond, -0-, -0(C(R c ) 2 ) m -, or - (C(R c ) 2 ) m O-;
• L can be a bond, -(CH 2 ) m -, -N R d -, or substituted or unsubstituted phenylene; n can be an integer 0-4;
• n can be an integer 0-3;
• R can be H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclyl, and preferably R can be substituted by R ;
• Ri can be H, substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl
• R 2 can be H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclyl;
• Zi and Z 2 are independently selected from a bond or NR B and provided that when NR] is directly connected to S0 2 R 2 then both Z] and Z 2 are absent;
• Ri and Zi are together attached with N atom to form a cyclic ring which can be mono cyclic ring, bicyclic ring or tricyclic ring and preferably they can be selected from
• R X , and R Y are independently selected from H, halogen, substituted or unsubstituted alkyl, or R X and R Y are together attached with ring C atom to form C 3 _ 6 cyclic ring or C 3 . 6 heterocyclic ring;
• R A , R B , R c , and R D are independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, and preferably R A , R B , R C , and R D can be substituted by R ;
• R can be H, OH, halogen, NR", C(0) 2 R", C(0)NR" substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyloxy, or substituted or unsubstituted heterocyclyloxy;
• R" can be H, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl.
• the present invention also provides the process for making the compounds of formula (I).
• the present invention further provides a pharmaceutical composition
• a pharmaceutical composition comprising a therapeutically effective amount of a compound or combination of compounds of the present invention, or a pharmaceutically acceptable salt form, stereoisomer and a pharmaceutically acceptable carrier.
• prodrugs of the compounds of the formula (I), including ester prodrugs are also contemplated.
• a compound of formula (I) wherein R x and R y are selected from H, methyl or fluorine and R x and R are together attached with ring C atom to form C 3 . hetero cyclic ring.
• R x and R y are selected from H, methyl or fluorine and R x and R are together attached with ring C atom to form C 3 . hetero cyclic ring.
• n is 0, 1 or 2.
• Bi and B 2 are independently selected from O, CO, C (R a )2, or NR b ;
• X can be a bond, -0-, -0((CR c ) 2 ) m -, or - ((CR c ) 2 ) m O-;
• L can be a bond, -(CH 2 ) m -, -N R d -, or substituted or unsubstituted phenylene; n can be an integer 0-4;
• n can be an integer 0-3;
• R can be H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclyl, and preferably R can be substituted by R ' ;
• Ri can be H, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl;
• R 2 can be H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclyl;
• R x , and R y are independently selected from H, halogen, substituted or unsubstituted alkyl, or R x and R y are together attached with ring C atom to form C 3 _ 6 cyclic ring or C3.6 heterocyclic ring;
• R a , R b , R c , and R d are independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, and preferably R ⁇ R b , R c , and R d can be substituted by R ;
• R ' can be H, OH, halogen, NR", C(0) 2 R", C(0)NR" substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyloxy, or substituted or unsubstituted heterocyclyloxy;
• R" can be H, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl.
• B) and B 2 are independent and can be selected from O, CO, C (R a ) 2 , or NR b ;
• X can be a bond, -0-, -0(CR c 2 ) m -, or - (CR c 2 ) m O-;
• L can be a bond, -(CH 2 ) m -, -N R d -, or substituted or unsubstituted phenylene; n can be an integer 0-4;
• n can be an integer 0-3;
• R can be H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclyl, and preferably R can be substituted by R ;
• R 2 can be H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclyl;
• a bond or NR b can be mono cyclic ring, bicyclic ring or bridged ring and preferably they can selected
• R is independently can be H, halogen, substituted or unsubstituted alkyl, or R x and R y are together attached with ring C atom to form C 3-6 cyclic ring or C 3 _6 heterocyclic ring;
• R a , R b , R c , and R d are independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, and preferably R ⁇ R b , R°, and R d can be substituted by R ;
• R ' can be H, OH, halogen, NR", C(0) 2 R", C(0)NR" substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyloxy, or substituted or unsubstituted heterocyclyloxy;
• R" can be H, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl.
• the compounds and pharmaceutical compositions described herein are useful in the treatment of diseases, conditions and/or disorders mediated by, for example, viral infections, more particularly for treating HIV infection.
• the present invention further provides a method of treating a disease, condition and/or disorder mediated by, for example, viral infections, more particularly HIV infection in a subject in need thereof by administering to the subject one or more compounds described herein in an amount effective to treat that infection.
• a disease, condition and/or disorder mediated by, for example, viral infections, more particularly HIV infection in a subject in need thereof by administering to the subject one or more compounds described herein in an amount effective to treat that infection.
• the present invention relates to novel carboxamide compounds and, a composition for inhibiting Human Immunodeficiency Virus (HIV) and process for making the compounds.
• HIV Human Immunodeficiency Virus
• halogen or halo includes fluorine, chlorine, bromine, or iodine.
• alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to eight carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n- pentyl, and 1 , 1-dimethylethyl (t-butyl).
• alkenyl refers to an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be a straight or branched chain having from 2 to about 10 carbon atoms, e.g., ethenyl, 1-propenyl, 2-propenyl (ally]), iso- propenyl, 2-methyl- 1 -propenyl, 1 -butenyl, and 2-butenyl.
• haloalkyl is used to denote a group comprised of an alkyl group substituted with halogen atom, where alkyl group is as defined above and halogen is used to denote fluorine, chlorine, bromine or iodine, an example of such group is trifluoromethyl, difluoromethyl.
• acyl group is used to denote a linear or branched aliphatic acyl group (preferably a C 2-6 alkanoyl group) or an aromatic acyl group, which contains 2 to 10 carbon atoms.
• examples include an acetyl group, a propionyl group, a pivaloyl group, a butyryl group, an isobutyryl group, a valeryl group and a benzoyl group, with an acetyl group being preferred.
• alkoxy group is used to denote a linear or branched alkoxy group containing 1 to 6 carbon atoms. Preferred are CM alkoxy groups including a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, an n- butoxy group, an isobutoxy group and a tert-butoxy group.
• alkoxycarbonyl group is used to denote a structure composed of a linear or branched Ci_5 alkoxy group and a carbonyl group. Preferred are C 2 . 5 alkoxycarbonyl groups including a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group and a butoxycarbonyl group. Among them, a methoxycarbonyl group is preferred.
• cycloalkyl denotes a non-aromatic mono or multicyclic ring system of from 3 to about 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
• multicyclic cycloalkyl groups include, but are not limited to, perhydronapththyl, adamantyi and norbornyl groups, bridged cyclic groups and spirobicyclic groups, e.g., spiro (4,4) non-2-yl.
• cycloalkylalkyl refers to a cyclic ring-containing radical having from 3 to about 8 carbon atoms directly attached to an alkyl group.
• the cycloalkylalkyl group may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
• Non-limiting examples of such groups include cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl.
• cycloalkenyl refers to a cyclic ring-containing radical having from 3 to about 8 carbon atoms with at least one carbon-carbon double bond, such as cyclopropenyl, cyclobutenyl, and cyclopentenyl.
• cyclalkyloxy group is used to denote a cyclic ring-containing radical having from 3 to about 8 carbon atoms directly attached to an Oxygen atom.
• the cycloalkyloxy group may be attached to the main structure at Oxygen atom that results in the creation of a stable structure.
• Non-limiting examples of such groups include cyclopropyloxy, cyclobutyloxy, and cyclopentyloxy.
• aryl refers to an aromatic radical having from 6 to 14 carbon atoms such as phenyl, naphthyl, tetrahydronapthyl, indanyl, and biphenyl.
• arylalkyl refers to an aryl group as defined above directly bonded to an alkyl group as defined above, e.g., -CH2C6H5 and -C2H5C6H5.
• Substituted refers to 1-3 substituents on the same position or on different positions with the same groups or different groups.
• Alkynyl refers to alkynyl groups having from 2 to 6 carbon atoms and having at least on ⁇ alkynyl saturation, for example acetylenyl, and propargyl.
• Carbonyloxy refers to a group such as -C(0)0.
• Sulfonyl “sulfonyloxy” refers to the groups -S02R6, where R6 is selected from the groups consisting of alkyl, aryl, heteroaryl, heterocyclyl.
• heterocyclyl and “heterocyclic ring” refer to a stable 3- to 15- membered ring radical which consists of carbon atoms and from one to five heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur.
• the heterocyclic ring radical may be a monocyclic, bicyclic or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states.
• the nitrogen atom may be optionally quaternized; and the ring radical may be partially or fully saturated (i.e., heterocyclic or heteroaryl).
• heterocyclic ring radicals include, but are not limited to, azetidinyl, acridinyl, carbazolyl, cinnolinyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pyridyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl, imidazolyl, tetrahydroisouinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2- oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl,
• heterocyclylalkyl refers to a heterocyclic ring radical directly bonded to an alkyl group.
• the heterocyclylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
• heterocyclyloxy group is used to denote a heterocyclic ring- containing radical having from 3 to about 8 carbon atoms directly attached to an Oxygen atom.
• the heterocyclyloxy group may be attached to the main structure at Oxygen atom that results in the creation of a stable structure.
• Non-limiting examples of such groups include teterohedrofurnyloxy, pyrrolidinyloxy, and piperidinyloxy.
• heteroaryl refers to an aromatic heterocyclic ring radical.
• the heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
• heteroarylalkyl refers to a heteroaryl ring radical directly bonded to an alkyl group.
• the heteroarylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
• prodrug means a compound that is transformed in vivo to yield a compound of Formula (I) (1A) or (IB) or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms, such as through hydrolysis in blood.
• a discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the
• treating or “treatment” of a state, disease, disorder or condition includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disease, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disease, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disease, disorder or condition;
• the benefit to a subject receiving treatment is either statistically significant or at least perceptible to the subject or to the physician.
• subject includes, for example, mammals (especially humans), and other animals,
• a “therapeutically effective amount” means, for example, the amount of a compound that, when administered to a subject for treating a state, disease, disorder or condition, is sufficient to effect such treatment.
• the “therapeutically effective amount” will vary depending on the compound, the state, disease, disorder or condition and its severity and the age, weight, physical condition and responsiveness of the subject receiving treatment.
• the compound of the invention may form salts.
• pharmaceutically acceptable salts forming part of the invention include salts derived from inorganic/organic acids or bases and amino acids salts.
• Certain compounds of the invention are capable of existing in stereoisomeric forms (e.g. diastereomers and enantiomers). With respect to the overall compounds described by the Formula (I), Formula (IA) or Formula (IB), the invention extends to these stereoisomeric forms and to mixtures thereof. To the extent prior art teaches synthesis or separation of particular stereoisomers, the different stereoisomeric forms of the invention may be separated from one another by the method known in the art, or a given isomer may be obtained by stereospecific or asymmetric synthesis. Tautomeric forms and mixtures of compounds described herein are also contemplated.
• solvates includes, for example, hydrates and other solvents of crystallization (such as alcohols).
• the compounds of the present invention may form solvates with low molecular weight solvents by methods known in the art.
• compositions provided in the invention include at least one compound described herein and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent).
• pharmaceutically acceptable excipient such as a pharmaceutically acceptable carrier or diluent.
• the contemplated pharmaceutical compositions include a compound(s) described herein in an amount sufficient to treat viral infection in a subject.
• the subjects contemplated include, for example, a living cell and a mammal, including human beings.
• the compound of the present invention may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or be diluted by a carrier.
• suitable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.
• the carrier or diluent may include a sustained release material, such as, for example, glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
• a sustained release material such as, for example, glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
• the pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, emulsifying agents, suspending agents, preserving agents, salts for influencing osmotic pressure, buffers, sweetening agents, flavoring agents, colorants, or any combination of the foregoing.
• the pharmaceutical composition of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the subject by employing procedures known in the art.
• compositions described herein may be prepared, e.g., as described in Remington: The Science and Practice of Pharmacy, 20 th Ed., 2003 (Lippincott Williams & Wilkins).
• the pharmaceutical compositions may be, for example, capsules, tablets, aerosols, solutions, suspensions or products for topical application.
• the route of administration may be any route which effectively transports the active compound to the appropriate or desired site of action. Suitable routes of administration include, but are not limited to, oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, parenteral, rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic (such as with an ophthalmic solution) or topical (such as with a topical ointment).
• the oral route is preferred.
• Solid oral formulations include, but are not limited to, tablets, capsules (soft or hard gelatin), dragees (containing the active ingredient in powder or pellet form), troches and lozenges. Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Preferable carriers for tablets, dragees, or capsules include lactose, cornstarch, and/or potato starch. A syrup or elixir can be used in cases where a sweetened vehicle can be employed.
• a typical tablet that may be prepared by conventional tabletting techniques may contain: (1) Core: Active compound (as free compound or salt thereof), colloidal silicon dioxide (Aerosil®), microcrystalline cellulose (Avicel®), modified cellulose gum (Ac-Di-Sol®), and magnesium stearate; (2) Coating: HPMC, Mywacett 9-40 T and acylated monoglyceride.
• Liquid formulations include, but are not limited to, syrups, emulsions, soft gelatin and sterile injectable liquids, such as aqueous or non-aqueous liquid suspensions or solutions.
• injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
• Anti HIV activity and cytotoxicity of compounds of present invention can be measured in parallel by following the methods published in the literature.
• the cytotoxic effect of compounds can , be analyzed by measuring the proliferation of cells using the 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazlium bromide (MTT) staining.
• MTT 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazlium bromide
• MTT (5mg/ml in PBS) will be added to each well and incubated for an additional 4 hours at 37°C.
• the purple -blue MTT formazan precipitate will be dissolved in a triplex reagent containing 10% SDS, 5% isobutanol and 10 mmol/lit HC1.
• the activity of mitochondria, reflecting cellular growth and viability, will be evaluated by measuring the optical density at 570 nm on micro titer plate.
• lxlO 6 Sup-Tl cells with 100% cell viability will be seeded in RPMI 1640, 0.1 % FBS four 12 well plates. Increasing concentrations of Epap-1 peptides will be added to the cells and will be infected with HIV1 each at final concentration of virus equivalent to 2 ng of p24 per ml. The infected cells will be incubated at 37 C and 5% C02 incubator for 2 hours. After 2hrs the cells will be pelleted at 350 g for 10 min, supernatant will be discarded and cell will be held with RPMI 1640 containing 10% FBS.
• the cells will be resuspended in the same medium with increasing concentrations of Epap-1 peptides and will be incubated for 96 hours. The cells will be supplemented with peptides at every 24 hours. The supematants will be collected after 96 hours and analyzed using P24 antigen capture assay kit (SAIC Fredrick). The infection in the absence of Epap-1 will be considered to be 0% inhibition Azidothymidine (AZT) will be taken as positive control.
• SAIC Fredrick P24 antigen capture assay kit
• Action of compound on virus entry and quantification of virus entered can be done in terms of GFP expression by the following the methods published J. Virol. 72, 6988 (1998) by in Cecilia et al., and Analytical Biochemistry Volume 360, Issue 2, 15 January 2007, Pages 315-317 (Dyavar S. Ravi and Debashis Mitra).
• Cells will be seeded in to wells of 24 well plates 1 day prior to the experiment.
• the cells will be transfected with Tat-reporter.
• the virus inoculum will be adjusted to 1 ,000-4,000 TCID 50/ ml in assay medium (DMEM,10%FCS,glutamine and antibiotics ),50 ⁇ aliquots will be incubated with serial dilutions of compounds (50 ⁇ ) for lhr at 37 C .
• the reporter expression will be quantified at appropriate time calculated inhibitory doses referrers to the concentration of these agents in this preincubation mixture.
• the present invention provides compounds and pharmaceutical formulations thereof that are useful in the treatment of diseases, conditions and/or disorders mediated by viral infections.
• the connection between therapeutic effect and antiviral is illustrated.
• the invention further provides a method of treating a disease, condition and/or disorder mediated by viral infections in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition of the present invention.
• Diseases, conditions, and/or disorders that are mediated by viral infections are believed to include, but are not limited to, HIV infection, a retroviral infection genetically related to HIV, AIDS, or inflammatory disease
• the compounds of the present invention can obtain more advantageous effects than additive effects in the prevention or treatment of the above diseases when using suitably in combination with the above drugs.
• the administration dose can be decreased in comparison with administration of either drug alone, or adverse effects of co administrated drugs other than antiviral can be avoided or declined.
• the compounds described herein may be prepared by techniques known in the art.
• the compounds described herein may be prepared by following the reaction sequence as depicted in Scheme- 1.
• reaction sequence as depicted in Scheme- 1.
• specific bases, acids, reagents, solvents, coupling agents, etc. are mentioned, it is understood that other bases, acids, reagents, solvents, coupling agents etc., known in the art may also be used and are therefore included within the present invention.
• Variations in reaction conditions for example, temperature and/or duration of the reaction, which may be used as known in the art, are also within the scope of the present invention. All the stereo isomers of the compounds in these schemes, unless otherwise specified, are also encompassed within the scope of this invention.
• (2S,3S)l ,2-epoxy-3-amino-4-phenylbutane was prepared subjecting (2S, 3S)l -halo-2-hydoxy-3-amino-4-phenyl butane derivatives to ring closure under alkaline conditions as described in WO 96/17821 and Journal of Organic Chemistry, Volume 59, 365, 1994.
• esters of compounds of formula 3 can be converted to corresponding esters of compounds of formula 3 by reacting with alcohol of compounds of formula 2.
• the esters of compounds of formula 3 can reacted with halides of compounds of formula 4 [RI (where in R is alkyl, aryl, heteroaryl, or aralkyl)] to give the compounds of formula 5 in the presence of LDA THF solution at around -70 °C, the temperature then may be allowed to rise slowly to room temperature.
• the compounds of formula 5 can be converted to the intermediates of acid compounds of formula 6 by ester hydrolysis in the presence of a basic medium such as, for example, solutions of lithium hydroxide, sodium or potassium hydroxide or the like.
• (CH) m R) can be synthesized by reacting appropriate cycloalkyl- hydroxy compounds with a halo substituted compounds of hal-L-COOEt in the presence of base, for example, potassium or cesiumcarbonate or the like in a solvent such as acetone, acetonitrile, dimethyl formamide or the like.
• N-protected amino epoxide compounds of of formula 7 with specific stereochemistry are commercially available or can be prepared by known methods (Fassler.A et.al. in Bioorg. Med. Chem. Lett, 1993, 3, 2837-2842). All four possible stereoisomers can be separated according to the authors by chiracel OD analytical column.
• N-protected amino epoxide compounds of formula 7 can be reacted with the amino compounds of formula (RiN(Z]Z2H)H) (8 ) to give the N-protected amino alcohol compounds of formula 9 in presence of a suitable solvent like protic or non protic such as, isopropanol, methanol, ethanol or the like or ether such as, foe example tetrahydrofuran, dioxane or the like or toluene, dimethyl formamide, dimethylsulfoxide, or mixtures thereof in the conditions, for example, over a wide range of temperatures (from about 10-100 °C) or at a temperature which the solvent begins to reflux.
• a suitable solvent like protic or non protic such as, isopropanol, methanol, ethanol or the like or ether such as, foe example tetrahydrofuran, dioxane or the like or toluene, dimethyl formamide, dimethylsulfoxide, or mixtures thereof
• the N-protected amino alcohol compounds of formula 9 can be reacted with the compounds of sulfonyl chloride (R2SO2CI) of formula 10 to give the sulfonamide compounds of formula 1 1 in the presence of acid scavengers, for example, triethylamine, pyridine or the like in the suitable solvent, for example methylene chloride, tetrahydrofuran or the like.
• acid scavengers for example, triethylamine, pyridine or the like in the suitable solvent, for example methylene chloride, tetrahydrofuran or the like.
• the sulfonamide compounds of formula 1 1 can be deprotected into the amine compounds of formula 12 under the conditions which should not affect the remaining part of the molecule except BOC protected Nitrogen.
• acid in acid hydrolysis, can be organic or in-organic acid, for example, HC1, trifluoroacetic acid or the like in a suitable solvent, for example, dioxane, methylenechloride, ethylacetate or the like.
• a suitable solvent for example, dioxane, methylenechloride, ethylacetate or the like.
• the intermediates of formula 6 can be reacted with the free amine of compounds of formula 12 to give the final compounds of formula (I), either by converting intermediates of formula 6 to acid chloride in the solvent, such as methylene chloride or the like by using one of the halogenating agent such as, thionyl chloride or the like or an activating agent such as, DSC or the like either at room temperature or refluxing temperature of the solvent.
• the solvent such as methylene chloride or the like
• the halogenating agent such as, thionyl chloride or the like
• an activating agent such as, DSC or the like either at room temperature or refluxing temperature of the solvent.
• the compounds of formula (I) can be synthesized by reacting the compounds of formula 6 with the compounds of formula 12 in the presence of coupling reagent for example, l -hydroxybenzotrazolehydrate(HOBT),
• coupling reagent for example, l -hydroxybenzotrazolehydrate(HOBT)
• HBTU 0-benzotrazol-l-yl-N,N,N',N'-tetramethyluroniumhexafluorophosphate
• TBTU O- benzotrazol-l-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate
• BOP bis(2- oxo-3-oxazolidenyl)phosphenic chloride
• BOP benzotrazol-l-yloxy tris(dimefhylamino)phosphonium hexafluorophosphate
• BOP benzotrazol-l-yloxy tris(dimefhylamino)phosphonium hexafluorophosphate
• BOP benzotrazol-l-yloxy tris(dimefhylamino)phosphonium hexafluorophosphate
• BOP benzotrazol-l-yloxy tris(dimefhylamino)phosphonium he
• Step 1 Synthesis of ethyl cyclohexanecarboxylate:
• Step 2 Synthesis of ethyl 1 -ethy late:
• Ethyl cyclohexanecarboxylate (step 1 , about 5g in 30 ml THF) was added and stirred the reaction at same temp for about 30 minutes, then increased the reaction temperature to -35 °C and stirred for 45 minutes and again cooled to about -75°C then ethyl chloride (about 4.4 ml in 20 ml THF) was added drop wise and the reaction was slowly allowed to return to room temperature and stirred for about 12 hours. After completion of the reaction (monitored by TLC), reaction mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was washed with sat.
• Step 3 Synthesis of 1 -ethylcyclohexanecarboxylic acid:
• step 2 To a stirred solution of ethyl 1 -ethylcyclohexanecarboxylate (step 2, about 3.0 g) in ethanol, potassium hydroxide (about 2.9 g) was added and refluxed for 6 hours at 80 °C. Completion of the reaction (monitored by TLC), reaction mixture was evaporated under reduced pressure. The residue was taken in water, acidified with aq HC1 and extracted with ethyl acetate. The organic layer was washed with water, followed by brine the organic layer dried over Na 2 S0 4 and concentrated under reduced pressure.
• Step 1 Synthesis of ethyl 2-(( -tetrahydrofuran-3-yloxy) acetate:
• step 1 To a ethyl 2-((S)-tetrahydrofuran-3-yloxy) acetate (step 1 , about 4 g) in Aq MEOH, potassium hydroxide (about 3.8 g) was added and refluxed for about 6 hours at about 80°C. Completion of the reaction monitored by TLC, reaction temperature was evaporated under reduced pressure, the residue was taken in water and acidified with aq HC1 and extracted with ethyl acetate then the organic layer was washed with water, brine, dried over Na 2 S0 4 and concentrated under reduced pressure.
• potassium hydroxide about 3.8 g
• Step 1 Synthesis of ethyl cyclopentanecarboxylate:
• Step 2 Synthesis of ethyl 1 -ethy late:
• Di-isopropyl amine (6.5 ml) was taken in dry THF (about 25 ml) and cooled to -10°C, to this n-butyl lithium (about 23 ml) was added drop wise under nitrogen atmosphere and maintain the reaction temperature at about - 10 °C for about 45 minutes, after that the reaction mixture was cooled to about -75 °C, ethyl cyclopentanecarboxylate (step 1 , about 5 g in 30 ml THF) was added and stirred at same temperature for about 30 minutes then increase the reaction temperature to about -35 °C and stirred for about 45 minutes and again the reaction was cooled to about - 75°C, then ethyl chloride (about 4.4 ml in 20 ml THF) was added drop wise.
• reaction mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate.
• the organic layer was washed with sat. NaHC0 3 followed by brine sol, dried over Na 2 S0 4 and concentrated under reduced pressure.
• the residue was purified by silica gel column chromatography using 3% ethyl acetate in hexane as eluent to furnish the title compound (2.2 g) as light yellow colour liquid.
• Step 2 Synthesis of 1 -(methoxymethyl)cyclopentanecarboxylic acid:
• step 1 about 3.0 g in ethanol, potassium hydroxide (about 2.6 g) was added and refluxed for 6 hours at 80 °C. Completion of the reaction (monitored by TLC), reaction mixture was evaporated under reduced pressure. The residue was taken in water, acidified with aq HC1 and extracted with ethyl acetate. The organic layer was washed with water, followed by brine. The organic layer was dried over Na 2 S0 4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% ethyl acetate in hexane as eluent to furnish the title compound (2 g) as a light yellow liquid.
• Step 1 Synthesis of ethyl l-(2-ethoxyethyl)cyclopentanecarboxylate:
• reaction mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was washed with sat. NaHC0 3 followed by brine solution, dried over Na 2 S0 4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 3% ethyl acetate in hexane as eluent to furnish the title compound (2.2 g) as light yellow colour liquid.
• Step 2 Synthesis of 1 -(2-ethoxye carboxylic acid:
• step 1 To a stirred solution of ethyl l-(2-ethoxyethyl)cyclopentanecarboxylate (step 1, about 3.0 g) in efhanol, potassium hydroxide (about 2.6 g) was added and refluxed for about 6 hours at about 80 °C. Completion of the reaction (monitored by TLC), reaction mixture was evaporated under reduced pressure. The residue was taken in water, acidified with aq HC1 and extracted with ethyl acetate. The organic layer was washed with water, followed by brine the organic layer dried over Na 2 S0 4 and concentrated under reduced pressure.
• Step 1 Synthesis of ethyl 2-cyano- -cyclohexylideneacetate:
• reaction mixture was azeotropically refluxed for about 24 hours at about 120°C. Completion of the reaction was monitored by TLC, reaction temperature was evaporated under reduced pressure then the residue was taken in water, neutralized with saturated NaHC0 3 and extracted with DCM, the organic layer was dried over Na 2 SG 4 and concentrated under reduced pressure.
• Step 2 Synthesis of ethyl 2-cya -2-( l-(pyridin-2-yl)cyclohexyl)acetate:
• reaction mixture was slowly warm to about 25 °C and stirred for about 20 hours. Completion of the reaction was monitored by TLC, reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate, dried over Na 2 SC>4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using 4 % ethyl acetate in hexane as eluent to furnish the title compound as a brown liquid.
• step 2 To a ethyl 2-cyano-2-( 1 -(pyridin-2-yl)cyclohexyl)acetate (step 2, about 2.0 g) in DMSO (about 50 ml), sodium chloride (about 2 g) was added and heated at 80 °C for 16 hours. Completion of the reaction was monitored by TLC, solvent was evaporated under reduced pressure. The resulting residue was taken in water, extracted with DCM, dried over Na 2 S0 4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 20% ethyl acetate in hexane as eluent to furnish the title compound (0.8 g) as a yellow liquid.
• step 3 2-(l-(pyridin-2-yl)cyclohexyl)acetonitrile (step 3), about 5 g) in ethylene glycol (about 100 ml) potassium hydroxide (about 4.1 g) was added and refluxed for about 24 hours at 180 °C. Completion of the reaction was monitored by TLC. The reaction mixture was evaporated under reduced pressure. The resulting residue was taken in 150 ml of water and acidified with 5 % citric acid, extracted with 5 % MeOH in DCM, washed with water, brine, the organic layer was dried over Na 2 S0 4 and concentrated under reduced pressure.
• Step 2 Synthesis of (s)-tetrahy enzenesulfonate:
• step 3 To a (S)-methyl 2-(tetrahydrofuran-3-yloxy)benzoate (step 3, about 3 g) in MeOH (100 ml) potassium hydroxide (about 2.9 g) was added and refluxed for about 6 hours at about 80 °C. Completion of the reaction was monitored by TLC. Then reaction mixture was evaporated under reduced pressure. The resulting residue was taken in water and acidified with aq HC1, extracted with ethyl acetate, the organic layer was washed with water, brine, dried over Na 2 SC>4 and concentrated under reduced pressure.
• step 2 To (S)-methyl 2-(4-(tetrahydrofuran-3-yloxy)phenyl)acetate (step 2, about 10 g) in ethanol (about 150 ml) sulphuric acid (about 7.8 ml) was added and refluxed for about 6 hours at about 80 °C. Completion of the reaction monitored by TLC then reaction temperature was evaporated under reduced pressure. The resulting residue was taken in water, neutralized with saturated NaHC0 3 and extracted with DCM, the organic layer dried over Na 2 S0 4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% ethyl acetate in hexane as eluent to furnish the title compound (12 g) as a light yellow.
• Step 1 Synthesis of tert-butyl (2S,3R)-3-hydroxy-4-(isobutylamino)-l-phenylbutan- 2-ylcarbamate:
• Step 2 Synthesis of tert-butyl (2S,3R)-3-hydroxy-4-(N-isobutyl-4- nitrophenylsulfonamido -l-phenylbutan-2-ylcarbamate:
• Step 1 To a stirred solution of tert-butyl (2S,3R)-3-hydroxy-4-(isobutylamino)-l- phenylbutan-2-ylcarbamate (Step 1 , about 5 g) in DCM (about 75 ml) triethylamine (about 6.2 ml) was added and the reaction was cooled to about 0°c then 4- nitrobenzene-l -sulfonyl chloride (about 3.9 g) was added and stirred at room temperature for about 12 hours. Completion of reaction was monitored by TLC, then the reaction mixture was diluted with DCM, the organic layer was washed with saturated NaHC0 3 , brine, dried over Na 2 S0 4 and concentrated under reduced pressure.
• Step 3 Synthesis of N-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl-4- nitrobenzenesulfonamide:
• Step 1 Synthesis of N-((]R,5S)-8-benzyl-8-azabicyclo[3.2.] Joctan-.
• step 1 N-((lR,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-4- methoxybenzenesulfonamide (step 1 , about 1 g) in ethyl acetate (25 ml) palladium on carbon (about 0.3 g) was added and stirred under H 2 atmosphere (about 60 psi) for 6 hours. Completion of the reaction was monitored by TLC. The reaction mixture was filtered through celite bed and the filtrate was evaporated. The resulting residue was purified by silica gel column chromatography using 5% ethyl acetate in hexane as eluent to furnish the title compound (0.5 g) as a white solid.
• Step 3 Synthesis of tert-butyl (2S,3R)-3-hydroxy-4-((lR,5S)-3-(4- methoxyphenylsulfonamido )-8-azabicyclo[ 3.2.1 ]octan-8-yl )- 1 -phenylbutan-2- ylcarbamate:
• Step 4 Synthesis of N-((lR,5S)-8-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-8- az bicyclo[3.2.1 ]octan-3-yl)-4-methoxybenzenesulfonamide:
• reaction mixture was neutralized with saturated NaHC0 3 , extracted with dichloromethane; the organic layer was dried over Na 2 S0 4 and concentrated under reduced pressure.
• the residue was purified by silica gel column chromatography using 30% ethyl acetate in hexane as eluent to furnish the title compound (0.8 g) as a white solid.
• Step J synthesis of ethyl 2-((S)-tetrahydrofuran-3-yloxy)propanoate: To a stirred solution of sodium hydride (about 1.5g) in THF (25 ml) and cooled to about 0°C, (S)-tetrahydrofuran-3-ol (about 1 g) was added and stirred at about 0 °C for about 1 hour then ethyl 2-bromopropanoate (about 1.7 ml) was added drop wise at about 0 °C and allow the reaction to room temperature for about 12 hrs.
• step 1 ethyl 2-((S)-tetrahydrofuran-3-yloxy)propanoate (step 1 , about 0.9 g) in aq MeOH potassium hydroxide (about 0.8 g) was added and refluxed for about 6 hours at about 80 °C.
• reaction temperature was evaporated under reduced pressure.
• the residue was taken in 150 ml water and acidified with aqueous HC1 and extracted with ethyl acetate, the organic layer was washed with water followed by brine, the organic layer was dried over Na 2 S0 4 and concentrated under reduced pressure.
• Step 1 Synthesis of benzyl 3-oxocyclopentanecarboxylate:
• Step 2 Synthesis of benzyl 3-allyl-3 ntanecarboxylate:
• step 1 A stirred solution of benzyl 3-oxocyclopentanecarboxylate (step 1 , about 4.0 g, 18.39 mmol) in dry DCM (20 ml) at about 0 °C TiCL, (about 2.0 ml, 18.34 mmol) was added, after five minutes allyltrimethylsilane (about 11.7 ml, 73.39 mmol) was added slowly and allowed to stirred at room temperature for about 3 hours. After completion of the reaction (monitored by TLC), the reaction was quenched with water, extracted with EtOAc (200 ml x 2) and the organic layers were washed with brine, dried with Na 2 S0 4 and the solvent was evaporated.
• Step 4 Synthesis of benzyl l-oxaspi -7-carboxylate:
• Step 5 Synthesis of 1 -oxaspiro[4.4]nonane-7-carboxylic acid:
• step 4 A stirred solution of benzyl l-oxaspiro[4.4]nonane-7-carboxylate (step 4, about 1.35 g, 5.19 mmol) in EtOAc (8 ml) 10 % palladium on carbon (about 0.020 g) was added at room temperature and the reaction mixture was stirred under H 2 gas atmosphere at room temperature for about 3 hours. After completion of the reaction
• Step 1 Synthesis of ethyl tetrahydrofuran-2-carboxylate:
• step 2 To a stirred solution of ethyl 2-ethyltetrahydrofuran-2-carboxylate (step 2, about 3 g) in ethanol (25 ml) potassium hydroxide (about 2.6 g) was added and refluxed for about 6 hours at about 80 °C. Completion of the reaction was monitored by TLC, reaction mixture was evaporated under reduced pressure, the residue was taken in 150 ml of water and acidified with aqueous HC1 and extracted with ethyl acetate, the organic layer was washed with water followed by brine, the organic layer was dried over Na 2 S0 4 and concentrated under reduced pressure.
• Example 4 N-((2S,3R)-3-hvdroxy-4-(N-isobutyl-4-methylphenylsulfonamido)-l- phenylbutan-2-yl)-2-(tetrahvdrofuran-3-yloxy)acetamide: Yield: 0.8 g as a yellow solid. ⁇ NMR (300 MHz, CDC1 3 ): ⁇ 0.85-0.90 (m, 6H);
• Example 8 l -ethyl-N-((2S.3R -3-hvdroxy-4-(N-isobutyl-4- methoxyphenylsulfonamido) -phenylbutan-2-yl)cvclopentanecarboxamide:
• Example 12 N-((2S,3R)-4-(3-chloro-4-fluoro-N-isobutylphenylsulfonamido)-3- hvdroxy-l-phenylbutan-2-y -l -ethylcyclohexanecarboxamide:
• Example 13 l-ethyl-N-((2S,3R)-3-hvdroxy-4-(N-isobutyl-4- nitrophenylsulfonamido)- -phenylbutan-2-yl)cyclohexanecarboxamide:
• Example 14 N-((2S,3R)-4-(4-amino-N-isobutylphenylsulfonamido)-3-hydroxy- 1 - phenylbutan-2-yl)- 1 -ethylcyclohexanecarboxamide:
• Example 15 l-ethyl-N-((2S,3R)-4-(4-fluoro-N-isobutylphenylsulfonamido)-3- hydroxy- 1 -phenylbutan-2-yl)cyclohexanecarboxamide:
• Example 17A Preparation of l-ethyl-N-((2S.3R)-3-hydroxy-4-(3-(4- methoxyphenylsulfonamido)-8-azabicvclor3.2.11octan-8-yl)-l-phenylbutan-2- vDcyclopentanecarboxamide:
• Example 17 B l -(2-ethoxyethylVN-((2S.3R)-3-hvdroxy-4-(3-(4- methoxyphenylsulfonamido)-8-azabicyclo[3.2.1 loctan-8- ⁇ - 1 -phenylbutan-2- vDcyclopentanecarboxamid
• Example 20 Preparation of N-((2S.3R -4-(3-chloro-4-fluoro-N- isobutylphenylsulfonamido)-3-hydrox v- 1 -phenylbutan-2-yl)-2-( 1 -(pyridin-2- vPcyclohexyDacetamide:
• reaction mixture was quenched with water and extracted with DCM, washed with saturated NaHC0 3 followed by brine solution, dried over Na 2 SC>4 and concentrated under reduced pressure.
• the residue was purified by silica gel column chromatography using 15% ethyl acetate in hexane as eluent to furnish the title compound (0.8 g) as a yellow solid.
• reaction mixture was quenched with water and extracted with DCM, washed with saturated NaHC0 3 followed by brine solution, dried over Na 2 S0 4 and concentrated under reduced pressure.
• the residue was purified by silica gel column chromatography using 15% ethyl acetate in hexane as eluent to furnish the title compound (0.8 g) as a yellow solid.
• Example 36 3-chloro-N-((2S,3R)-3-hvdroxy-4-(N-isobutyl-4- methoxyphenylsulfOnamido)-l-phenylbutan-2-yl)-5-((R)-tetrahydrofuran-3- yloxy)benzamide :
• Example 37 3-chloro-N-((2S,3R)-3-hvdroxy-4-(N-isobutyl-4- nitrophenylsulfonamido)-l-phenylbutan-2-yl)-5-((S)-tetrahvdrofuran-3- yloxy)benzamide:
• Example 40 N-((2S,3R)-4-(3-chloro-4-fluoro-N-isobutylphenylsulfonamido)-3- hydroxy-l-phenylbutan-2-yl)-4-methyl-2-((R)-tetrahvdrofuran-3-yloxy)benzamide:
• Example 42 N-((2S,3R)-3-hvdroxy-4-(N-isobutyl-4-methoxyphenylsulfonamido)- l-phenylbutan-2-yl)-2-((R)-tetrahvdrofuran-3-yloxy)benzamide:
• Example 43 N-((2S,3R)-4-(4-amino-N-isobutylphenylsulfonamido)-3-hydroxy-l- phenylbutan-2-yl)-2-((R)-tetrahvdrofuran-3-yloxy)benzamide: ⁇ NMR (300 MHz, CDC1 3 ): 0.82-0.87 (m, 6H), 2.02 (m, IH), 2.02-2.22 (m,
• Example 44j 4-fluoro-N-((2S,3R)-3-hvdroxy-4-(N-isobutyl-4- methoxyphenylsulfonamido)-l-phenylbutan-2-yl)-2-((R)-tetrahydrofuran-3- yloxy)benzamide:
• Example 45 N-((2S,3R)-4-(3-chloro-4-fluoro-N-isobutylphenylsulfonamido)-3- hvdroxy-l-phenylbutan-2-yl)-2-(4-((R)-tetrahvdrofuran-3-yloxy)phenyl)acetamide:
• Example 46 N-((2S,3R)-3-hvdroxy-4-(N-isobutyl-4-methoxyphenylsulfonamido)- l-phenylbutan-2-yl)-2-(4-((R)-tetrahvdrofuran-3-yloxy)phenyl)acetamide:
• Example 48 N-((2S,3R)-3-hvdroxy-4-(N-isobutyl-4-methoxyphenylsulfonamido)- l-phenylbutan-2-yl)-2-(4-( -tetrahvdrofuran-3-yloxy)phenyl)acetamide:
• Example 50 N-((2S,3R)-4-(4-amino-N-isobutylphenylsulfonamido)-3-hydroxy- 1 - phenylbutan-2-vD- 1 -(2-ethoxyethyl)cvclopentanecarboxamide:
• Example 54 N-((2S R)-3-hvdroxy-4-(N-isobutyl-4-methoxyphenylsulfonamido)- l -phenylbutan-2-vI)-2-((S)-tetrahydrofuran-3-yloxy)propanamide:
• reaction mixture was quenched with water and extracted with DCM, washed with saturated NaHC(3 ⁇ 4 followed by brine solution, dried over Na 2 S0 4 and concentrated under reduced pressure.
• the residue was purified by silica gel column chromatography using 15% ethyl acetate in hexane as eluent to furnish the title compound (0.10 g) as a light yellow solid. (0.8g) as a yellow solid.
• Example 56 N-((2S,3R)-4-(3-chloro-4-fluoro-N-isobutylphenylsulfonamido)-3- hydrox v- 1 -phenylbutan-2-y - 1 -oxaspiror4.41nonane-7-carboxamide:
• Example 60 N-((2S,3R)-4-(4-fluoro-N-isobutylphenylsulfonamido)-3-hvdroxy-l- phenylbutan-2-yl)-2-((S)-tetrahvdrofuran-3-yloxy)acetamide:
• Example 65 4,4-dimethyl-2-oxotetrahydrofuran-3-yl (2R,3S)-4-(N-cyclopentyl-4- methoxyphenylsulfonamido')- -hvdroxy-l-phenylbutan-2-ylcarbamate:
• Example 70 N-((2SV3-hvdroxy-4-((lR,5S)-3-(4-methoxyphenylsulfonamidoV8- azabicyclor3.2.1 loctan-8-yl " )- 1 -phenylbutan-2-yl)- 1 - (methoxymethvDcyclopentanecarboxamide:
• Example 74 (3-methyloxetan-3-yl)methyl (2S,3R)-4-(4-amino-N- isobutylphenylsulfonamido -3-hvdroxy- l-phenylbutan-2-ylcarbamate:
• Example 75 (2-ethyltetrahydrofuran-2-yl)methyl (2S,3R)-4-(4-amino-N- isobutylphenylsulfonamido -3-hvdroxy-l-phenylbutan-2-ylcarbamate:
• Example 77 N-((2S ⁇ )-4-(N-(2-(lH-indol-2-vnethyl)-4-aminophenylsulfonamido)-3- hydroxy- 1 -phenylbutan-2-yl)- 1 -(methoxymethyl)cvclopentanecarboxamide:
• Example 78 N-((2S)-4-(4-amino-N-cvclopentylphenylsulfonamido)-3-hydroxy-l - phenylbutan-2-yl)- 1 -ethylcyclopentanecarboxamide:
• Example 81 N-((2S,3R)-4-(4-amino-N-isobutylphenylsulfonamido)-3-hydroxy- 1 - phenylbutan-2-yl ' )-3-methyl-5-(tetrahvdrofuran-3-yloxy)benzamide:
• Example 82 N-((2R,3S)-4-(N-cvclopentyl-4-methoxyphenylsulfonamido)-3- hvdroxy-l-phenylbutan-2- -l-(methoxymethyl)cvclopentanecarboxamide:
• Example 83 N-((2R,3S)-4-(N-cvclopentyl-4-methoxyphenylsulfonamido)-3- hydroxy- 1 -phenylbutan-2- - 1 -ethylcyclopentanecarboxamide :
• MT2 cells were infected with HrV-1 strain 92HT599 (10 TCID 50/30000 cells). The infected cells were plated at the concentration of -30000 cells per well in 96 well plate. Test compound was added to the microplate in defined format with the final concentration of DMSO (vehicle) not more than 1%. Incubation was carried out in a C02 incubator for -96 hours for viral infection. At the end of incubation period an aliquot from each well was taken for p24 estimation. The quantitation of p24 is an index for antiviral activity of the compound. Percent inhibition was calculated with reference to control values (vehicle controls).
• lOmM stock was made by dissolving test compound in DMSO. Subsequent dilutions were made with DMSO to make necessary working stocks (100X).
• cytotoxicity assay For cytotoxicity assay the same amount of MT-2 cells as in antivirus without HrV-1 virus was added to the cytotoxicity plates. The cytotoxicity was measured using MTT reagent in parallel with P24 estimation. The percent viability is calculated in comparison with vehicle control.

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