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Cannabis: Compositions

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Application US20200330602


Published 2020-10-22

Method For Improving The Oral Bioavailability Of A Drug

The invention is in the field of medical sciences. It provides new pharmaceutical methods and preparations. In particular, the invention relates to a method for increasing the oral bioavailability of drugs. The invention also provides new compositions comprising a drug covalently attached to a saccharide as in formula (I) below. More in particular, the invention relates to a method for increasing the oral bioavailability of a drug by covalently attaching a sugar-linked, N-substituted or unsubstituted carbamoylalkylidene moiety to a hydroxyl or thiol group of a drug, wherein the substituents are as defined in the claims. ##STR00001##


Classification


Slightly More than Average Length Specification


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USPTO Full Text Publication >

10 Independent Claims

  • Independent Claim 1. A method for increasing the oral bioavailability of a drug HX-DM. wherein HX represents an OH or SH functional group, comprising the step of linking a sugar-carbamoylalkylidene unit of formula (II) ##STR00030## wherein Sugar is selected from the group consisting of alpha- and beta-linked monosaccharides and disaccharides, wherein optionally one or more OH groups are replaced by a group R4wherein R4 is selected from the group consisting of C.sub.1-C.sub.6 alkoxy, chlorine, fluorine, cyano, CF.sub.3, NH.sub.2, C.sub.1-C.sub.6 alkyl-NH, C.sub.1-C.sub.6 dialkyl-N, C.sub.1-C.sub.6 cycloalkyl-N, C.sub.1-C.sub.6 alkyl-C(O)NH, C.sub.1-C.sub.6 alkyl-C(O)(C.sub.1-C.sub.6 alkyl)--N, HC(O)(C.sub.1-C.sub.6 alkyl)--N, C.sub.1-C.sub.6 alkyl-O--C(O)NH, C.sub.1-C.sub.6 alkyl-O--C(O)(C.sub.1-C.sub.6 alkyl)--N, and C.sub.1-C.sub.6 alkyl-O--C(O)--OR1 is selected from the group consisting of H, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, --R5--O--R7, --R5--S--R7, --R6--C(O)--R7, --R6--C(O)--O--R7, --R5--SO.sub.2--R7, --R5--SO.sub.2--NR7R8, C.sub.3-C.sub.7 cycloalkyl, C.sub.4-C.sub.7 cycloalkenyl, a 4 to 7 membered heterocycle, aryl and (C.sub.1-C.sub.3alkyl)-arylwherein R5 is C.sub.2 or C.sub.3 alkyl, R6 is C.sub.1-C.sub.3 alkyl, R7 and R8 are independently hydrogen or C.sub.1-C.sub.3-alkyland wherein the C.sub.3-C.sub.7 cycloalkyl, C.sub.4-C.sub.7 cycloalkenyl, a 4 to 7 membered heterocycle, aryl and (C.sub.1-C.sub.3alkyl)-aryl groups can be optionally substituted by R9, wherein R9 is selected from the group consisting of C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, chlorine, fluorine, cyano, CF.sub.3, amine, amide, carbamate and --C(O)O--(C.sub.1-C.sub.4-alkyl)R2 and R3 are both H, or one of R2 and R3 is H and the other is C.sub.1-C.sub.6 alkyland wherein ----- represents a leaving group, to the OH or SH functional group of the drug HX-DM in order to obtain a compound according to formula (I) ##STR00031##

  • Independent Claim 4. The method according to any one of claims 1 to 3, wherein Sugar is an alpha- or beta-linked monosaccharide or dissacharide, wherein optionally one or more OH groups are replaced by a group R4.

  • Independent Claim 8. The method according to any one of the preceding claims wherein R2 and R3 are both H.

  • Independent Claim 9. The method according to any one of the preceding claims, wherein the drug moiety is selected from the group consisting of quetiapine, montelukast, venlafaxine, mesalazine, desvenlafaxine, metoprolol, paliperidone, buprenorphine, morphine, ganciclovir, tapentadol, rotigotine, abiraterone, acetaminophen, saxagliptin, fulvestrant, afimoxifene, testosterone, simvastatin, tolterodine, tramadol, atenolol, naloxone, nabilone, metaraminol, dihydroartemisinin, orciprenaline, labetalol, kalydeco, azacitidine, niclosamide, tetrahydrocannabinol, raloxifene, propofol, gemcitabine, cannabidiol, carvedilol, edavarone, cytaribine, dasatinib, perrilyl alcohol, butorphanol and bazedoxifene.

  • Independent Claim 10. A compound obtainable by the method of any one of claims 1 to 9 having formula (I) ##STR00033## wherein Sugar is selected from the group consisting of alpha- and beta-linked monosaccharides and disaccharides, wherein optionally one or more OH groups are replaced by a group R4wherein R4 is selected from the group consisting of C.sub.1-C.sub.6 alkoxy, chlorine, fluorine, cyano, CF.sub.3, NH.sub.2, C.sub.1-C.sub.6 alkyl-NH, C.sub.1-C.sub.6 dialkyl-N, C.sub.1-C.sub.6 cycloalkyl-N, C.sub.1-C.sub.6 alkyl-C(O)NH, C.sub.1-C.sub.6 alkyl-C(O)(C.sub.1-C.sub.6 alkyl)-N, HC(O)(C.sub.1-C.sub.6 alkyl)-N, C.sub.1-C.sub.6 alkyl-O--C(O)NH, C.sub.1-C.sub.6 alkyl-O--C(O)(C.sub.1-C.sub.6 alkyl)-N, and C.sub.1-C.sub.6 alkyl-O--C(O)--OR1 is selected from the group consisting of H, C.sub.1-CH.sub.6 alkyl, C.sub.2-CH.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, --R5--O--R7, --R5--S--R7, --R6--C(O)--R7, --R6--C(O)--O--R7, --R5--SO.sub.2--R7, --R5--SO.sub.2--NR7R8, C.sub.3C.sub.7 cycloalkyl, C.sub.4-C.sub.7 cycloalkenyl, a 4 to 7 membered heterocycle, aryl and (C.sub.1-C.sub.3 alkyl)-arylwherein R5 is C.sub.2 or C.sub.3 alkyl, R6 is C.sub.1-C.sub.3 alkyl, R7 and R8 are independently hydrogen or C.sub.1-C.sub.3-alkyland wherein the C.sub.3-C.sub.7 cycloalkyl, C.sub.4-C.sub.7 cycloalkenyl, a 4 to 7 membered heterocycle, aryl and (C.sub.1-C.sub.3alkyl)-aryl groups can be optionally substituted by R9, wherein R9 is selected from the group consisting of C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, chlorine, fluorine, cyano, CF.sub.3, amine, amide, carbamate and --C(O)O--(C.sub.1-C.sub.4-alkyl)R2 and R3 are both H, or one of R2 and R3 is H and the other is C.sub.1-C.sub.6 alkylX-DM represents a drug moiety wherein X is O or Sor a pharmaceutically acceptable salt thereof.

  • Independent Claim 13. The compound according to any one of claims 10 to 12, wherein Sugar is an alpha- or beta-linked monosaccharide or dissacharide, wherein optionally one or more OH groups are replaced by a group R4.

  • Independent Claim 17. The compound according to any one of the preceding claims wherein R2 and R3 are both H.

  • Independent Claim 18. The compound according to any one claims 10 to 17, wherein the drug moiety is selected from the group consisting of quetiapine, montelukast, venlafaxine, mesalazine, desvenlafaxine, metoprolol, paliperidone, buprenorphine, morphine, ganciclovir, tapentadol, rotigotine, abiraterone, acetaminophen, saxagliptin, fulvestrant, afimoxifene, testosterone, simvastatin, tolterodine, tramadol, atenolol, naloxone, nabilone, metaraminol, dihydroartemisinin, orciprenaline, labetalol, kalydeco, azacitidine, niclosamide, tetrahydrocannabinol, raloxifene, propofol, gemcitabine, cannabidiol, carvedilol, edavarone, cytaribine, dasatinib, perrilyl alcohol, butorphanol and bazedoxifene.

  • Independent Claim 19. Pharmaceutical composition comprising a compound according to any one of claims 10 to 18 and a pharmaceutically acceptable carrier.

  • Independent Claim 20. The compound according to any one of claims 10 to 17 for use as a medicament.