TW201540714A - N-substituted NORIBOGAINE prodrugs - Google Patents

Abstract

This invention relates generally to prodrugs of noribogaine. This invention also relates to pharmaceutical compositions comprising the prodrugs of noribogaine as well as method of treating pain, addiction and/or stress using such compounds and/or pharmaceutical compositions.

Description

N-substituted proribomycin (NORIBOGAINE) prodrug

SUMMARY OF THE INVENTION The present invention relates to noribogaine prodrugs or noribogaine derivatives. The invention also relates to pharmaceutical compositions comprising such noribogaine prodrugs or noribogaine derivatives and methods of using such compounds and/or pharmaceutical compositions for the treatment of pain, addiction and/or stress.

Ipogaine is a metabolite of ibogaine and is sometimes referred to as 12-hydroxy ibogamine. U.S. Patent No. 2,813,873, which claims to be a "12-O-desmethyl ibogaine base", provides the wrong structural formula of ibogaine base. The structure of the noribogaine base has been fully evaluated and found to combine the characteristics of tryptamine, tetrahydrohavaine and indolazepine. The noribogaine base can be represented by the following formula:

Ibogaine base and its pharmaceutically acceptable salts have recently been widely used as non-addicted alkaloids (U.S. Patent No. 6,348,456) for the treatment of drug dependence and as an effective analgesic (U.S. Patent No. 7,220,737). attention.

Certain of the reduced ibogaine derivatives and their use are described, for example, in U.S. Patent No. 8,362,007, the disclosure of which is incorporated herein in its entirety by reference.

Iopigain base is usually administered orally or intravenously and can be used systemically for treatment Treat patients. Although the reduced ibogaine base binds the μ and κ receptors ectopically, the systemic circulation of noribogaine increases the likelihood of undesirable side effects, and the availability of noribogaine is affected by it. Limitation of efficiency through the blood-brain barrier.

Therefore, there is a need in the industry to reduce the systemic circulation of noribopurine base while maintaining or increasing its concentration in the brain, particularly at the mu and kappa receptors.

The present invention is directed, in part, to a class of noribogaine prodrugs which release noribogaine base in vivo after administration. The prodrug moiety is selected to be readily dissociable by dissociable linker or by dissociation of the prothrombin base prodrug entity such that noribogaine base is produced in vivo. In a preferred embodiment, the prodrug moiety is selected to promote mu and/or κ in the brain by promoting passage through the blood-brain barrier or by targeting brain receptors other than mu and/or κ receptors. Binding of receptors. The invention also relates, in part, to a class of prodrugs of noribogaine derivatives.

Thus, in one embodiment, the invention relates to a compound represented by Formula I or Formula II below:

Wherein L is selected from the group consisting of a covalent bond and a cleavable linker group; R is selected from the group consisting of hydrogen, selected from -C(O)R ² , -C(O)NR ³ R ⁴ and a hydrolyzable group of the group consisting of -C(O)OR ⁵ wherein R ² is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl and The substituted alkynyl group, R ³ and R ⁴ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, An aryl group, a substituted aryl group, a heteroaryl group, a substituted heteroaryl group, a heterocyclic group, and a substituted heterocyclic group, and R ⁵ is selected from the group consisting of an alkyl group, a substituted alkyl group, Alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, The condition is that R is not a sugar or an oligosaccharide; R ¹ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aromatic Base, substituted aryl Cycloalkyl, the substituted cycloalkyl, heteroaryl, substituted heteroaryl of aryl, heterocyclic group and the substituted heterocyclic group, with the proviso that R ¹ is not a sugar or oligosaccharide; R ¹⁰ or hydrogen-based -OR; R ¹¹ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, (CH ₂ ) _m OC(O)alkyl, (CH _{2 m} OH, (CH ₂ ) _m Oalkyl, CH ₂ -X-CH ₃ or (CH ₂ ) _m O(CH ₂ ) _p O(CH ₂ ) _q O(CH ₂ ) _r CH ₃ , wherein m, Each of p and q is 1, 2 or 3; and r is 0, 1 or 2, X is O or NH; or a pharmaceutically acceptable salt and/or solvate thereof, provided that L When a covalent bond and R ¹ is hydrogen, R is selected from the group consisting of -C(O)NR ³ R ⁴ and -C(O)OR ⁵ or R ^{11 is} not an alkyl group; and another precondition is when When R is hydrogen or -C(O)R ² and L is a covalent bond, R ^{1 is} not hydrogen.

In one embodiment, R ¹¹ is selected from the group consisting of hydrogen, C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, and substituted C ₁ -C ₃ alkoxy.

In one embodiment, R ¹¹ is H. In one embodiment, R ¹¹ is C ₁ -C ₃ alkyl, such as ethyl. In one embodiment, R ¹¹ is CH ₂ CH ₂ OH. In one embodiment, R ¹¹ is CH ₂ CH ₂ OCH ₃ . In one embodiment, R ¹¹ is CH ₂ CH ₂ OCH ₂ Ph. Ph stands for phenyl. In one embodiment, R ¹¹ is CH ₂ CH ₂ OC(O)alkyl, such as CH ₂ CH ₂ OC(O)(CH ₂ ) ₁₀ CH ₃ . In one embodiment, R ¹¹ is CH ₂ CH ₂ O(CH ₂ ) _p O(CH ₂ ) _q O(CH ₂ ) _r CH ₃ .

In one embodiment, R ¹¹ is optionally substituted by C ₁ -C ₃ alkyl: YH, YR ¹² , YC(O)R ¹² , C(O)YR ¹² , C(O)NH ₂ , C (O) NHR ¹² , C(O)NR ¹² R ¹³ , NH ₂ , NHR ¹² , NR ¹² R ¹³ , NHC(O)R ¹² or NR ¹² C(O)R ¹³ , where Y is O or S, R ¹² and R ^{13 are} independently C ₁ -C ₃ alkyl.

In one embodiment, R ¹¹ is optionally substituted by C ₁ -C ₃ alkoxy: YH, YR ¹² , YC(O)R ¹² , C(O)YR ¹² , C(O)NH ₂ , C(O)NHR ¹² , C(O)NR ¹² R ¹³ , NH ₂ , NHR ¹² , NR ¹² R ¹³ , NHC(O)R ¹² or NR ¹² C(O)R ¹³ , wherein Y is O or S, R ¹² and R ^{13 are} independently C ₁ -C ₃ alkyl.

In one embodiment, R is hydrogen and L is a dissociable group.

In one embodiment, R-based hydrogen, L based -C (O) -, - C (O) O- or -C (O) NH-, and R ¹ lines of the substituted alkyl group. Preferably, R ¹ is an alkyl group substituted with -NR ⁶ R ⁷ wherein R ⁶ and R ⁷ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, substituted alkenyl, alkynyl And substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic.

In one embodiment, R is selected from the group consisting of -C(O)NR ³ R ⁴ and -C(O)OR ⁵ and R ¹ is hydrogen.

In one embodiment, a compound of Formula II, which is selected from those described in Table I below, or a pharmaceutically acceptable salt and/or solvate thereof, is provided:

In one embodiment, the compound of Formula I is a compound or a pharmaceutically acceptable salt and/or solvate thereof wherein R ¹⁰ is H, L and R ¹ are as defined above in Table I, and R ¹¹ is C ₁ -C ₃ alkyl substituted by the following: YH, YR ¹² , YC(O)R ¹² , C(O)YR ¹² , C(O)NH ₂ , C(O)NHR ¹² , C(O) NR ¹² R ¹³ , NH ₂ , NHR ¹² , NR ¹² R ¹³ , NHC(O)R ¹² or NR ¹² C(O)R ¹³ , wherein Y is O or S, and R ¹² and R ^{13 are} independently C ₁ - C ₃ alkyl.

In one embodiment, the compound of Formula I is a compound or a pharmaceutically acceptable salt and/or solvate thereof wherein R ¹⁰ is -OR, R, L and R ¹ are as defined above in Table I, and R ¹¹ is a C ₁ -C ₃ alkyl group substituted as follows: YH, YR ¹² , YC(O)R ¹² , C(O)YR ¹² , C(O)NH ₂ , C(O)NHR ¹² , C (O)NR ¹² R ¹³ , NH ₂ , NHR ¹² , NR ¹² R ¹³ , NHC(O)R ¹² or NR ¹² C(O)R ¹³ , wherein Y is O or S, and R ¹² and R ^{13 are} independently C ₁ -C ₃ alkyl.

In one of the compositions of the present invention, the present invention relates to a pharmaceutical combination comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of Formula I or Formula II or Table I above. Things.

In one of the aspects of the method of the invention, the invention relates to a method of treating addiction to a patient, the method comprising administering to the patient a pharmaceutically acceptable excipient and a therapeutically effective amount of Formula I or Formula II or a pharmaceutical composition of a compound of Table I above.

In another of the aspects of the method of the invention, the invention relates to a method of treating pain, addiction and/or stress in a patient, the method comprising administering to the patient a pharmaceutically acceptable excipient and treatment An effective amount of a pharmaceutical composition of Formula I or Formula II or a compound of Table I above.

The present invention relates to a novolac base prodrug, a pharmaceutical composition of such prodrugs, and a method of using the same. However, before the present invention is explained in more detail, the following terms will first be defined.

It is to be understood that the invention is not limited to the specific embodiments described, as it may of course vary. It is also understood that the terminology used herein is for the purpose of describing the particular embodiments, and is not intended to be limiting.

It must be noted that the singular forms "a", "an" and "the" Thus, for example, reference to "pharmaceutically acceptable excipient" includes a plurality of such excipients.

1. Definition

Unless otherwise defined, all scientific and technical terms used herein have the same meaning as commonly understood by those skilled in the art. The following terms as used herein have the following meanings.

The term "comprising or comprises" as used herein means that the compositions and methods include the recited elements, but do not exclude other elements. When "substantially composed of" is used to define a composition and method, it is intended to exclude other elements that have any essential meaning for the combination. Therefore, a composition consisting essentially of the elements as defined herein will not exclude other materials or steps that do not substantially affect the basic and novel characteristics of the claimed invention. "Consisting of" shall mean the exclusion of other ingredients and substantive method steps that exceed the trace elements. Embodiments defined by each of these transition terms are within the scope of the invention.

The term "about" when used in reference to a numeral (eg, temperature, time, amount, and concentration, including range), indicates an approximation that may vary (+) or (-) by 10%, 5%, or 1%.

In some embodiments, the invention relates to compositions comprising prodrugs and excipients described herein that facilitate transport across the blood brain barrier.

"Alkyl" means a monovalent saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms and preferably 1 to 6 carbon atoms. This term includes, for example, straight-chain and branched hydrocarbon groups such as methyl (CH ₃ -), ethyl (CH ₃ CH ₂ -), n-propyl (CH ₃ CH ₂ CH ₂ -), isopropyl Base ((CH ₃ ) ₂ CH-), n-butyl (CH ₃ CH ₂ CH ₂ CH ₂ -), isobutyl ((CH ₃ ) ₂ CHCH ₂ -), second butyl ((CH ₃ ) ( CH ₃ CH ₂ )CH-), tert-butyl ((CH ₃ ) ₃ C-), n-pentyl (CH ₃ CH ₂ CH ₂ CH ₂ CH ₂ -) and neopentyl ((CH ₃ ) ₃ CCH ₂ -).

"Alkenyl" means a straight chain having 2 to 6 carbon atoms and preferably 2 to 4 carbon atoms and having at least 1 and preferably 1 to 2 vinyl (>C=C<) unsaturation sites. Or with a branched hydrocarbon group. Such groups are exemplified, for example, by vinyl, allyl and but-3-en-1-yl. Included within this term are cis and trans isomers or mixtures of such isomers.

"Alkynyl" means a straight chain having from 2 to 6 carbon atoms and preferably from 2 to 3 carbon atoms and having at least one and preferably from 1 to 2 acetylene (-C≡C-) sites of unsaturation. Or a branched monovalent hydrocarbon group. Examples of such alkynyl groups include ethynyl (-C≡CH) and propargyl (-CH ₂ C≡CH).

"Substituted alkyl group" means an alkyl group having 1 to 5, preferably 1 to 3 or more preferably 1 to 2 substituents selected from the group consisting of alkoxy groups, substituted alkoxy groups Base, fluorenyl, decylamino, decyloxy, amine, substituted amine, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyl Oxyl, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, carbenyl, aryl, substituted aryl, aryloxy, substituted aryloxy, aromatic Thiothio group, substituted arylthio group, carboxyl group, carboxy ester, (carboxy ester) amine group, (carboxy ester)oxy group, cyano group, cycloalkyl group, substituted cycloalkyl group, cycloalkyloxy group Substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy , cycloalkenylthio, substituted cycloalkenylthio, fluorenyl, substituted fluorenyl, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted Aryloxy, heteroarylthio, Substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, Nitro, SO ₃ H, substituted sulfonyl, sulfonyloxy, thiodecyl, fluorenyl, alkylthio, and substituted alkylthio, wherein the substituents are as defined herein .

The "substituted alkenyl group" means an alkenyl group having 1 to 3 substituents and preferably 1 to 2 substituents selected from the group consisting of alkoxy groups, substituted alkoxy groups, mercapto groups, Merylamino, decyloxy, amine, substituted amine, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, amine Sulfonyl, aminosulfonyloxy, aminosulfonylamino, carbenyl, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, Substituted arylthio, carboxyl, carboxy ester, (carboxy ester) amine, (carboxy ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted ring Alkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenyl sulfide Substituted, substituted cycloalkenylthio, fluorenyl, substituted fluorenyl, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, hetero Arylthio group Heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro , SO ₃ H, the sulfo substituted acyl, sulfo acyl group, acyl thio group, a mercapto group, an alkylthio group and the substituted alkylthio, wherein such substituents are as defined herein and provided The condition is that any hydroxyl or thiol substitution is not attached to a vinyl (unsaturated) carbon atom.

The "substituted alkynyl group" means an alkynyl group having 1 to 3 substituents and preferably 1 to 2 substituents selected from the group consisting of alkoxy groups, substituted alkoxy groups, fluorenyl groups, Merylamino, decyloxy, amine, substituted amine, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, amine Sulfonyl, aminosulfonyloxy, aminosulfonylamino, carbenyl, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, Substituted arylthio, carboxyl, carboxy ester, (carboxy ester) amine, (carboxy ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted ring Alkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenyl sulfide Substituted, substituted cycloalkenylthio, fluorenyl, substituted fluorenyl, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, hetero Arylthio group Heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro , SO ₃ H, the sulfo substituted acyl, sulfo acyl group, acyl thio group, a mercapto group, an alkylthio group and the substituted alkylthio, wherein such substituents are as defined herein and provided The condition is that any hydroxyl or thiol substitution is not attached to the acetylene carbon atom.

"Alkoxy" means a group wherein the alkyl group is as defined herein -O-alkyl. Alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, second butoxy and n-pentyloxy.

"Substituted alkoxy" means a group wherein the substituted alkyl group is as defined herein -O-(substituted alkyl).

"Amidino" refers to the group HC(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl- C(O)-, alkynyl-C(O)-, substituted alkynyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, Cycloalkenyl-C(O)-, substituted cycloalkenyl-C(O)-, aryl-C(O)-, substituted aryl-C(O)-, heteroaryl-C ( O)-, substituted heteroaryl-C(O)-, heterocyclyl-C(O)-, and substituted heterocyclic-C(O)-, wherein alkyl, substituted alkyl, Alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, hetero Aryl, substituted heteroaryl, heterocyclyl and substituted heterocyclic are as defined herein. The sulfhydryl group includes the "Ethyl" CH ₃ C(O)-.

"N-mercaptoalkyl" refers to the group -NR ¹⁷ C(O)alkyl, -NR ¹⁷ C(O) substituted alkyl, -NR ¹⁷ C(O)cycloalkyl, -NR ¹⁷ C(O Substituted cycloalkyl, -NR ¹⁷ C(O)cycloalkenyl, -NR ¹⁷ C(O) substituted cycloalkenyl, -NR ¹⁷ C(O)alkenyl, -NR ¹⁷ C(O) Substituted alkenyl, -NR ¹⁷ C(O)alkynyl, -NR ¹⁷ C(O) substituted alkynyl, -NR ¹⁷ C(O)aryl, -NR ¹⁷ C(O) substituted aromatic , -NR ¹⁷ C(O)heteroaryl, -NR ¹⁷ C(O) substituted heteroaryl, -NR ¹⁷ C(O)heterocyclyl and -NR ¹⁷ C(O) substituted heterocycle a group wherein R ¹⁷ is hydrogen or alkyl and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, Cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl are as defined herein.

"Alkoxy" refers to the group alkyl-C(O)O-, substituted alkyl-C(O)O-, alkenyl-C(O)O-, substituted alkenyl-C ( O) O-, alkynyl-C(O)O-, substituted alkynyl-C(O)O-, aryl-C(O)O-, substituted aryl-C(O)O- , cycloalkyl-C(O)O-, substituted cycloalkyl-C(O)O-, cycloalkenyl-C(O)O-, substituted cycloalkenyl-C(O)O- , heteroaryl-C(O)O-, substituted heteroaryl-C(O)O-, heterocyclyl-C(O)O-, and substituted heterocyclic-C(O)O- , wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, taken The cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclic are as defined herein.

"Amine" refers to the group -NH ₂ .

"Substituted amine group" refers to the group -NR ¹⁸ R ¹⁹ wherein R ¹⁸ and R ¹⁹ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted Alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted Heteroaryl, heterocyclic, substituted heterocyclic, -SO ₂ -alkyl, -SO ₂ -substituted alkyl, -SO ₂ -alkenyl, -SO ₂ -substituted alkenyl, - SO ₂ - cycloalkyl, -SO ₂ - substituted the cycloalkyl, -SO ₂ - cycloalkenyl, -SO ₂ - substituted cycloalkenyl of, -SO ₂ - aryl, -SO ₂ - substituted An aryl group, -SO ₂ -heteroaryl, -SO ₂ -substituted heteroaryl, -SO ₂ -heterocyclyl and -SO ₂ -substituted heterocyclic group, and wherein R ¹⁸ and R ^{19 are} regarded The case is bonded to the nitrogen to which it is bonded to form a heterocyclic group or a substituted heterocyclic group, provided that both R ¹⁸ and R ¹⁹ are not hydrogen, and wherein the alkyl group, the substituted alkyl group, the alkenyl group Substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted naphthenes , Cycloalkenyl, substituted cycloalkenyl the group, an aryl group, the substituted aryl group, a heteroaryl group, as defined by the substituted heteroaryl, heterocyclyl and substituted heterocyclyl group of lines herein. When R ¹⁸ is hydrogen and R ¹⁹ is alkyl, the substituted amine group is sometimes referred to herein as an alkylamine group. When R ¹⁸ and R ¹⁹ are alkyl groups, the substituted amine group is sometimes referred to herein as a dialkylamino group. When referring to a monosubstituted amine group, it means R ¹⁸ or R ¹⁹ system but not simultaneously hydrogen. When referring to a disubstituted amine group, it means that neither R ¹⁸ nor R ¹⁹ is hydrogen.

"Aminocarbonyl" refers to the group -C(O)NR ²⁰ R ²¹ wherein R ²⁰ and R ²¹ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, a substituted heteroaryl group, a heterocyclic group, and a substituted heterocyclic group, wherein R ²⁰ and R ^{21 are} bonded together with the nitrogen to which they are bonded, to form a heterocyclic group or a substituted heterocyclic group, and wherein the alkane Substituted, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl Substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclic are as defined herein.

"Aminothiocarbonyl" refers to the group -C(S)NR ²⁰ R ²¹ wherein R ²⁰ and R ²¹ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl Substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl a substituted heteroaryl group, a heterocyclic group, and a substituted heterocyclic group, wherein R ²⁰ and R ^{21 are} optionally bonded together with the nitrogen to which they are bonded to form a heterocyclic group or a substituted heterocyclic group, and Wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, Aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclic are as defined herein.

"Aminocarbonylamino" refers to the group -NR ¹⁷ C(O)NR ²⁰ R ²¹ wherein R ¹⁷ is hydrogen or alkyl and R ²⁰ and R ²¹ are independently selected from the group consisting of hydrogen, alkane Alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, Substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclic and wherein R ²⁰ and R ^{21 are} bonded together with the nitrogen to which they are attached to form a heterocyclic group Or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl The substituted, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclic are as defined herein.

"Aminothiocarbonylamino" refers to the group -NR ¹⁷ C(S)NR ²⁰ R ²¹ wherein R ¹⁷ is hydrogen or alkyl and R ²⁰ and R ²¹ are independently selected from the group consisting of hydrogen. , alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl a substituted cycloalkenyl group, a heteroaryl group, a substituted heteroaryl group, a heterocyclic group, and a substituted heterocyclic group, wherein R ²⁰ and R ^{21 are} bonded together with the nitrogen to which they are combined to form a hetero a cyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, Cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl are as defined herein.

"Aminocarbonyloxy" refers to the group -OC(O)NR ²⁰ R ²¹ wherein R ²⁰ and R ²¹ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl Substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl a substituted heteroaryl group, a heterocyclic group, and a substituted heterocyclic group, wherein R ²⁰ and R ^{21 are} optionally bonded together with the nitrogen to which they are bonded to form a heterocyclic group or a substituted heterocyclic group, and Wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, Aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclic are as defined herein.

"Aminosulfonyl" refers to the group -SO ₂ NR ²⁰ R ²¹ , wherein R ²⁰ and R ²¹ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, a substituted heteroaryl group, a heterocyclic group, and a substituted heterocyclic group, wherein R ²⁰ and R ^{21 are} bonded together with the nitrogen to which they are bonded, to form a heterocyclic group or a substituted heterocyclic group, and wherein the alkane Substituted, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl Substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclic are as defined herein.

"Aminosulfonyloxy" refers to the group -O-SO ₂ NR ²⁰ R ²¹ wherein R ²⁰ and R ²¹ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, Alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, hetero An aryl group, a substituted heteroaryl group, a heterocyclic group, and a substituted heterocyclic group, wherein R ²⁰ and R ^{21 are} optionally bonded together with the nitrogen to which they are bonded to form a heterocyclic group or a substituted heterocyclic group. And wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl The aryl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclic are as defined herein.

"Aminosulfonylamino" refers to the group -NR ¹⁷ -SO ₂ NR ²⁰ R ²¹ wherein R ¹⁷ is hydrogen or alkyl and R ²⁰ and R ²¹ are independently selected from the group consisting of hydrogen, Alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl a substituted cycloalkenyl group, a heteroaryl group, a substituted heteroaryl group, a heterocyclic group, and a substituted heterocyclic group, wherein R ²⁰ and R ^{21 are} bonded together with the nitrogen to which they are bonded to form a heterocyclic ring Or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, ring Alkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl are as defined herein.

"Mercapto" refers to the group -C(=NR ²² )NR ²⁰ R ²¹ , wherein R ²⁰ , R ²¹ and R ²² are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl. Alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, a heteroaryl group, a substituted heteroaryl group, a heterocyclic group, and a substituted heterocyclic group, wherein R ²⁰ and R ^{21 are} bonded together with the nitrogen to which they are bonded, to form a heterocyclic group or a substituted heterocyclic group. And wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl The aryl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclic are as defined herein.

"Aryl" or "Ar" means a monovalent aromatic carbocyclic group having from 6 to 14 carbon atoms of a single ring (eg, phenyl) or a plurality of fused rings (eg, naphthyl or anthracenyl), The fused rings may or may not be aromatic (for example, 2-benzoxazolinone, 2H-1,4-benzoxazine-3(4H)-one-7-yl, and the like), The prerequisite is that the point of attachment is at the aromatic carbon atom. Preferred aryl groups include phenyl and naphthyl.

"Substituted aryl" means an aryl group substituted with 1 to 5, preferably 1 to 3 or more preferably 1 to 2 substituents selected from the group consisting of alkyl, substituted alkyl Alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, fluorenyl, decylamino, decyloxy, amine, substituted amine , Aminocarbonyl, Aminothiocarbonyl, Aminocarbonylamino, Aminothiocarbonylamino, Aminocarbonyloxy, Aminosulfonyl, Aminosulfonyloxy, Aminosulfonyl Amino, decyl, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxy, carboxy ester, (carboxy ester) amine , (carboxy ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkyl Thio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, fluorenyl, substituted Sulfhydryl, halo, hydroxy, hetero Aryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclyl, substituted heterocyclyl, hetero Cyclooxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO ₃ H, substituted sulfonyl, sulfonyloxy, sulphur An alkyl group, a fluorenyl group, an alkylthio group, and a substituted alkylthio group, wherein the substituents are as defined herein.

"Aryloxy" refers to the group -O-aryl, wherein aryl is as defined herein and includes, by way of example, phenoxy and naphthyloxy.

"Substituted aryloxy" refers to the group -O-(substituted aryl) wherein the substituted aryl is as defined herein.

"Arylthio" refers to the group -S-aryl, wherein aryl is as defined herein.

"Substituted arylthio" refers to the group -S-(substituted aryl) wherein the substituted aryl is as defined herein.

"Carbonyl" means a divalent group -C(O)- equivalent to -C(=O)-.

"Carboxylic acid" means -COOH or a salt thereof.

"Carboxyl ester or carboxy ester" refers to the group -C(O)O-alkyl, -C(O)O-substituted alkyl, -C(O)O-alkenyl, -C (O) O-substituted alkenyl, -C(O)O-alkynyl, -C(O)O-substituted alkynyl, -C(O)O-aryl, -C(O)O - substituted aryl, -C(O)O-cycloalkyl, -C(O)O-substituted cycloalkyl, -C(O)O-cycloalkenyl, -C(O)O- Substituted cycloalkenyl, -C(O)O-heteroaryl, -C(O)O-substituted heteroaryl, -C(O)O-heterocyclyl and -C(O)O- a substituted heterocyclic group wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, Substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclic are as defined herein.

"(Carboxy ester) Amine" refers to the group -NR ¹⁷ -C(O)O-alkyl, -NR ¹⁷ -C(O)O-substituted alkyl, -NR ¹⁷ -C(O)O Alkenyl, -NR ¹⁷ -C(O)O-substituted alkenyl, -NR ¹⁷ -C(O)O-alkynyl, -NR ¹⁷ -C(O)O-substituted alkynyl, - NR ¹⁷ -C(O)O-aryl, -NR ¹⁷ -C(O)O-substituted aryl, -NR ¹⁷ -C(O)O-cycloalkyl, -NR ¹⁷ -C(O) O-substituted cycloalkyl, -NR ¹⁷ -C(O)O-cycloalkenyl, -NR ¹⁷ -C(O)O-substituted cycloalkenyl, -NR ¹⁷ -C(O)O- Heteroaryl, -NR ¹⁷ -C(O)O-substituted heteroaryl, -NR ¹⁷ -C(O)O-heterocyclyl and -NR ¹⁷ -C(O)O-substituted heterocycle a group wherein R ¹⁷ is alkyl or hydrogen, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl A cycloalkenyl group, a substituted cycloalkenyl group, an aryl group, a substituted aryl group, a heteroaryl group, a substituted heteroaryl group, a heterocyclic group, and a substituted heterocyclic group are as defined herein.

"(Carboxy ester)oxy" refers to the group -O-C(O)O-alkyl, substituted -O-C(O)O- Alkyl, -OC(O)O-alkenyl, -OC(O)O-substituted alkenyl, -OC(O)O-alkynyl, -OC(O)O-substituted alkynyl, - OC(O)O-aryl, -OC(O)O-substituted aryl, -OC(O)O-cycloalkyl, -OC(O)O-substituted cycloalkyl, -OC ( O) O-cycloalkenyl, -OC(O)O-substituted cycloalkenyl, -OC(O)O-heteroaryl, -OC(O)O-substituted heteroaryl, -OC ( O) O-heterocyclyl and -OC(O)O-substituted heterocyclic group, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, Cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted Ring groups are as defined herein.

"Cyano" refers to the group -CN.

"Cycloalkyl" means a cyclic alkyl group of from 3 to 10 carbon atoms having a single or multiple rings including fused, bridged and spiro ring systems. The one or more rings may be aryl, heteroaryl or heterocyclic, provided that the point of attachment passes through a non-aromatic, non-heterocyclic ring carbocyclic ring. Examples of suitable cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclooctyl. Other examples of cycloalkyl groups include bicyclo[2,2,2,]octyl, norbornyl and spirobicyclo, such as spiro[4.5]dec-8-yl:

"Cycloalkenyl" means 3 to 10 carbons having one or more rings and having at least one >C=C<ring-unsaturated site and preferably 1 to 2>C=C<ring-unsaturation sites A non-aromatic cyclic alkyl group of an atom.

"Substituted cycloalkyl" and "substituted cycloalkenyl" mean a cycloalkyl or cycloalkenyl group having from 1 to 5 or preferably from 1 to 3 substituents selected from the group consisting of: side Oxyl, thioketo, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, fluorenyl, fluorenyl Amine, decyloxy, amine, substituted amine, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonate Amino, sulfonyloxy, aminosulfonylamino, carbenyl, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted Arylthio, carboxyl, carboxy ester, (carboxy ester) amine, (carboxy ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyl An oxy group, a cycloalkylthio group, a substituted cycloalkylthio group, a cycloalkenyl group, a substituted cycloalkenyl group, a cycloalkenyloxy group, a substituted cycloalkenyloxy group, a cycloalkenylthio group, Substituted cycloalkenylthio Sulfhydryl, substituted fluorenyl, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroaryl Thio group, heterocyclic group, substituted heterocyclic group, heterocyclic oxy group, substituted heterocyclic oxy group, heterocyclic thio group, substituted heterocyclic thio group, nitro group, SO ₃ H Substituted sulfonyl, sulfonyloxy, thiodecyl, decyl, alkylthio and substituted alkylthio, wherein the substituents are as defined herein.

"Cycloalkyloxy" means an -O-cycloalkyl group.

"Substituted cycloalkyloxy" means -O-(substituted cycloalkyl).

"Cycloalkylthio" means an -S-cycloalkyl group.

"Substituted cycloalkylthio" means -S-(substituted cycloalkyl).

"Cycloalkenyloxy" means an -O-cycloalkenyl group.

"Substituted cycloalkenyloxy" means -O-(substituted cycloalkenyl).

"Cycloalkenylthio" means an -S-cycloalkenyl group.

The "substituted cycloalkenylthio group" means -S-(substituted cycloalkenyl).

"Amidino" refers to the group -NHC(=NH)NH ₂ .

"Substituted thiol" means -NR ²³ C(=NR ²³ )N(R ²³ ) ₂ wherein each R ²³ is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl , an aryl group, a substituted aryl group, a heteroaryl group, a substituted heteroaryl group, a heterocyclic group, and a substituted heterocyclic group, and two R ²³ groups bonded to a common fluorenyl nitrogen atom, as appropriate The bound nitrogens are joined together to form a heterocyclic group or a substituted heterocyclic group, provided that at least one R ^{23 is} not hydrogen, and wherein the substituents are as defined herein.

"Halo" or "halogen" means fluoro, chloro, bromo and iodo and preferably fluoro or chloro.

"Haloalkyl" means an alkyl group substituted by 1 to 5, 1 to 3 or 1 to 2 halo, wherein alkyl and halo are as defined herein.

"Haloalkoxy" means an alkoxy group substituted by 1 to 5, 1 to 3 or 1 to 2 halo, wherein alkoxy and halo are as defined herein.

"Haloalkylthio" refers to an alkylthio group substituted with 1 to 5, 1 to 3 or 1 to 2 halo, wherein alkylthio and halo are as defined herein.

"Hydroxy" or "hydroxyl" refers to the group -OH.

"Heteroaryl" means an aromatic group having from 1 to 10 carbon atoms and having from 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the ring. These heteroaryl groups may have a single ring (for example, pyridyl or furyl) or a plurality of fused rings (for example, pyridazinyl or benzothienyl), wherein the fused rings may or may not be aromatic And/or containing a hetero atom, provided that the point of attachment is through the atom of the aromatic heteroaryl group. In one embodiment, the nitrogen and/or sulfur ring atoms of the heteroaryl group are optionally oxidized to provide an N-oxide (N→O), sulfinyl, and/or sulfonyl moiety. Preferred heteroaryl groups include pyridyl, pyrrolyl, indolyl, thienyl and furanyl.

"Substituted heteroaryl" means a group of 1 to 5, preferably 1 to 3 or more preferably 1 to 2, selected from the group consisting of the same substituent group defined for the substituted aryl group. A substituted heteroaryl group.

"Heteroaryloxy" means an -O-heteroaryl group.

"Substituted heteroaryloxy" refers to the group -O-(substituted heteroaryl).

"Heteroarylthio" refers to the group -S-heteroaryl.

"Substituted heteroarylthio" refers to the group -S-(substituted heteroaryl).

"Heterocyclic" or "heterocyclic" or "heterocycloalkyl" or "heterocyclyl" means a ring having from 1 to 10 ring carbon atoms and from 1 to 4 members selected from the group consisting of nitrogen, sulfur or oxygen. Heteroatom And or partially saturated non-aromatic groups. Heterocycles encompass single or multiple fused rings, including fused, bridged, and spiro ring systems. In a fused ring system, one or more of the rings may be a cycloalkyl, aryl or heteroaryl group, provided that the point of attachment passes through a non-aromatic heterocyclic ring. In one embodiment, the nitrogen and/or sulfur atom of the heterocyclyl is optionally oxidized to provide an N-oxide, sulfinyl, and/or sulfonyl moiety.

"Substituted heterocyclic" or "substituted heterocycloalkyl" or "substituted heterocyclic" means 1 to 5 or preferably 1 to 3 as defined for substituted cycloalkyl A heterocyclic group substituted with the same substituent as defined.

"Heterocyclyloxy" refers to the group -O-heterocyclyl.

The "substituted heterocyclic oxy group" means a group -O-(substituted heterocyclic group).

"Heterocyclylthio" refers to the group -S-heterocyclyl.

The "substituted heterocyclic thio group" means a group -S-(substituted heterocyclic group).

Examples of heterocyclic and heteroaryl groups include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, pyridazine, isoindole, indole, indoline, Carbazole, anthracene, quinolizine, isoquinoline, quinoline, pyridazine, naphthylpyridine, quinoxaline, quinazoline, Porphyrin, acridine, oxazole, porphyrin, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolium, imidazoline, hexahydropyridine, hexahydro Pyrazine, porphyrin, quinone imine, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, tetrahydrothiazole, thiophene Benzo[b]thiophene, morpholinyl, thiomorpholinyl (also known as thiamorpholinyl), 1,1-dioxathiomorpholinyl, hexahydropyridyl, pyrrolidine and tetrahydrofuranyl.

"Nitro" refers to the group -NO ₂ .

"Oxo" means the atom (= O) or (-O ^-).

"Spiro-ring system" means a two-ring system having a single ring of carbon atoms shared by two rings.

"Sulfo" refers to the divalent group -S(O) ₂ -.

"Substituted sulfonyl" refers to the group -SO ₂ -alkyl, -SO ₂ -substituted alkyl, -SO ₂ -alkenyl, -SO ₂ -substituted alkenyl, -SO ₂ - cycloalkyl, -SO ₂ - substituted the cycloalkyl, -SO ₂ - cycloalkenyl, -SO ₂ - substituted cycloalkenyl of, -SO ₂ - aryl, -SO ₂ - substituted aryl group of , -SO ₂ -heteroaryl, -SO ₂ -substituted heteroaryl, -SO ₂ -heterocyclyl, -SO ₂ -substituted heterocyclic group, wherein alkyl, substituted alkyl, alkene Alkyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl The substituted, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. The substituted sulfonyl group includes groups such as methyl-SO ₂ -, phenyl-SO ₂ -, and 4-methylphenyl-SO ₂ -. The term "alkylsulfonyl group" means -SO ₂ - group. The term "haloalkyl alkylsulfonyl group" means -SO ₂ - haloalkyl group, wherein haloalkyl is as defined herein based. The term "(substituted sulfonyl)amino" refers to -NH (substituted sulfonyl), and the term "(substituted sulfonyl)aminocarbonyl" refers to -C(O)NH ( Substituted sulfonyl), wherein the substituted sulfonyl group is as defined herein.

"Sulfonyloxy" refers to the group -OSO ₂ -alkyl, -OSO ₂ -substituted alkyl, -OSO ₂ -alkenyl, -OSO ₂ -substituted alkenyl, -OSO ₂ -cyclo alkyl, -OSO ₂ - of substituted cycloalkyl, -OSO ₂ - cycloalkenyl, -OSO ₂ - of substituted cycloalkenyl, -OSO ₂ - aryl, -OSO ₂ - the substituted aryl group, -OSO ₂ -heteroaryl, -OSO ₂ -substituted heteroaryl, -OSO ₂ -heterocyclyl, -OSO ₂ -substituted heterocyclic group, wherein alkyl, substituted alkyl, alkenyl Substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl Substituted heteroaryl, heterocyclyl and substituted heterocyclic are as defined herein.

"Thiothio" refers to the group HC(S)-, alkyl-C(S)-, substituted alkyl-C(S)-, alkenyl-C(S)-, substituted alkene -C(S)-, alkynyl-C(S)-, substituted alkynyl-C(S)-, cycloalkyl-C(S)-, substituted cycloalkyl-C(S) -, cycloalkenyl-C(S)-, substituted cycloalkenyl-C(S)-, aryl-C(S)-, substituted aryl-C(S)-, heteroaryl- C(S)-, substituted heteroaryl-C(S)-, heterocyclyl-C(S)-, and substituted heterocyclic-C(S)-, Alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, Aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclic are as defined herein.

"巯基" means the group -SH.

"Thiocarbonyl" means a divalent group -C(S)- equivalent to -C(=S)-.

"Thionyl" means an atom (=S).

"Alkylthio" refers to the group -S-alkyl wherein alkyl is as defined herein.

"Substituted alkylthio" refers to the group -S-(substituted alkyl) wherein the substituted alkyl is as defined herein.

As used herein, "compound or compound" is intended to include stereoisomers and tautomers of the formula shown.

"stereoisomer or stereoisomers" refers to compounds that differ in the palm of one or more stereocenters. Stereoisomers include mirror image isomers and non-image isomers.

"Tautomer" means an alternative form of a compound that differs at the proton position, such as an enol-ketone and an imine-enamine tautomer, or a link to a ring-NH- moiety and a ring-N- moiety. A tautomeric form of a heteroaryl group of a ring atom, such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole.

The term "norbogaine base" as used herein refers to the following compounds:

And a pharmaceutically acceptable salt thereof and/or a solvate thereof. Conventionally, noribogaine base is prepared by demethylation of natural ibogaine base:

This natural ibogaine base is isolated from Tabernanth iboga , a species of West African shrub. Demethylation can be achieved by conventional techniques such as reaction with boron tribromide/dichloromethane at room temperature followed by conventional purification. The method of synthesizing and purifying ipofibine base is described in U.S. Patent Application Serial No. 61/333,476, the entire disclosure of which is hereby incorporated by reference. The way to incorporate. The invention is not limited to any particular chemical form of noribogaine base, and the drug may be a free base of noribogaine base or a pharmaceutically acceptable addition salt or a drug which is a noribogaine base or a salt thereof. An acceptable solvate is administered to the patient.

The term "pharmaceutically acceptable salt" as used herein refers to a salt derived from an organic or inorganic acid. Examples of such acids include, but are not limited to, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, phosphorous acid, nitric acid, perchloric acid, acetic acid, tartaric acid, lactic acid, succinic acid, citric acid, malic acid, horses. Acid, aconitic acid, salicylic acid, thalic acid, methylene pamoic acid, heptanoic acid, and the like.

The term solvate as used herein, refers to a solid form compound that captures solvent molecules in the interior upon crystallization, and includes, but is not limited to, compounds of the invention with less than one, one or more solvent molecules or from about 0.1 to about 100. , or a complex of from about 1 to about 10, or about 0.5, 1, 2, 3 or 4 solvent molecules. A "pharmaceutically acceptable solvate" of a compound of the invention means a solvate complex which is pharmaceutically acceptable and which has the desired pharmacological activity of the parent compound. Examples of several solvents that can be used to generate solvates (eg, pharmaceutically acceptable solvates) include, but are not necessarily limited to, water, methanol, ethanol, isopropanol, butanol, general C1-C6 alcohols (as appropriate) Substituted), tetrahydrofuran, acetone, ethylene glycol, propylene glycol, acetic acid, formic acid, water and mixtures thereof. Other biocompatible solvents which may aid in the preparation of pharmaceutically acceptable solvates are well known in the art and are suitable for use in the present invention. In addition, various organic and inorganic acids and bases may be added or used alone as a solvent to produce the desired solvate. Such acids and bases are known in the art. When the solvent is water, the solvate is called Hydrates, such as hemihydrate (combination of two compound molecules with one water molecule), monohydrate (a compound molecule complexed with one water molecule) or dihydrate (a compound molecule complexed with two water molecules).

The term "therapeutically effective amount" as used herein refers to an amount when a composition of the invention is administered to an individual in need of treatment to a level sufficient to achieve a treatment as defined herein. The therapeutically effective amount will vary depending on the individual being treated and the condition, the weight and age of the individual, the severity of the condition, the particular composition or excipient selected, the dosage regimen being administered, the time of administration, The mode of administration and the like are readily determined by those skilled in the art.

The term "treatment" or "treating" as used herein means any treatment of a disease or condition of a patient, including: ‧ prevention or protection of an individual at risk of suffering from the disease or condition, for example, from disease or condition, ie The clinical symptoms are caused, thereby substantially preventing the onset of the disease or condition; ‧ inhibiting the disease or condition, ie preventing or suppressing the production of clinical symptoms; and/or ‧ reducing the disease or condition, even if the clinical symptoms subsided.

The term "pain" as used herein refers to all types of pain, including neuropathic pain and nociceptive pain. It is also contemplated that the compositions disclosed herein can be used to treat other types of pain, such as phantom pain, from painful sensations of limbs or organs that have lost or no longer received body signals and that are both amputees and quadriplegics. A generally reported experience.

The term "addiction" as used herein refers to a pattern of persistent behavior characterized by physical and/or psychological dependence of a substance, such as an anesthetic, stimulant, and sedative, including but not limited to heroin. , cocaine, alcohol, nicotine, caffeine, amphetamine, methamphetamine, methadone, and combinations thereof. As used herein, "treating a patient's addiction" refers to reducing the withdrawal symptoms associated with drug dependence and alleviating the drug cravings of the addict. These symptom packs It includes nausea, vomiting, anxiety, abdominal cramps, muscle pain, chills and headaches.

The term "blood brain barrier" or "BBB" as used herein refers to a barrier formed by a tight junction between the brain and the spinal cord through the cortical membrane in the cerebral capillaries, resulting in the transport of restricted molecules to the brain. Tight barrier. The blood-brain barrier in the brain, the blood-to-spinal wall in the spinal cord, and the blood-retinal barrier in the retina are adjacent capillary barriers in the central nervous system (CNS) and are collectively referred to herein as blood-brain barriers or BBB.

The term "dissociable linking group" as used herein, refers to a linking group that can be attached to a noribogaine base or derivative at any possible position. Preferably, the linking system is biocompatible (ie, does not produce undesirable side effects or does not have intolerable toxicity), readily dissociates in vivo (preferably in the brain), and does not inhibit or alter the Ibo The desired physiological effect of the base or derivative. In particular, the linking group is preferably sufficiently stable in the circulatory system (serum or blood), but dissociates upon entry into the brain to release the noribogaine base or derivative. Suitable biocompatible dissociable linking groups comprise from 1 to 20 atoms selected from the group consisting of carbon, nitrogen, oxygen, sulfur and phosphorus, and are generally susceptible to dissociation conditions or reagents in the brain (ie pH, redox potential or presence) Degradation of molecules, such as enzymes). The biocompatible dissociable linking group can be an ester-based dissociable linking group (-C(O)O- or -OC(O)-), a guanamine-based dissociable linking group (-C(O) NR ⁹ - or -NR ⁹ C(O)-) or a phosphate-based dissociable linking group (-P(O)(OR ⁹ )-O-, -OP(S)(OR ⁹ )-O- , -OP(S)(SR)-O-, -SP(O)(OR ⁹ )-O-, -OP(O)(OR ⁹ )-S-, -SP(O)(OR ⁹ )-S -, -OP(S)(OR ⁹ )-S-, -SP(S)(OR ⁹ )-O-, -OP(O)(R ⁹ )-O-, -OP(S)(R ⁹ ) -O-, -SP(O)(R ⁹ )-O-, -SP(S)(R ⁹ )-O-, -SP(O)(R ⁹ )-S- or -OP(S)(R ⁹ )-S-), wherein R ⁹ may be hydrogen or an alkyl group.

The term "sugar" or "monosaccharide" as used herein, refers to a sugar having at least 6 carbon atoms which may be linear, branched or cyclic and having an oxygen, nitrogen or sulfur atom bonded to each carbon atom or Its derivatives. The term "oligosaccharide" includes oligosaccharides containing from about 2 to about 9 monosaccharide units. Specific monosaccharides include C ₅ and C ₅ or higher (preferably C ₅ -C ₈ ) sugars, such as erythritol, zylitol, galactose, lactose, xylose, galactitol, inositol, fructose, Mannitol, sorbitol, glucose, arabinose, cellobiose, maltose, raffinose, rhamnose, melibiose, ribose, sagoditol, arabitol, trehalose, lyxose, glucosamine Sugars, mannosamines and galactosamines; disaccharides and trisaccharides include sugars having two or three monosaccharide units.

The term "patient" as used herein refers to mammals and includes both human and non-human mammals.

2. Compound

Thus, in one embodiment, the invention relates to a compound represented by the following formula I:

Wherein L is selected from the group consisting of a covalent bond and a cleavable linker group; R ¹ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkyne a substituted alkynyl group, an aryl group, a substituted aryl group, a cycloalkyl group, a substituted cycloalkyl group, a heteroaryl group, a substituted heteroaryl group, a heterocyclic group, and a substituted heterocyclic group, The prerequisite is that R ^{1 is} not a sugar or an oligosaccharide; R ¹⁰ is hydrogen or -OR; R ¹¹ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy , (CH ₂ ) _m OC(O)alkyl, (CH ₂ ) _m OH, (CH ₂ ) _m Oalkyl, CH ₂ -X-alkyl or (CH ₂ ) _m O(CH ₂ ) _p O (CH ₂ ) _q O(CH ₂ ) _r CH ₃ , wherein each of m, p and q is 1, 2 or 3; and r is 0, 1 or 2, X is O or NH; a group of free consisting of hydrogen, a hydrolyzable group selected from the group consisting of -C(O)R ² , -C(O)NR ³ R ⁴ and -C(O)OR ⁵ , wherein R ² is selected from the group consisting of: hydrogen, alkyl, the substituted alkyl group, alkenyl group, the substituted alkenyl group, an alkynyl group and the substituted alkynyl group, R ³ and R ⁴ are independently selected from the group consisting of lines to Group of constituents: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted An aryl group, a heterocyclic group and a substituted heterocyclic group, and R ⁵ is selected from the group consisting of an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an alkynyl group, a substituted alkyne a aryl group, an aryl group, a substituted aryl group, a heteroaryl group, a substituted heteroaryl group, a heterocyclic group, and a substituted heterocyclic group, provided that R is not a sugar or an oligosaccharide; or it is pharmaceutically acceptable a salt and/or a solvate, provided that when L is a covalent bond and R ¹ is hydrogen, R is selected from the group consisting of -C(O)NR ³ R ⁴ and -C(O)OR ⁵ ; And another precondition is that when R is hydrogen or -C(O)R ² and L is a covalent bond, R ^{1 is} not hydrogen.

In one embodiment, R ¹¹ is selected from the group consisting of hydrogen, C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, and substituted C ₁ -C ₃ alkoxy.

In one embodiment, R ¹¹ is H. In one embodiment, R ¹¹ is C ₁ -C ₃ alkyl, such as ethyl. In one embodiment, R ¹¹ is CH ₂ CH ₂ OH. In one embodiment, R ¹¹ is CH ₂ CH ₂ OCH ₃ . In one embodiment, R ¹¹ is CH ₂ CH ₂ OCH ₂ Ph. In one embodiment, R ¹¹ is CH ₂ CH ₂ OC(O)alkyl, such as CH ₂ CH ₂ OC(O)(CH ₂ ) ₁₀ CH ₃ . In one embodiment, R ¹¹ is CH ₂ -X-CH ₃ . In one embodiment, R ¹¹ is CH ₂ CH ₂ O(CH ₂ ) _p O(CH ₂ ) _q O(CH ₂ ) _r CH ₃ .

In one embodiment, R ¹¹ is optionally substituted by C ₁ -C ₃ alkyl: YH, YR ¹² , YC(O)R ¹² , C(O)YR ¹² , C(O)NH ₂ , C (O) NHR ¹² , C(O)NR ¹² R ¹³ , NH ₂ , NHR ¹² , NR ¹² R ¹³ , NHC(O)R ¹² or NR ¹² C(O)R ¹³ , where Y is O or S, R ¹² and R ^{13 are} independently C ₁ -C ₃ alkyl.

In one embodiment, R ¹¹ is optionally substituted by C ₁ -C ₃ alkoxy: YH, YR ¹² , YC(O)R ¹² , C(O)YR ¹² , C(O)NH ₂ , C(O)NHR ¹² , C(O)NR ¹² R ¹³ , NH ₂ , NHR ¹² , NR ¹² R ¹³ , NHC(O)R ¹² or NR ¹² C(O)R ¹³ , wherein Y is O or S, R ¹² and R ^{13 are} independently C ₁ -C ₃ alkyl.

In one embodiment, L is a suitable biocompatible dissociable linking group as described herein.

In one embodiment, the L is -C(O)-. In another embodiment, the L is -C(O)O-. In still another embodiment, L is -C(O)NR-, wherein R is hydrogen or alkyl.

In one embodiment, the L is selected from the group consisting of -P(O)(OR ⁹ )-O-, -OP(S)(OR ⁹ )-O-, -OP(S)(SR ⁹ ) -O-, -SP(O)(OR ⁹ )-O-, -OP(O)(OR ⁹ )-S-, -SP(O)(OR ⁹ )-S-, -OP(S)(OR ⁹ )-S-, -SP(S)(OR ⁹ )-O-, -OP(O)(R ⁹ )-O-, -OP(S)(R ⁹ )-O-, -SP(O) ^{(R 9) -O -, -} SP (S) (R 9) -O -, - SP (O) (R 9) -S- , and ^{-OP (S) (R 9)} -S-, wherein R ⁹ Hydrogen or alkyl.

In one embodiment, R a hydrogen-based, L-based covalent bond or -C (O) -, and R ¹ lines of the substituted alkyl group. In one embodiment, R ¹ is alkyl substituted with -NR ⁶ R ⁷ wherein R ⁶ and R ⁷ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, substituted alkenyl, Alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclic .

In one embodiment, R is selected from the group consisting of -C(O)NR ³ R ⁴ and -C(O)OR ⁵ and R ¹ is hydrogen.

In one embodiment, the compound of Formula I is a compound or a pharmaceutically acceptable salt and/or solvate thereof wherein R ¹⁰ is H, L and R ¹ are as defined in Table II below, and R ¹¹ is C ₁ -C ₃ alkyl substituted by the following: YH, YR ¹² , YC(O)R ¹² , C(O)YR ¹² , C(O)NH ₂ , C(O)NHR ¹² , C(O) NR ¹² R ¹³ , NH ₂ , NHR ¹² , NR ¹² R ¹³ , NHC(O)R ¹² or NR ¹² C(O)R ¹³ , wherein Y is O or S, and R ¹² and R ^{13 are} independently C ₁ - C ₃ alkyl.

In one embodiment, the compound of Formula I is a compound or a pharmaceutically acceptable salt and/or solvate thereof wherein R ¹⁰ is H, L and R ¹ are as defined in Table II below, and R ¹¹ is selected From H, CH ₂ CH ₂ OH, CH ₂ CH ₂ OCH ₃ , CH ₂ CH ₂ OCH ₂ Ph, CH ₂ CH ₂ OC(O)alkyl and CH ₂ CH ₂ O(CH ₂ ) _p O(CH ₂ ) _q O(CH ₂ ) _r CH ₃ .

In one embodiment, the compound of Formula I is a compound or a pharmaceutically acceptable salt and/or solvate thereof wherein R ¹⁰ is -OR, R, L and R ¹ are as defined in Table II below, and R ¹¹ is a C ₁ -C ₃ alkyl group substituted as follows: YH, YR ¹² , YC(O)R ¹² , C(O)YR ¹² , C(O)NH ₂ , C(O)NHR ¹² , C (O)NR ¹² R ¹³ , NH ₂ , NHR ¹² , NR ¹² R ¹³ , NHC(O)R ¹² or NR ¹² C(O)R ¹³ , wherein Y is O or S, and R ¹² and R ^{13 are} independently C ₁ -C ₃ alkyl.

In one embodiment, the compound of Formula I is a compound or a pharmaceutically acceptable salt and/or solvate thereof wherein R ¹⁰ is -OR, R, L and R ¹ are as defined in Table II below, and R ¹¹ is selected from the group consisting of H, CH ₂ CH ₂ OH, CH ₂ CH ₂ OCH ₃ , CH ₂ CH ₂ OCH ₂ Ph, CH ₂ CH ₂ OC(O)alkyl, and CH ₂ CH ₂ O(CH ₂ ) _p O ( CH ₂ ) _q O(CH ₂ ) _r CH ₃ .

In one embodiment, the compound of Formula I is a compound or a pharmaceutically acceptable salt and/or solvate thereof wherein R ¹⁰ is -OR, R, L and R ¹ are as defined in Table II below, and R ¹¹ is selected from the group consisting of H, CH ₂ CH ₂ OH, CH ₂ CH ₂ OCH ₃ , CH ₂ CH ₂ OCH ₂ Ph, CH ₂ CH ₂ OC(O)alkyl, and CH ₂ CH ₂ O(CH ₂ ) _p O ( CH ₂ ) _q O(CH ₂ ) _r CH ₃ .

In one embodiment, the compound of Formula I is a compound or a pharmaceutically acceptable salt and/or solvate thereof wherein R ¹⁰ is -OR, R, L and R ¹ are as defined in Table II below, and R ¹¹ series H.

In one embodiment, the compound of Formula I is a compound or a pharmaceutically acceptable salt and/or solvate thereof wherein R ¹⁰ is -OR, R, L and R ¹ are as defined in Table II below, and R ¹¹ series CH ₂ CH ₂ OH.

In one embodiment, the compound of Formula I is a compound or a pharmaceutically acceptable salt and/or solvate thereof wherein R ¹⁰ is -OR, R, L and R ¹ are as defined in Table II below, and R ¹¹ series CH ₂ CH ₂ OCH ₃ .

In one embodiment, the compound of Formula I is a compound or a pharmaceutically acceptable salt and/or solvate thereof wherein R ¹⁰ is -OR, R, L and R ¹ are as defined in Table II below, and R ¹¹ series CH ₂ OCH ₃ .

In one embodiment, the compound of Formula I is a compound or a pharmaceutically acceptable salt and/or solvate thereof wherein R ¹⁰ is -OR, R, L and R ¹ are as defined in Table II below, and R ¹¹ series CH ₂ CH ₂ OCH ₂ Ph.

In one embodiment, the compound of Formula I is a compound or a pharmaceutically acceptable salt and/or solvate thereof wherein R ¹⁰ is -OR, R, L and R ¹ are as defined in Table II below, and R ¹¹ is a CH ₂ CH ₂ OC(O)alkyl group, for example a C ₁₂ alkyl group.

In one embodiment, the compound of Formula I is a compound or a pharmaceutically acceptable salt and/or solvate thereof wherein R ¹⁰ is -OR, R, L and R ¹ are as defined in Table II below, and R ¹¹ series CH ₂ CH ₂ O(CH ₂ ) _p O(CH ₂ ) _q O(CH ₂ ) _r CH ₃ .

In one embodiment, the compound of Formula I is a compound or a pharmaceutically acceptable salt and/or solvate thereof wherein R ¹⁰ is -OR, R, L and R ¹ are as defined in Table II below, and R ¹¹ series methyl.

In one embodiment, the compound of Formula I is a compound or a pharmaceutically acceptable salt and/or solvate thereof wherein R ¹⁰ is -OR, R, L and R ¹ are as defined in Table II below, and R ¹¹ series C ₃ alkyl.

In one embodiment, a compound represented by the following formula II is provided:

Wherein R is selected from the group consisting of hydrogen, a hydrolyzable group selected from the group consisting of -C(O)R ² , -C(O)NR ³ R ⁴ and -C(O)OR ⁵ , wherein R ² is selected from the group consisting of hydrogen, an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an alkynyl group, and a substituted alkynyl group, and R ³ and R ⁴ are independently selected from the group consisting of Groups: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl a group, a heterocyclic group and a substituted heterocyclic group, and R ⁵ is selected from the group consisting of an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an alkynyl group, a substituted alkynyl group, An aryl group, a substituted aryl group, a heteroaryl group, a substituted heteroaryl group, a heterocyclic group, and a substituted heterocyclic group, provided that R is not a sugar or an oligosaccharide; and L is selected from a covalent bond and a group of dissociable linker groups; R ¹ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aromatic Base, substituted aryl a cycloalkyl group, a substituted cycloalkyl group, a heteroaryl group, a substituted heteroaryl group, a heterocyclic group, and a substituted heterocyclic group, provided that R ^{1 is} not a sugar or an oligosaccharide; or a pharmaceutical thereof An acceptable salt, provided that when L is a covalent bond and R ¹ is hydrogen, R is selected from the group consisting of -C(O)NR ³ R ⁴ and -C(O)OR ⁵ ; and another premise The condition is that when R is hydrogen or -C(O)R ² and L is a covalent bond, R ^{1 is} not hydrogen.

In one embodiment, R is hydrogen and L is a dissociable group.

In one embodiment, L is a suitable biocompatible dissociable linking group. Suitable biocompatible dissociable linking groups comprise covalent bonds and linking groups having from 1 to 20 atoms selected from the group consisting of carbon, nitrogen, oxygen, sulfur and phosphorus and are generally susceptible to dissociation conditions or reagents in the brain ( That is, pH, redox potential or the presence of degrading molecules such as enzymes, such as proteases, lipases, etc.). Generally, dissociation conditions or agents should be found more commonly in the brain than in serum or blood or at higher levels or activity. Examples of the degradation reagent include: a redox agent selected for a specific substrate or without a substrate specificity, including, for example, an oxidase or a reductase or a reducing agent such as an esterase; which can be hydrolyzed by use as a general acid Or an enzyme that decomposes the acid to dissociate the linking group, a peptidase (which may be receptor-specific), and a phosphatase.

In general, the suitability of a candidate cleavable linking group can be assessed by testing the ability of the dissociating agent (or condition) to dissociate the linking group. It will also be desirable to also test the ability of the linking group to resist dissociation in serum, blood, or resistance to dissociation when in contact with another non-target tissue. The relative sensitivity to dissociation can thus be determined between a first condition indicative of dissociation in the brain and a second condition indicative of dissociation in serum, blood or another non-target tissue. Such assessments can be performed in a cell-free system, in cells, in cell culture, in organ or tissue culture, or throughout the animal. In a preferred embodiment, the rate of dissociation of the cleavable linking group in the brain is at least 2, 4, 10 or 100 times in serum, blood or another non-target tissue.

In one embodiment, the linking group is based on an ester linking group. In another embodiment, the linking group is based on a linking group of a guanamine. In still another embodiment, the linking group is based on a phosphate linking group. In another embodiment of the compounds of the invention, the L system is Price key.

In one embodiment, the L is -C(O)-. In another embodiment, the L is -C(O)O-. In still another embodiment, L is -C(O)NR ⁹ -, wherein R ⁹ is hydrogen or alkyl.

In one embodiment, the L is selected from the group consisting of -P(O)(OR ⁹ )-O-, -OP(S)(OR ⁹ )-O-, -OP(S)(SR ⁹ ) -O-, -SP(O)(OR ⁹ )-O-, -OP(O)(OR ⁹ )-S-, -SP(O)(OR ⁹ )-S-, -OP(S)(OR ⁹ )-S-, -SP(S)(OR ⁹ )-O-, -OP(O)(R ⁹ )-O-, -OP(S)(R ⁹ )-O-, -SP(O) ^{(R 9) -O -, -} SP (S) (R 9) -O -, - SP (O) (R 9) -S- , and ^{-OP (S) (R 9)} -S-, wherein R ⁹ Hydrogen or alkyl.

In one embodiment, R a hydrogen-based, L-based covalent bond or -C (O) -, and R ¹ lines of the substituted alkyl group. Preferably, R ¹ is an alkyl group substituted with -NR ⁶ R ⁷ wherein R ⁶ and R ⁷ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, substituted alkenyl, alkynyl And substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic.

In one embodiment, R is selected from the group consisting of -C(O)NR ³ R ⁴ and -C(O)OR ⁵ and R ¹ is hydrogen.

In one embodiment, the compound of Formula II is a compound described in Table I below, or a pharmaceutically acceptable salt and/or solvate thereof:

3. How to use

The compounds of the invention are expected to be useful as active ingredients or prodrugs for the treatment of pain and/or addiction. In some embodiments, a compound of the invention is a R and/or -LR ¹ group that is cleaved in vivo to produce a pro-bogaine base or a noribogaine derivative. In a preferred embodiment, the stability of the compound in serum plasma is at least 2-fold, 5-fold or 10-fold greater in the central nervous system (e.g., brain). In a more preferred embodiment, the prodrug has improved BBB penetration properties compared to noribogaine base or noribogaine derivative, for example, the BBB penetration ability of the compounds of the invention is lower than that of noribogaine or The reduced ibogaine derivative is at least 20%, 50% or 100% higher.

Treatment of pain

In one of the aspects of the method of the invention, the invention relates to a method of treating pain in a patient, the method comprising administering to the patient a compound of the invention or a pharmaceutically acceptable salt and/or solvate thereof or comprising A pharmaceutical composition of a compound of the invention and a pharmaceutically acceptable excipient. The pain can be any type of pain including, but not limited to, neuropathic or nociceptive pain and its various types, including somatic pain, visceral pain, and phantom pain. The use of a reduced ibogaine base for the treatment of pain is described, for example, in U.S. Provisional Patent Application Serial No. 61/952,738, filed on March 13, 2014, entitled &lt;RTIgt;&quot; USE OF NORIBOGAINE FOR THE TREATMENT OF PAIN&quot; The full text is incorporated herein by reference. in.

In the other of the aspects of the method of the invention, the invention relates to a method of reducing the tolerance of a patient undergoing pain treatment to an opioid analgesic. The use of a reduced ibogaine base for reducing the tolerance to an opioid analgesic is described, for example, in the U.S. Patent Application filed on March 13, 2014, entitled "METHODS AND COMPOSITIONS FOR REDUCING TOLERANCE TO OPIOID ANALGESICS" In the case of No. 61/952,741, the entire disclosure of which is incorporated herein by reference.

Addiction treatment

In another of the aspects of the method of the invention, the invention relates to a method of treating addiction to a patient, the method comprising administering to the patient a compound of the invention or a pharmaceutically acceptable salt and/or solvate thereof Or a composition comprising a compound of the invention and a pharmaceutically acceptable excipient.

In certain embodiments, the patient's addiction treatment comprises ameliorating symptoms associated with withdrawal medication dependence. These symptoms include nausea, vomiting, anxiety, abdominal cramps, muscle aches, chills and headaches. In addition, treatment with the compounds of the invention is contemplated to reduce the drug cravings typically experienced by addicts after discontinuing self-administration of substance abuse. The compositions disclosed herein are expected to be particularly useful for treating opioid addictions such as heroin and methadone. However, it can also be used to treat patients who are addicted to other substances, including cocaine, alcohol, amphetamines, tobacco, caffeine, opioids, cannabinoids, benzodiazepines and any other prohibited A prescription or an addictive substance that is usually available, and a combination of such drugs.

The invention also relates to the treatment of drug addiction (involving drug dependence or drug abuse) during withdrawal therapy by administering a compound of the invention to a patient at a dose sufficient to reduce or eliminate one or more symptoms associated with withdrawal. method. Acute withdrawal symptoms include nausea, vomiting, anxiety, abdominal cramps, muscle pain, chills, and headaches. In addition, it is contemplated that treatment with a compound of the invention reduces the addict's cessation of self-administration of substances of abuse (eg, such as heroin) And the cravings of drugs that are usually experienced after opioids such as methadone. However, it is expected that the compounds of the invention may also be used to treat patients who are addicted to other substances, such as cocaine, alcohol, amphetamines, tobacco, caffeine, opioids, cannabinoids, benzodiazepines, and the like. Any other illicit drug or an addictive substance that is generally available, and a combination of such drugs. A compound of the invention may be administered to a patient suffering from drug dependence or abuse, and an opioid antagonist (eg, naloxone, eg, between 0.15 mg and 0.5 mg per mg of the compound of the invention administered, Naltrexone or nalorphine).

The present invention also relates to the prevention of administration of a compound of the present invention to a patient by a dose sufficient to reduce or eliminate one or more of the symptoms associated with acute withdrawal (including craving), after the drug has been discontinued (eg, in therapy) After improving drug abuse, the method of reusing the drug. The compound can be administered at a lower dose (e.g., "maintenance") than the dose used to treat addiction and acute withdrawal symptoms.

The use of noribogaine for acute and long-term treatment of drug abuse and withdrawal symptoms is described, for example, in the following applications: U.S. Patent Application Serial Nos. 14/214,157, 14/346,655, and 14/195,822; US Provisional Patent Application No. 61/941,390, filed on Feb. 18, 2014, entitled &quot; LOW DOSE NORIBOGAINE FOR TREATING NICOTINE ADDICTION AND PREVENTING RELAPSE OF NICOTINE USE; 61/952,731, Application dated March 13, 2014, entitled "METHODS FOR ACUTE AND LONG-TERM TREATMENT OF ALCOHOL DEPENDENCE"; and No. 61/952,727, filed on March 13, 2014, with the title "METHODS FOR ACUTE" AND LONG-TERM TREATMENT OF SUBSTANCE ABUSE"; the entire contents of each of these applications are hereby incorporated by reference.

Treatment of depression

In the other of the method aspects of the present invention, the present invention relates to treatment requiring treatment A method of treating depression in a patient, the method comprising administering to the patient a compound of the invention, or a pharmaceutically acceptable salt and/or solvate thereof, or a composition comprising a compound of the invention and a pharmaceutically acceptable excipient . Depression includes major depression and neurological depression (American Psychiatric Association, 1994a; American Psychiatric Association, 1994b). Major depression is characterized by one or more major depressive episodes of no manic or convulsive episodes. A major depressive episode is defined as a significant and relatively persistent depression or anxiety that normally interferes with daily function (almost every day, lasting at least 2 weeks); it can include at least 4 of the following 8 symptoms: appetite changes, sleep changes, psychomotor activity Sexual agitation or delay, loss of interest in habitual activities or reduced sexual impulses, increased fatigue, guilt or worthlessness, slow thinking or lack of concentration and suicidal attempts or suicidal ideation. Neurofunctional depression involves a type of depression that is not severe enough to be called a major depressive episode but that lasts much longer than major depression and has no high stage. The use of noribogaine for the treatment of depression is described, for example, in U.S. Provisional Patent Application Serial No. 61/952,733, filed on March 13, 2014, entitled &quot;METHODS AND COMPOSITIONS FOR TREATING DEPRESSION&quot; This is incorporated herein by reference.

Treatment of stress and/or anxiety

In another of the aspects of the method of the invention, the invention relates to a method of treating the pressure of a patient in need of treatment, such as post-traumatic stress disorder, the method comprising administering to the patient a compound of the invention or a pharmaceutically acceptable compound thereof Salts and/or solvates or compositions comprising a compound of the invention and a pharmaceutically acceptable excipient.

Stress or anxiety refers to the result of a patient's inability to respond appropriately to an emotional or physical threat that may be real or imaginary. Stress symptoms or conditions can be cognitive, emotional, physical or behavioral, including but not limited to panic state and adrenaline production, short-term resistance as a coping mechanism, exhaustion, irritability, muscle tension, inability to concentrate, judgment Poor, general negative outlook, excessive anxiety, mood change, irritability, excitement, inability to relax, feeling lonely, isolated or suppressed Depression, pain, diarrhea or constipation, nausea, dizziness, chest pain, headache, rapid heartbeat, excessive or insufficient eating, excessive or insufficient sleep, avoidance of socialization, procrastination or neglect of responsibility, increased consumption of alcohol, nicotine or drugs, and neurological habits (such as pacing or biting nails). Stress can develop into disability disorders of excessive and irrational fear, such as obsessive-compulsive disorder, panic disorder, acute stress disorder, and post-traumatic stress disorder (PTSD).

PTSD is a severe stress disorder that can result from exposure to an event that causes a psychological trauma. Such incidents usually involve the death of others, threats of death to themselves or others, or trauma to the physical, sexual or psychological integrity of themselves or others. PTSD can be an acute or long-term stress response to an event when the event exceeds one's ability to respond.

Symptoms of PTSD include some or all of the following: repeated re-experience of trauma, for example, an annoying memory of an event, an illusion of a traumatic event (behavior or feeling like an event is happening again), a recurring nightmare (incidents or other horrifying things); feeling strongly and/or strongly physical reactions when recalling trauma; avoiding the victim's perception of the location of the wound, the extent to which the person and experience have reached fear, and generally numb the emotional response; Can not remember the important situation of trauma; and excessive signs of awakening, including sleep problems, difficulty in concentration, irritability, anger, poor concentration, transient black sputum or difficulty in writing, frightened tendency and reaction, and excessive alertness to threats. Other symptoms include lack of pleasure, lack of interest in activities for enjoyment, emotional deadness, alienation and/or a sense of a limited future (eg, cannot think of the future or develop a future plan, Do not believe that you will live longer), guilty, ashamed, self-blame, depression and despair, suicidal thoughts and feelings, feeling alienation and loneliness, headache, stomach problems, chest pain and substance abuse.

The use of a reduced ibogaine base for the treatment of PTSD is described, for example, in U.S. Provisional Patent Application Serial No. 61/952,733, filed on March 13, 2014, entitled &quot;METHODS AND COMPOSITIONS FOR TREATING DEPRESSION&quot; The citations are incorporated herein by reference.

Combination therapy

The compounds of the invention may be used alone or in combination with other compounds to treat the above mentioned diseases or conditions. When administered with another agent, co-administration can be carried out in any manner in which the pharmacological effects of both can be manifested simultaneously in the patient. Thus, co-administration does not require the use of a single pharmaceutical composition, the same dosage form, or even the same route of administration to administer either a compound of the invention and another agent or require that both agents be administered at the same time. However, co-administration will most conveniently be achieved at substantially the same time by the same dosage form and the same route of administration. Obviously, this administration is most advantageously carried out by simultaneously delivering two active ingredients in a novel pharmaceutical composition according to the invention.

In some embodiments, the compounds of the invention are useful as an adjunct to conventional drug withdrawal therapy, and in particular to the administration of a compound of the invention with one or more opioid antagonists.

4. Composition

In another aspect, the invention is also directed to a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of the invention or a mixture of one or more of such compounds.

While compositions suitable for oral, intravenous or intra-arterial delivery will most likely be used, other routes that may be used include oral, pulmonary, rectal, nasal, vaginal, lingual, intramuscular, intraperitoneal, intradermal, and Subcutaneous route. In addition, it is contemplated that the composition can be administered transdermally, wherein the drug is administered as part of a lactic acid, gel or patch (for examples of transdermal formulations, see U.S. Patent Nos. 4,806,341, 5,149,538 and 4,626,539). . Other dosage forms include tablets, capsules, pills, powders, aerosols, suppositories, parenterals, and oral solutions, including suspensions, solutions, and emulsions. Sustained release dosage forms can also be used, for example, in the form of a transdermal patch. All dosage forms can be prepared using standard industry methods (see, for example, Remington's Pharmaceutical Sciences, 16th Ed., A. Oslo editor, Easton Pa. 1980). Intranasal administration is an effective method of delivering a therapeutic agent directly to the respiratory tract that rapidly absorbs the therapeutic agent.

Such compositions typically comprise a compound of the invention or a mixture thereof and at least one physician A pharmaceutically acceptable excipient. Acceptable excipients are non-toxically administered and do not adversely affect the therapeutic benefit of the compounds of the invention. Such excipients can be any solid, liquid, semi-solid, or in the case of an aerosol composition, which are conventionally available to those skilled in the art. Pharmaceutical compositions in accordance with the present invention are prepared by conventional methods using methods known in the art.

Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, tannin, magnesium stearate, sodium stearate, glyceryl monostearate, Sodium chloride, skim milk powder and the like. The liquid and semi-solid excipients may be selected from the group consisting of glycerin, propylene glycol, water, ethanol, and various oils, including petroleum, animal, vegetable, or synthetic sources of oil, for example, peanut oil, soybean oil, mineral oil, sesame oil, and the like. Preferred liquid carriers, especially injectable solutions, include water, saline, aqueous dextrose, and diols.

Compressed gases can be used to disperse the compounds of the invention in aerosol form. Nitrogen, carbon dioxide, etc. of the inert gas system suitable for this purpose. Other suitable pharmaceutical excipients and formulations thereof are set forth in Remington's Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 18th ed., 1990).

The compositions disclosed herein may be combined with any of the vehicles and excipients commonly used in pharmaceutical preparations such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa. Fat, aqueous or non-aqueous solvents, oils, paraffin derivatives, glycols, and the like. Coloring agents and flavoring agents can also be added to the formulation, especially for oral administration. The solution may be prepared using water or a physiologically compatible organic solvent such as ethanol, 1,2-propanediol, polyglycol, dimethyl hydrazine, fatty alcohol, triglyceride, partial ester of glycerol and And so on. Parenteral compositions containing the compounds described herein can be prepared using conventional techniques which may include sterile isotonic saline, water, 1,3-butanediol, ethanol, 1,2-propanediol, polyglycol mixed with water , Ringer's solution, etc.

The amount of the compound in the formulation can be used within the full range of the skilled artisan. Variety. Typically, the formulation will contain from about 0.01% to about 99.99% by weight, based on the total formulation, of the compound of the invention in weight percent (wt%), with the balance being one or more suitable pharmaceutical excipients. Preferably, the compound is present at a level of from about 1% to 80% by weight. In liquid compositions, the compounds of the invention will generally be present in such compositions at a concentration of between about 0.1 mg/ml and 20 mg/ml. When naloxone or naltrexone is combined with a compound of the invention, it should be present in an amount of from 0.05 mg to 0.5 mg per mg of the compound of the invention.

The choice of formulation depends on various factors such as the mode of drug administration and the bioavailability of the drug substance. For delivery via inhalation, the compound can be formulated as a liquid solution, suspension, aerosol propellant or dry powder and loaded into a suitable dispenser for administration. There are several types of medical inhalation devices - nebulizer inhalers, metered dose inhalers (MDI), and dry powder inhalers (DPI). The nebulizer device produces a high velocity air stream that causes the therapeutic agent (which is formulated in a liquid form) to spray a mist that is carried into the patient's respiratory tract. MDI is typically formulated with a compressed gas package. Upon actuation, the device provides a reliable method of administering a defined amount of medicament by compressing the measured amount of therapeutic agent. The DPI dispenses a therapeutic agent in the form of a free-flowing powder that can be dispersed in the patient's inhalation air stream by the device during breathing. In order to achieve a free-flowing powder, a therapeutic agent is formulated using an excipient such as lactose. The measured therapeutic agent is stored in capsule form and dispensed with each actuation.

Recently, pharmaceutical formulations have been developed which are particularly useful for drugs exhibiting poor bioavailability based on the principle that bioavailability can be increased by increasing surface area (i.e., reducing particle size). For example, U.S. Patent No. 4,107,288 describes pharmaceutical formulations having particles ranging in size from 10 nm to 1,000 nm, wherein the active material is supported on a macromolecular crosslinked matrix. U.S. Patent No. 5,145,684 describes the production of pharmaceutical formulations in which the drug substance is pulverized into nanoparticles (average particle size of 400 nm) in the presence of a surface modifying agent and then dispersed in a liquid medium to obtain a relatively high organism. The pharmaceutical formulation of the degree of utilization.

In a preferred embodiment, a narrow therapeutic dose of a compound of the invention is administered to a patient such that The QT interval of the patient did not extend to an unacceptable level. In some embodiments, a therapeutic dose of a compound is administered to a patient in a clinical setting with cardiac monitoring. In some embodiments, the patient will be pre-screened to assess tolerance to QT interval prolongation, for example to determine if the patient has any existing heart condition that would make it unsuitable for treatment with the compound. In some embodiments, the patient's QT interval is extended by no more than about 50 ms, preferably no more than about 30 ms and more preferably no more than about 20 ms. In some embodiments, the patient has a QT interval of no more than about 500 ms, preferably no more than about 450 ms and more preferably no more than about 420 ms.

In some embodiments, the dose of the compound of the invention administered to the patient is sufficient to provide an average serum concentration of about 50 ng/mL to about 850 ng/mL (area under the curve/24 hours, AUC/24h) or any subrange between them or Secondary value. In a preferred embodiment, the dosage of the noribogaine base, the noribogaine derivative or a pharmaceutically acceptable salt and/or solvate thereof administered to the patient is provided in an amount from about 50 ng/mL to about 400 ng/ The mean serum concentration of mL (AUC/24h).

Generally, the compounds of the invention are administered in an effective amount. The dosage required to treat pain or addiction or a combination thereof is expected to vary depending on the condition being treated, however, the dosage regimen can be readily determined by the attending clinician based on the desired treatment. It is contemplated that the total dose of a compound of the invention typically administered to a patient can range from about 1 mg/kg body weight/day to about 8 mg/kg body weight/day (mg/kg/day) or from about 1 mg/kg/day to about 4 mg/kg/ Days, preferably from about 1 mg/kg/day to about 3 mg/kg/day. For example, for administration to a 70 kg person, the dosage range may preferably be from about 70 mg/day to 210 mg/day. In some embodiments, a lower dose of a compound of the invention is administered, for example, from about 50 ng/kg body weight/day to less than 10 [mu]g/kg body weight/day. In other embodiments, administration of a maintenance dose of a compound of the invention (e.g., a therapeutically effective dose of about 80% or less) is effective to prevent re-use of the drug by the treated addicted patient to improve its substance abuse.

In some embodiments, a patient is pre-selected for screening with a compound of the invention to determine if the patient is a candidate for treatment with the compound, for example, by using the compound to treat whether the patient's QT interval is extended to an unacceptable extent. In a preferred embodiment, The patient is treated with an insufficient therapeutic amount of the compound (e.g., from about 50% to about 90% of a therapeutically effective amount of the compound) and the patient's response to the compound is monitored. In a particularly preferred embodiment, the QT interval of the patient is monitored before and during treatment with the compound. For a method of pre-screening a patient prior to treatment, see, for example, U.S. Provisional Patent Application Serial No. 61/952,744, filed on March 13, 2014, entitled &quot;METHODS AND COMPOSITIONS FOR PRE-SCREENING PATIENTS FOR TREATMENT WITH NORIBOGAINE. The entire text is incorporated herein by reference.

In addition to the above methods, the invention is also directed to pharmaceutical compositions comprising the preferred unit dosage forms of the compounds of the invention. When administered to a patient, one or more unit doses provide an amount of a compound of the invention effective to treat a disease or condition, including pain, depression, stress and/or addiction, as described above.

The amount of composition administered will depend on a number of factors including, but not limited to, the desired final concentration of the compound, the pharmacokinetic and pharmacodynamic properties of the compound, the size of the patient, age and physiological characteristics, and the like. The active compounds are effective over a wide dosage range and are usually administered in a pharmaceutically effective amount. It should be understood, however, that the actual amount of administration of the compound will be determined by the physician on the basis of the following conditions: the condition to be treated, the route of administration chosen, the compound actually administered, the age, weight and response of the individual patient, the symptoms of the patient Severity and the like.

Determination of the dosage is certainly within the knowledge of those skilled in the art; however, it will be appreciated that the final dose estimate can be made by approximating the concentration of the compound necessary to achieve the desired therapeutic activity (eg, to treat pain and/or addiction). . Extrapolation to a prescribed mammalian dose range or, more specifically, a human dose range is certainly within the skill of the practitioner.

In some embodiments, the composition is administered as a single dose of a single formulation, and in other embodiments, the composition is administered in a single dose of multiple doses over a defined period of time. In some embodiments, the period is between about 3 hours and about 6 hours. In other embodiments, the period is between about 6 hours and 12 hours. In other embodiments, the period is about 12 small Between 24 hours and 24 hours. In still another embodiment, the period is between about 24 hours and 48 hours. The administration of the individual formulations can be carried out simultaneously or in stages throughout the specified period of time so that all ingredients are administered within the specified period of time.

5. Synthesis method

The compounds of the present invention can be prepared from readily available starting materials using the following general methods and procedures. It should be understood that while typical or preferred process conditions (i.e., reaction temperatures, times, molar ratios of reactants, solvents, pressures, etc.) are given, other process conditions can be used unless otherwise indicated. Optimum reaction conditions may vary with the particular reactants or solvents employed, but such conditions can be determined by those skilled in the art by routine optimization procedures.

Additionally, as will be appreciated by those skilled in the art, it may be desirable to employ a protecting group to prevent undesired reactions of certain functional groups. Suitable protecting groups for the various functional groups and suitable conditions for protecting and removing the protection of a particular functional group are well known in the art. For example, a number of protecting groups are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999 and references cited therein.

In addition, the compounds of the invention will typically contain one or more pairs of palmar centers. Thus, if desired, such compounds may be prepared as a pure stereoisomer (ie, as individual enantiomers or diastereomers) or as a mixture enriched in stereoisomers or Separation. All such stereoisomers (and mixtures thereof) are included within the scope of the invention unless otherwise indicated. Pure stereoisomers (or mixtures thereof) can be prepared using, for example, optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, palmar column chromatography, palm resolving agents, and the like.

Furthermore, some of the compounds defined herein include vinyl groups which may be present in cis form, trans form or in a mixture of cis form and trans form. All combinations of these forms are within the scope of the invention.

The starting materials used in the following reactions are well known compounds or can be prepared by known procedures or their modifications. For example, many starting materials are purchased from commercial suppliers such as Aldrich Chemical Company (Milwaukee, Wis., USA), Bachem (Torrance, Calif., USA), Emka-Chemce or Sigma (St. Louis, Mo., USA). . Other materials may be prepared by procedures described in standard references such as the following, or modifications thereof: Fieser and Fieser, Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplements (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry (John Wiley and Sons, 4th Edition) And Larock's Comprehensive Organic Transformations (VCH Publishers, Inc., 1989).

The compound of formula II can be readily prepared from noribogaine base by the methods described herein and by methods known to those skilled in the art. Those skilled in the art will appreciate that the reactivity of the hydroxyl group with the hydrazine nitrogen is different, so that selectivity can be achieved by selecting suitable reagents and suitable reaction conditions that can react with one of them but leave the other intact. The desired product. For example, it is expected that a hydroxyl group will selectively react with an acid R ² C(O)OH in the presence of triphenylphosphine (Ph ₃ P) and diethyl azodicarboxylate (DEAD) to give compounds 1-1 and 1- 3 . Therefore, as shown in Scheme 1, a noribogaine base can be reacted with LG-R (wherein a LG-based leaving group such as a hydroxyl group, an alkoxy group, a halogen group, etc.) to give a compound 1-1 , which is 1 -1 can be further reacted with LG-LR ¹ to form compound 1-2 . In other embodiments (i.e., when R is H), phenol is protected by reaction with a suitable protecting group PG-LG (wherein the LG is, for example, a leaving group as defined above) to utilize LR ¹ Nitrogen derivatization. Suitable protecting groups are well known in the art (see TW Greene, PGM Wuts, Protective Groups in Organic Synthesis, 4th Ed., Wiley-Interscience, New York, 2006). In another alternative embodiment (i.e., when the L chain is bonded and the R ¹ is H), the niobium nitrogen is protected with a suitable protecting group PG (see Greene et al., supra) to derivatize the phenol with R.

Alternatively, as shown in Scheme 2, the compound of the invention wherein LR ^{1 is} not hydrogen can be prepared by reacting ibogaine base with LG-LR ¹ to give compound 2-1 . Compound 2-1 may be by methods known in the art of demethylation, for example, boron tribromide / methylene chloride to give compound 1-4 is reacted with at room temperature, the compound 1-4 can be further reacted with LG-R Compound 1-2 was obtained.

The compounds described herein can also be prepared as shown in any of Schemes 3-5, wherein R, R ¹ , L, R ¹⁰ and R ¹¹ are as defined herein, and LG is such as hydroxy, alkoxy, A halogen group is a leaving group, and X is iodine (I) or bromine (Br). Compounds 3-1 and 4-1 can be prepared according to the procedures described in, for example, U.S. Patent No. 6,211,360 or U.S. Patent Publication No. 2013/0165647.

In Scheme 3, compound 3-1 is reacted with LG-LR ¹ to give compound 3-2 . Compound 3-2 may be described herein or by methods known in the art of decarboxylation, for example using hydrazine or reflux -COOCH ₃ group hydrolyzed to the acid and the corresponding salt of sodium or lithium is reacted with an aqueous mineral acid, to give compound 3 -3 . An exemplary decarboxylation procedure for the preparation of intermediate 7-3 is illustrated in Scheme 7, when the starting material 7-1 is a racemic mixture or when racemization occurs during reduction, Procedure for the preparation of intermediate 7-3 of the mirror image isomer. Intermediate 7-3 can be reacted with LG-LR ¹ to give a compound of the invention.

In Scheme 4, compound 4-1 is halogenated to compound 4-2 . When X is iodine, the iodine group can be conveniently incorporated into the anthracene ring by reacting compound 4-1 with, for example, and without limitation, N-iodosuccinimide (NIS). It may also be used by the intermediate iodonium PhI (OH) OTs reaction, and then via the OH ^- removal reaction of phenyl group into iodo. When X is iodine or bromine, it can be formed by nitration to form a nitro intermediate, then reducing the nitro group to an amine group, diazotizing the amine group to form a diazo group, and reacting the diazonium compound with CuI or CuBr. Incorporation of iodine or bromo groups. An exemplary halogenation procedure is illustrated in Scheme 6 below. Then, for example in the presence of a copper catalyst can be used to incorporate -OR group (e.g., benzyloxy or substituted benzyloxy it) and by the ROH or RO ^- reaction of Compound 4-2 Compound 4-3 is converted into the The copper catalyst is, for example, CuI and a ligand such as tetramethylmorpholine (for example, see "An Improved Cu-Based Catalyst System for the Reactions of Alcohols with Aryl Halides", Altman et al., J. Org. Chem., 2008. , 73, 284-286, which is incorporated herein by reference); or CuBr (U.S. Patent No. 4,422,955, incorporated herein by reference). Compound 4-3 is reacted with LG-LR ¹ to provide compound 4-4 which is decarboxylated by methods described herein or known in the art to provide compound 4-5 .

In Scheme 5, Compound 4-1 is decarboxylated by methods described herein or known in the art to provide Compound 5-1 . The methods described herein using a halogenated compound 5-1 to compound 5-2, which is reacted with ROH to afford compound 5-3, then reacted with LG-LR ^1, to give compound 4-5.

Option 3

Option 6

Instance

The invention is further defined by reference to the following examples. It will be apparent to those skilled in the art that many modifications of the materials and methods can be made without departing from the scope of the invention.

The compounds of the present invention can be prepared from readily available starting materials using, for example, the following general methods and procedures. It should be understood that while typical or preferred process conditions (i.e., reaction temperatures, times, molar ratios of reactants, solvents, pressures, etc.) are given, other process conditions can be used unless otherwise indicated. Optimum reaction conditions can vary with the particular reactants or solvents employed, but such conditions can be determined by those skilled in the art by routine optimization procedures.

Additionally, as will be appreciated by those skilled in the art, it may be desirable to employ a protecting group to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for the various functional groups and suitable conditions for protecting and deprotecting specific functional groups are well known in the art. For example, many protecting groups are described in T.W. Greene, P.G.M. Wuts, Protective Groups in Organic Synthesis, 4th edition, Wiley-Interscience, New York, 2006 and references cited therein. The starting materials used in the following reactions are well known compounds or can be prepared by known procedures or their modifications. For example, many starting materials are purchased from commercial suppliers such as Aldrich® Chemical Company (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce or Sigma (St. Louis, Missouri, USA). Other materials may be prepared by procedures such as those set forth in the following standard references, or modifications thereof: Fieser and Fieser, Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Vol. 1-5 and Supplement (Elsevier Science Publishers, 1989), Organic Reactions, Vol. 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley and Sons, 5th Edition, 2001) and Larock's Comprehensive Organic Transformations (VCH Publishers, Inc., 1989).

Example 1. Preparation of Compound 1

Compound 1 can be prepared by reacting a noribogaine base with at least two equivalents of (CH ₃ ) ₂ NCH ₂ CH ₂ C(O)Cl in the presence of a base in a suitable solvent. In one embodiment, the reaction is carried out in a polar solvent. After completion of the reaction, Compound 1 can be recovered by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration, and the like; or, without purification and/or separation.

Example 2. Preparation of Compound 2

Compound 2 can be prepared by reacting a noribogaine base with at least one equivalent of (CH ₃ ) ₂ NCH ₂ CH ₂ C(O)Cl in the presence of a base in a suitable solvent to give the intermediate product. In one embodiment, the reaction is carried out in a polar solvent. The intermediate product can be demethylated by reaction with boron tribromide/dichloromethane at room temperature to obtain compound 2 , and after completion of the reaction, compound 2 can be subjected to, for example, neutralization, extraction, precipitation, chromatography, Recycling by filtration and other conventional techniques; or, without purification and/or separation.

Example 3. Preparation of Compound 3

Compound 3 can be reacted with one equivalent of (CH ₃ ) ₂ NCH ₂ CH ₂ C(O)Cl or in triphenylphosphine (Ph ₃ ) by deferoxine base in the presence of a base such as pyridine in a suitable solvent. It is prepared by reacting P) with diethyl azodicarboxylate (DEAD) in the presence of one equivalent of (CH ₃ ) ₂ NCH ₂ CH ₂ C(O)OH. In one embodiment, the reaction is carried out in a polar solvent. After the reaction is reasonably completed, Compound 3 can be recovered by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration, and the like; or, without purification and/or separation.

Example 4. Preparation of Compound 8

a) Preparation of TBS-norpogaine base 8-A

A suspension of noribogaine hydrochloride (852 mg, 2.56 mmol), TBS-Cl (444 mg, 2.94 mmol) and imidazole (227 mg, 3.33 mmol) in DMF (6 mL) was stirred at room temperature for 20 h. The resulting clear solution was diluted with 10% 2-propanol / dichloromethane and washed with water and brine. The aqueous phase was extracted with EtOAc. The organic layers were combined and concentrated by (EtOAc / hexanes, v / v, 2/1 ) was purified by column chromatography to afford a white solid of compound 8-A (911mg, 87% ).

_{(C 25 H 38 N 2 OSi} ) of MS calcd: 410; MS Found, (M + 1): 411 .

b) Preparation of Compound 8-B

The NaHMDS (0.75mL, 1.0M in THF, the solution) was added to TBS- noribogaine 8-A (205mg, 0.5mmol) (10mL) in the solution in THF at -78 ℃. The resulting solution was stirred at -78.degree. C. for 10 min then a solution of &lt;RTI ID=0.0&gt;&gt; The reaction mixture was allowed to warm to room rt and stirred 1 hr then EtOAc &lt;~&gt; After stirring for an additional 1 hour at room temperature, the reaction mixture was diluted with 10% 2-propanol / dichloromethane and washed with water and brine. The aqueous phase was extracted with EtOAc. The combined organic layers were concentrated and purified by EtOAc EtOAc EtOAc EtOAc The desired product compound 8-B (138 mg, 53%) was obtained as a white solid.

_{(C 30 H 48 N 4 O} 2 Si) of MS calcd: 524; MS Found, (M + 1): 525 .

c) Preparation of compound 8

To a solution of compound 8-B (178 mg, 0.34 mmol) in THF (12 mL), EtOAc (EtOAc) The resulting solution was stirred at -78.degree. C. for 40 min then quenched by 1N aqueous HCI (2 mL). The reaction mixture was allowed to warm to room temperature and concentrated. By the residue was purified by preparative HPLC to give a white solid of hydrochloride salt form and the compound 8 (110mg, HCl salt, 72%).

_{(C 24 H 34 N 4 O} 2) of MS calcd: 410; MS Found, (M + 1):. 411 1 H NMR (300MHz, CD 3 OD) δ 8.20 (bs, 1H), 7.49 (d , 1H), 6.87 (s, 1H), 6.80 (d, 1H), 3.50-3.92 (m, 6H), 3.36-3.58 (m, 4H), 3.00-3.36 (m, 2H), 2.80-3.00 (m , 6H), 2.50 (td, 1H), 1.85-2.20 (m, 3H), 1.48-1.82 (m, 3H), 1.22-1.46 (m, 1H), 1.04 (t, 3H).

Example 5. Preparation of Compound 15

a) Preparation of acetic acid reduced ibogaine base 15-A

A mixture of noribogaine base (300 mg, 0.9 mmol) and DMAP (10 mg, 0.09 mmol) in acetic acid (6 mL). Acetic anhydride was co-evaporated with toluene at 40 ° C under reduced pressure. The residue was dissolved in ethyl acetate (100 mL), the stirred together and the resulting solution for 2h at rt and a saturated NaHCO ₃ solution (50mL). The organic phase was separated and concentrated under reduced pressure. By chromatography on silica gel (ethyl acetate / hexane: = 1/2) The crude product was purified, to give a white solid of the compound was 15-A (280mg, 90% ).

MS calculated for (C ₂₁ H ₂₆ N ₂ O ₂ ) ⁺ : 338; MS, m. ¹ H NMR (300 MHz, CD ₃ OD) δ 7.18 (d, J = 8.4 Hz, 1H), 7.06 (d, J = 2.4 Hz, 1H), 6.7 (dd, J = 8.4 Hz, J = 2.4 Hz, 1H ), 3.38 (m, 1H), 3.1 (m, 4H), 2.95 (m, 2H), 2.65 (m, 1H), 2.27 (s, 3H), 2.14 (m, 1H), 1.88 (m, 2H) , 1.64 - 1.45 (m, 4H), 1.23 (m, 1H), 0.94 (t, J = 7.5 Hz, 3H).

b) Preparation of compound 15

To a solution of N,N-dimethylethanolamine (0.6 mL, 6 mmol) in EtOAc. The reaction mixture was stirred at rt until the sodium disappeared. The resulting sodium N,N-dimethylethanolamine solution was used in the following reaction.

NaHMDS (0.59 mL, 0.59 mmol) was added dropwise to a solution of compound 15-A (200 mg, 0.59 mmol) in THF (2 mL). The reaction mixture was stirred at -78 °C for 10 min, and then the obtained mixture was transferred to a solution of 4-nitrophenyl chloroformate (143 mg, 0.71 mmol) in THF (1 mL). in. The reaction mixture was allowed to warm to rt and stirred for 30 min. The reaction mixture was then cooled to -78.degree. C., and a solution of sodium N,N-dimethylethanolamine (1.4 mL, 1.4 mmol, 1M in THF). The reaction mixture was allowed to warm to rt and stirred for 30 min. Water (5 mL) was added and the mixture was extracted with ethyl acetate (2×20 mL). The combined organic layers were concentrated under reduced pressure and the crude material was purified by flash chromatography (ethyl acetate/methanol/triethylamine:=100/5/1). The resulting yellow oil was purified by EtOAc (EtOAc)

_{(C 24 H 33 N 3 O} 3) + The MS calcd: 411; MS Found, (M + 1): 412 . ¹ H NMR (300 MHz, CD ₃ OD) δ 7.79 (d, J = 8.7 Hz, 1H), 6.7 (d, J = 2.4 Hz, 1H), 6.66 (dd, J = 2.4 and 8.7 Hz, 1H), 4.4 (m, 3H), 3.75 (m, 1H), 3.0 (m, 3H), 2.87 (m, 2H), 2.8 (m, 2H), 2.7 (m, 3H), 2.5 (m, 3H), 2.29 ( s, 6H), 2.14 (m, 1H), 1.85 (m, 2H), 1.61-1.23 (m, 5H), 1.1 (m, 1H), 0.94 (t, J = 7.2 Hz, 3H).

Example 6. Preparation of Compound 16

NaHMDS (0.87 mL, 0.87 mmol) was added dropwise to a solution of Compound 15-A (310 mg, 0.92 mmol) in THF (3 mL). The reaction mixture was stirred at -78 °C for 10 min, then the resulting reaction mixture was transferred to a solution of 4-nitrophenyl chloroformate (185 mg, 0.92 mmol) in THF (1 mL). in. The reaction mixture was allowed to warm to rt and stirred for 30 min. The reaction mixture was again cooled to -78.degree. C. and N,N-dimethylethylenediamine (79 mg, 0.9 mmol). The reaction mixture was allowed to warm to rt and stirred for 30 min. Water (5 mL) was added and the mixture was extracted with ethyl acetate (2×20 mL). The combined organic layers were concentrated under reduced pressure and the crude material was purified by flash chromatography (ethyl acetate/methanol/triethylamine:=100/5/1). By further purified by preparative HPLC resulting yellow oil to afford 16 (50mg, 14%) of a white solid.

_{(C 26 H 36 N 4 O} 3) + The MS calcd: 452; MS Found, (M + 1): 453 . _{^{1 H NMR (300MHz, CD 3}} OD) δ 7.5 (d, J = 8.7Hz, 1H), 7.12 (d, J = 2.4Hz, 1H), 6.8 (dd, J = 2.4 and 8.7Hz, 1H), 3.5 (m, 3H), 3.4 (m, 1H), 3.2 (m, 2H), 3.0 (m, 3H), 2.8 (m, 1H), 2.6 (m, 3H), 2.3 (s, 6H), 2.27 ( s, 3H), 2.14 (m, 1H), 1.85 (m, 2H), 1.61-1.23 (m, 5H), 1.1 (m, 1H), 0.94 (t, J = 6.9 Hz, 3H).

Example 7. Preparation of Compound 38

a) Preparation of compound 38-A

NaHMDS (0.14 mL, 0.14 mmol) was added dropwise to a solution of Compound 15-A (42 mg, 0.12 mmol) in THF (1 mL). The reaction mixture was stirred at -78 °C for 10 min and then 4-nitrophenyl chloroformate (27 mg, 0.14 mmol) was then added at -78. The reaction mixture was allowed to warm to rt and stirred 1 h. A saturated NaHCO ₃ solution (5 mL) was added and the mixture was extracted with ethyl acetate (2×10 mL). The combined organic layers were concentrated under reduced pressure. The crude product was purified by chromatography EtOAcjjjjjjjj

_{(C 28 H 29 N 3 O} 6) + the MS calcd: 503; MS Found, (M + 1): 504 .

b) Preparation of compound 38

At rt Compound 2 (150mg, 0.3mmol) and methylamine (1mL, 33wt% in ethanol) in the in CH ₂ Cl ₂ (5mL) The reaction mixture was stirred for 1h. The reaction mixture was washed with saturated NaHCO ₃ solution, and the aqueous layer was extracted with ethyl acetate (2 × 20mL). The combined organic extracts were concentrated under reduced pressure. On silica gel by chromatography (ethyl acetate / methanol / triethylamine: 100/2/1) to give crude product was obtained in 80% yield as a yellow oil of compound 3 (80mg).

MS calculated for (C ₂₁ H ₂₇ N ₃ O ₂ ) ⁺ 353; MS found, (M+1): 354.

Example 8. Preparation of Compound 18

The reaction mixture of compound 38 (80 mg, 0.22 mmol) and D.sub.3 (10 mg, 0.09 mmol) Acetic anhydride was co-evaporated with toluene at 40 ° C under reduced pressure. The residue was dissolved in ethyl acetate (50mL) in 30min and the stirred together at rt The resulting solution was mixed with saturated NaHCO ₃ solution (50mL). The organic phase was separated and concentrated under reduced pressure. The crude product was purified by EtOAc EtOAc (EtOAc:EtOAcHHHHHHH Compound 18 (50 mg, 60%).

_{(C 23 H 29 N 3 O} 3) + The MS calcd: 395; MS Found, (M + 1): 396 . ¹ H NMR (300 MHz, CD ₃ OD) δ 7.44 (d, J = 8.7 Hz, 1H), 7.13 (d, J = 2.4 Hz, 1H), 6.7 (dd, J = 2.4 and 8.7 Hz, 1H), 3.2 (m, 1H), 3.05 (m, 4H), 2.98 (s, 3H), 2.95 (m, 2H), 2.83 (m, 1H), 2.6 (m, 1H), 2.27 (s, 3H), 2.14 ( m, 1H), 1.88 (m, 2H), 1.64-1.45 (m, 4H), 1.23 (m, 1H), 0.92 (t, J = 7.2 Hz, 3H).

Example 9. Preparation of Compound 31

NaHMDS (0.68 mL, 0.68 mmol) was added dropwise to a solution of Compound 15-A (200 mg, 0.59 mmol) in THF (2 mL). The reaction mixture was stirred at -78 °C for 10 min, then methyl chloroformate (78.6 uL, &lt;RTI ID=0.0&gt; The reaction mixture was allowed to warm to rt and stirred 1 h. A saturated NaHCO ₃ solution (5 mL) was added and the mixture was extracted with ethyl acetate (2×20 mL). The combined organic extracts were concentrated under reduced pressure to afford crude crystals crystals crystals crystals

_{(C 23 H 28 N 2 O} 4) + The MS calcd: 396; MS Found, (M + 1): 397 . ¹ H NMR (400 MHz, CD ₃ OD) δ 7.95 (d, J = 9.2 Hz, 1H), 7.06 (d, J = 1.2 Hz, 1H), 6.7 (dd, J = 9.2 Hz, J = 1.2 Hz, 1H) ), 4.84 (s, 3H), 3.8 (m, 1H), 3.1 (m, 3H), 2.99 (m, 2H), 2.8 (m, 1H), 2.68 (m, 1H), 2.15 (s, 3H) , 2.14 (m, 1H), 1.85 (m, 2H), 1.61 (m, 2H), 1.58 (m, 1H), 1.46 (m, 1H), 1.23 (m, 1H), 0.94 (t, J = 7.2) Hz, 3H).

Example 10. Preparation of Compound 39

a) Preparation of TBS-norpogaine base 8-A

A suspension of noribogaine hydrochloride (852 mg, 2.56 mmol), TBS-Cl (444 mg, 2.94 mmol) and imidazole (227 mg, 3.33 mmol) in DMF (6 mL) was stirred at room temperature for 20 h. The resulting clear solution was diluted with 10% 2-propanol / dichloromethane and washed with water and brine. The aqueous phase was extracted with EtOAc. The combined organic extracts were concentrated and the (EtOAc / hexanes, v / v, 2/1 ) was purified by column chromatography to afford a white solid of compound 8-A (911mg, 87% ).

_{(C 25 H 38 N 2 OSi} ) of MS calcd: 410; MS Found, (M + 1): 411 .

b) Preparation of compound 9-A

To a solution of compound 8-A (246 mg, 0.6 mmol) in THF (6 mL), EtOAc (EtOAc) The resulting solution was stirred at -78.degree. C. for 15 min then ethyl chloroformate (0.12 mL, 1.2 mmol). The reaction mixture was allowed to warm to rt and stirred 1 hr then partitioned betweenEtOAc and water. The organic layer was washed with brine and dried over Na ₂ SO _4. The crude product was obtained as a pale yellow oil, which was used in the next step without further purification.

_{(C 28 H 42 N 2 O} 3 Si) of MS calcd: 482; MS Found, (M + 1): 483 .

c) Preparation of compound 39

TBAF (1.5 mL, 1.0 M solution in THF) was added to a solution of compound 9-A (cr., about 0.6 mmol) in THF (12 mL). The resulting solution was stirred at -78 °C for 20 min and then allowed to warm to room temperature. After 1 hour, the reaction mixture was diluted with 10% 2-propanol / dichloromethane and washed with water and brine. The aqueous phase was extracted with EtOAc. The organic layers were combined and concentrated by (dichloromethane / MeOH, v / v, 10 /1) was purified by column chromatography to afford a white solid of compound 39 (187mg, 85%, via two steps).

_{(C 22 H 28 N 2 O} 3) of the MS calcd: 368; MS Found, (M + 1): 369 . ¹ H NMR (300 MHz, CD ₃ OD) δ 7.83 (d, 1H), 6.82 (s, 1H), 6.78 (d, 1H), 4.49 (q, 2H), 4.08 (dd, 1H), 3.65-3.92 ( m, 2H), 3.40-3.62 (m, 2H), 3.15-3.20 (m, 1H), 2.95-3.07 (m, 2H), 2.42-2.62 (m, 1H), 2.20 (bs, 1H), 1.80- 2.10 (m, 2H), 1.40 - 1.80 (m, 4H), 1.48 (t, 3H), 1.05 (t, 3H).

Example 11. Preparation of Compound 32

A solution of compound 39 (137 mg, 0.37 mmol) and CDI (181 mg, 1.12 mol) in THF (10 mL). The mixture was then cooled to room temperature and N-methyl hexahydropyrazine (0.27 mL, 0.24 mmol) was added. After 1 hour, the reaction mixture was diluted with 10% 2-propanol / dichloromethane and washed with water and brine. The aqueous phase was extracted with EtOAc. The combined organic extracts were concentrated and purified by preparative HPLC to give a white solid of hydrochloride salt form and the compound 32 (159mg, HCl salt, 81%).

_{(C 28 H 38 N 4 O} 4) of MS calcd: 494; MS Found, (M + 1): 495 . _{^{1 H NMR (400MHz, CD 3}} OD) δ 8.07 (d, 1H), 7.35 (s, 1H), 7.09 (d, 1H), 4.57 (q, 2H), 4.40-4.60 (m, 1H), 4.25- 4.40 (m, 1H), 4.12 (dd, 1H), 3.80-3.92 (m, 1H), 3.84 (s, 1H), 3.42-3.62 (m, 5H), 3.16-3.42 (m, 5H), 2.98 ( s, 3H), 2.57 (td, 1H), 2.24 (bs, 1H), 1.98-2.11 (m, 2H), 1.50-1.82 (m, 3H), 1.42-1.50 (m, 2H), 1.51 (t, 3H), 1.05 (t, 3H).

Example 12. Preparation of Compound 40

NaHMDS (0.68 mL, 0.68 mmol) was added dropwise to a solution of Compound 15-A (200 mg, 0.59 mmol) in THF (2 mL). The reaction mixture was stirred at -78.degree. C. for 10 min and then methyl chloroformate (7.. The reaction mixture was allowed to warm to rt and stirred 1 h. A saturated NaHCO ₃ solution (5 mL) was added and the mixture was extracted with ethyl acetate (2×20 mL). Concentrated under reduced pressure the combined organic extracts, a crude product was obtained, by prep HPLC purified to afford 40 (116mg, 55%) of a white solid.

_{(C 23 H 28 N 2 O} 4) + The MS calcd: 396; MS Found, (M + 1): 397 . ¹ H NMR (400 MHz, CD ₃ OD) δ 7.95 (d, J = 9.2 Hz, 1H), 7.06 (d, J = 1.2 Hz, 1H), 6.7 (dd, J = 9.2 Hz, J = 1.2 Hz, 1H) ), 4.84 (s, 3H), 3.8 (m, 1H), 3.1 (m, 3H), 2.99 (m, 2H), 2.8 (m, 1H), 2.68 (m, 1H), 2.15 (s, 3H) , 2.14 (m, 1H), 1.85 (m, 2H), 1.61 (m, 2H), 1.58 (m, 1H), 1.46 (m, 1H), 1.23 (m, 1H), 0.94 (t, J = 7.2 Hz, 3H).

Example 13. Preparation of Compound 36

a) Preparation of compound 36-A

The NaHMDS (1.05mL, 1.0M in THF, the solution) was added to TBS- noribogaine 8-A (288mg, 0.7mmol) in a solution of 8 mL of THF at -78 ℃. The resulting solution was stirred at -78.degree. C. for 10 min then a solution of chlorodichloromethane (0.15 mL, 1.4 mmol) in 2 mL THF. The reaction mixture was allowed to warm to room rt and stirred 1 hr then diluted with EtOAc EtOAc EtOAc The aqueous phase was extracted with EtOAc. The combined organic extracts were concentrated and purified by EtOAc EtOAc EtOAc The desired product compound 36-A (305 mg, 84%) was obtained as a white solid.

_{(C 27 H 43 N 2 O} 4 PSi) of MS calcd: 518; MS Found, (M + 1): 519 .

b) Preparation of compound 36

TBAF (1.1 mL, 1.0 M solution in THF) was added to a solution of compound 36-A (305 mg, 0.59 mmol) in 8 mL THF. The resulting solution was stirred at -78 °C for 40 min then quenched by the addition of 2 mL 1N aqueous HCI. The reaction mixture was diluted with 5% 2-propanol / dichloromethane and washed with water and brine. The aqueous phase was extracted with EtOAc. The combined organic layers were concentrated and purified by column chromatography (dichloromethane / 2-propanol, v/v, 15/1 to 10/1) and then preparative HPLC to give a white solid as hydrochloric acid. Salt pure compound 36 (220 mg, HCl salt, 85%).

MS calculated for (C ₂₁ H ₂₉ N ₂ O ₄ P): 404; MS, (M+1): 405. _{^{1 H NMR (300MHz, CDCl 3}} ) δ 10.38 (bs, 1H), 7.45 (d, 1H), 6.97 (s, 1H), 6.91 (d, 1H), 3.98-4.15 (m, 1H), 3.40-3.85 (m, 10H), 2.70-3.20 (m, 3H), 2.40-2.60 (m, 1H), 2.18 (bs, 1H), 1.72-2.05 (m, 4H), 1.38-1.50 (m, 1H), 0.95 (t, 3H).

Example 14. Preparation of Compound 41

A solution of compound 36 (44 mg, 0.11 mmol), CDI (54 mg, 0.33 mol) and one drop of DIPEA in 2 mL THF was stirred at 50 ° C for 2 hr and then cooled to room temperature. N-methylhexahydropyrazine (3 drops) was added. After 1 h, the reaction mixture was concentrated and purified EtOAc mjjjjjj Pure compound 41 (28 mg, 48%) was obtained as a white solid.

_{(C 27 H 39 N 4 O} 5 P) of MS calcd: 530; MS Found, (M + 1): 531 . _{^{1 H NMR (300MHz, CDCl 3}} ) δ 7.95 (d, 1H), 7.13 (s, 1H), 6.95 (d, 1H), 3.65-3.82 (m, 8H), 3.55-3.65 (m, 3H), 3.47 (s, 1H), 3.40-3.45 (m, 1H), 2.96-3.40 (m, 5H), 2.72-2.95 (m, 1H), 2.40-2.70 (m, 4H), 2.35 (s, 3H), 2.08 -2.25 (m, 1H), 1.78-1.95 (m, 2H), 1.38-1.70 (m, 2H), 1.15-1.20 (m, 2H), 0.89 (t, 3H).

Example 15

The following examples illustrate how to treat opioid addiction patients who are eager for opioids. special To be determined, a bolus injection containing 0.1 weight/vol% of the compound of the present invention in sterile buffered saline was administered to a 65 kg cocaine-addicted male patient who presented an urgent desire for cocaine "fix". The aqueous composition is administered in an intravenous mode and the serum concentration of the compound of formula II and the noribogaine base produced by dissociation of the compound of the invention in vivo is monitored. A sufficient amount of the compound is administered until the therapeutic serum concentration of the compound and or ipoxine base is reached. The patient is then monitored until eager to lower or release.

Example 16

The following examples illustrate how to treat severe pain in a patient. In particular, a 80 kg male patient presenting a severe trauma resulting from several shots from the chest and legs was administered a bolus of a compound of formula II containing 1 gm in 10 mL sterile buffered saline. The aqueous composition is injected into a patient to provide immediate analgesia to pain. The transdermal patch is then placed on the back of the patient. The patch contains a sufficient amount of the compound in sustained release form, wherein the amount of noribogaine released is sufficient to maintain the serum concentration of noriboblastine produced by the compound or dissociated in vivo from the compound of the invention. Up to 48 hours.

Example 17: Lozenge Formulation

The following ingredients were intimately mixed and compressed into a single score tablet.

Example 18: Capsule formulation

The following ingredients were intimately mixed and loaded into hard shell gelatin capsules.

Example 19: Suspension formulation

The following ingredients were mixed to form a suspension for oral administration (q.s. = sufficient).

Example 20: Injectable Formulations

The following ingredients are combined to form an injectable formulation.

Example 21: Suppository formulation

A suppository having a total weight of 2.5 g was prepared by mixing a compound of the present invention with Witepsol® H-15 (triglyceride of saturated vegetable fatty acid; Riches-Nelson, New York), and having the following composition:

Claims (26)

a compound of formula I or formula II, Wherein L is selected from the group consisting of a covalent bond and a cleavable linker group; R ¹ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkyne a substituted alkynyl group, an aryl group, a substituted aryl group, a cycloalkyl group, a substituted cycloalkyl group, a heteroaryl group, a substituted heteroaryl group, a heterocyclic group, and a substituted heterocyclic group, The prerequisite is that R ^{1 is} not a sugar or an oligosaccharide; R ¹⁰ is hydrogen or -OR; and R ¹¹ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy , (CH ₂ ) _m OC(O)alkyl, (CH ₂ ) _m OH, (CH ₂ ) _m Oalkyl, CH ₂ -X-alkyl or (CH ₂ ) _m O(CH ₂ ) _p O (CH ₂ ) _q O(CH ₂ ) _r CH ₃ , wherein each of m, p and q is 1, 2 or 3; and r is 0, 1 or 2, X is O or NH; a group of free consisting of hydrogen, a hydrolyzable group selected from the group consisting of -C(O)R ² , -C(O)NR ³ R ⁴ and -C(O)OR ⁵ , wherein R ² is selected from the group consisting of: hydrogen, alkyl, the substituted alkyl group, alkenyl group, the substituted alkenyl group, an alkynyl group and the substituted alkynyl group, R ³ and R ⁴ are independently selected from the group consisting of lines Group of lower constituents: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted a heteroaryl group, a heterocyclic group and a substituted heterocyclic group, R ⁵ is selected from the group consisting of an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an alkynyl group, a substituted alkyne a aryl group, an aryl group, a substituted aryl group, a heteroaryl group, a substituted heteroaryl group, a heterocyclic group and a substituted heterocyclic group, provided that R is not a sugar or an oligosaccharide; R ³ and R ⁴ are Independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl a substituted heteroaryl group, a heterocyclic group and a substituted heterocyclic group, and R ⁵ is selected from the group consisting of an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an alkynyl group. a substituted alkynyl group, an aryl group, a substituted aryl group, a heteroaryl group, a substituted heteroaryl group, a heterocyclic group and a substituted heterocyclic group, provided that R is not a sugar or an oligosaccharide; Or a pharmaceutically acceptable salt and/or solvate thereof, provided that when L is covalently bonded and R ¹ is hydrogen, R is selected from -C(O)NR ³ R ⁴ and -C(O) A group consisting of OR ⁵ ; and another precondition is that when R is hydrogen or -C(O)R ² and the L is a covalent bond, R ^{1 is} not hydrogen. The compound of claim 1, wherein R ¹¹ is selected from the group consisting of hydrogen, C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, and substituted C ₁ -C ₃ alkoxy. The compound of claim 1, wherein the L is hydrogen or a biocompatible dissociable linking group and R ¹¹ is optionally substituted by C ₁ -C ₃ alkoxy: YH, YR ¹² , YC(O)R ¹² , C(O)YR ¹² , C(O)NH ₂ , C(O)NHR ¹² , C(O)NR ¹² R ¹³ , NH ₂ , NHR ¹² , NR ¹² R ¹³ , NHC(O)R ¹² or NR ¹² C(O)R ¹³ , wherein Y is O or S, and R ¹² and R ^{13 are} independently C ₁ -C ₃ alkyl. The compound of claim 1, wherein R is hydrogen, L is a covalent bond or -C(O)-, and R ¹ is an alkyl group substituted with -NR ⁶ R ⁷ , wherein R ⁶ and R ⁷ are independently selected Free group of: hydrogen, alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, hetero An aryl group, a substituted heteroaryl group, a heterocyclic group, and a substituted heterocyclic group. The compound of claim 1, wherein R ¹¹ is selected from the group consisting of H, CH ₂ CH ₂ OH, CH ₂ CH ₂ OCH ₃ , CH ₂ CH ₂ OCH ₂ Ph, CH ₂ CH ₂ OC(O)alkyl, and CH ₂ CH ₂ O(CH ₂ ) _p O(CH ₂ ) _q O(CH ₂ ) _r CH ₃ , wherein p, q and r are independently 0, 1, 2 or 3; or a pharmaceutically acceptable salt thereof and/or Solvate. The compound of claim 1, wherein R ¹¹ is H; or a pharmaceutically acceptable salt and/or solvate thereof. The compound of claim 1, wherein R ¹ or R ¹⁰ is H; or a pharmaceutically acceptable salt and/or solvate thereof. The compound of claim 1, wherein R is hydrogen and L is a cleavable group. The compound of claim 1, wherein L is a biocompatible dissociable linking group comprising from 1 to 20 atoms selected from the group consisting of carbon, nitrogen, oxygen, sulfur, and phosphorus. A compound of claim 1 wherein L is -C(O)-. The compound of claim 1, wherein the L is -C(O)O-. The compound of claim 1, wherein L is -C(O)NR-, wherein R is hydrogen or alkyl. The compound of claim 1, wherein the L is selected from the group consisting of -P(O)(OR ⁹ )-O-, -OP(S)(OR ⁹ )-O-, -OP(S)(SR ⁹ )-O-, -SP(O)(OR ⁹ )-O-, -OP(O)(OR ⁹ )-S-, -SP(O)(OR ⁹ )-S-, -OP(S) (OR ⁹ )-S-, -SP(S)(OR ⁹ )-O-, -OP(O)(R ⁹ )-O-, -OP(S)(R ⁹ )-O-, -SP( O) (R ⁹ )-O-, -SP(S)(R ⁹ )-O-, -SP(O)(R ⁹ )-S-, -OP(S)(R ⁹ )-S-, wherein R ⁹ is hydrogen or an alkyl group. The compound of claim 1, wherein R is hydrogen, L is a covalent bond or -C(O), and R ¹ is a substituted alkyl group. The compound of claim 14, wherein R ¹ is alkyl substituted with -NR ⁶ R ⁷ and wherein R ⁶ and R ⁷ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, substituted alkene Alkyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted Ring base. The compound of claim 1, wherein R is selected from the group consisting of -C(O)NR ³ R ⁴ and -C(O)OR ⁵ and R ¹ is hydrogen. The compound of claim 1, which is selected from the group consisting of: Or a pharmaceutically acceptable salt and/or solvate thereof. A composition comprising a compound according to any one of claims 1 to 17 and a pharmaceutically acceptable excipient. A use of a compound according to any one of claims 1 to 17 for the manufacture of a medicament for the treatment of pain. A use of a compound according to any one of claims 1 to 17 for the manufacture of a medicament for treating addiction to at least one addictive substance. The use of claim 20, wherein the at least one addictive substance is selected from the group consisting of Groups: opioids, opioids, cocaine, alcohol, amphetamine, methamphetamine, tobacco, caffeine, cannabinoids, and benzodiazepines. Use of a compound according to any one of claims 1 to 17 for the manufacture of a medicament for the treatment of stress. The use of claim 22, wherein the stress is a post-traumatic stress disorder. A use of a compound according to any one of claims 1 to 17 for the manufacture of a medicament for the treatment of depression. A use of a compound according to any one of claims 1 to 17 for the manufacture of a medicament for the treatment of anxiety. A method of screening a patient to determine the patient's tolerance to a therapeutic dose of a compound according to any one of claims 1 to 17, the method comprising: measuring a pre-dose QT interval of the patient; administering to the patient An insufficient therapeutic dose of the compound; and measuring the QT interval of the patient after administration.