JPWO2020092823A5

JPWO2020092823A5 -

Info

Publication number: JPWO2020092823A5
Application number: JP2021548568A
Authority: JP
Publication date: 2022-11-07

Claims

Compounds of Formula I

, or a salt or cannabinoid derivative thereof:
During the ceremony,
R ¹ is C ₅ -C ₂₀ haloalkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₂₀ hydroxyalkyl, deuterated C ₁ -C ₂₀ alkyl, tritiated C ₁ -C ₂₀ alkyl, and C ₂ -C ₂₀ selected from the group consisting of alkenyl,
^R2 is selected from the group consisting of ^COOR2a and H;
R ^2a is selected from the group consisting of H and C ₁ -C ₆ alkyl;
^R3 is selected from the group consisting of a prenyl moiety and H;

R ¹ is C ₅ -C ₁₀ haloalkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₁₀ hydroxyalkyl, deuterated C ₁ -C ₁₀ alkyl, tritiated C ₁ -C ₁₀ alkyl, and C ₂ -C 10 alkyl 2. A compound, or a salt or cannabinoid derivative thereof, according to claim 1, selected from the group consisting of ₁₀ alkenyls.

R ¹ is selected from the group consisting of C ₅ -C ₁₀ haloalkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₁₀ hydroxyalkyl, deuterated C ₁ -C ₁₀ alkyl, and tritiated C ₁ -C ₁₀ alkyl 3. The compound of claim 1, or a salt or cannabinoid derivative thereof, wherein

3. The compound, or salt or cannabinoid derivative thereof, of claim 1, wherein R ¹ is C ₅ -C ₁₀ haloalkyl or C ₁ -C ₄ haloalkyl.

5. The compound, or salt or cannabinoid derivative thereof, of claim 4, wherein ^R1 is selected from the group consisting of fluoropentyl, fluoroethyl, fluoropropyl, fluorobutyl, fluorohexyl, fluorooctyl, and fluorononyl.

5. The compound, or salt or cannabinoid derivative thereof, of claim 4, wherein ^R1 is selected from the group consisting of 5-fluoropropyl, 4-fluorobutyl, and 3-fluoropentyl.

5. A compound, or a salt or cannabinoid derivative thereof, according to claim 4, wherein R ¹ is C ₁ -C ₁₀ bromoalkyl or C ₁ -C ₁₀ chloroalkyl.

3. The compound, or salt or cannabinoid derivative thereof, of claim 1, wherein R ¹ is C ₁ -C ₁₀ hydroxyalkyl.

2. The compound, or a salt or cannabinoid derivative thereof, of claim 1, wherein R ¹ is deuterated C ₁ -C ₁₀ alkyl or tritiated C ₁ -C ₁₀ alkyl.

2. The compound, or salt or cannabinoid derivative thereof, of claim 1, wherein ^R2 is selected from the group consisting of COOH and H.

^3. The compound, or salt or cannabinoid derivative thereof, of claim 1, wherein R2 is COOH.

2. A compound, or a salt or cannabinoid derivative thereof, according to claim 1, wherein ^R2 is H.

2. A compound, or a salt or cannabinoid derivative thereof, according to claim ¹ , wherein R3 is H.

^3. The compound, or salt or cannabinoid derivative thereof, of claim 1, wherein R3 is a prenyl moiety.

2. The compound, or salt or cannabinoid derivative thereof, of claim 1, wherein said prenyl moiety is 3,7-dimethyloct-2,6-dien-1-yl.

wherein said compound has the structure of formula Ia

3. The compound of claim 1, or a salt or cannabinoid derivative thereof, having

A cannabinoid derivative of the compound of claim 1 or a salt thereof.

Halogenated Cannabidiolic Acids, Halogenated Cannabidiols, Halogenated Δ ⁹ -tetrahydrocannabinolic Acids, Halogenated Δ ⁸ -tetrahydrocannabinolic Acids, Halogenated Cannabichromenic Acids, Halogenated Cannabichromenes, Halogenated Cannabinols, Halogenated Cannabi Nodiol, halogenated cannabinolic acids, cannabivarin, halogenated cannabivaric acid, halogenated Δ ⁹ -tetrahydrocannabivarin, halogenated Δ ⁸ -tetrahydrocannabivarin, halogenated Δ ⁹ -tetrahydrocannabivaric acid, halogenated Δ ⁸ - tetrahydrocannabivaric acid, halogenated cannabigerovarin, halogenated cannabigerovaric acid, halogenated cannabichromevalin, halogenated cannabichromevalic acid, halogenated cannabidivarin, halogenated cannabidivaric acid, halogenated cannabtriol, 18. The cannabinoid derivative or pharmaceutically acceptable salt thereof according to claim 17, which is selected from the group consisting of cannabinoid derivatives and halogenated cannabicyclols.

A pharmaceutical composition comprising the cannabinoid derivative of claim 17 or claim 18 and a pharmaceutically acceptable excipient.

19. A pharmaceutical composition for treating a disease or condition mediated by cannabinoid receptor activity in a subject , comprising an effective amount of the cannabinoid derivative of claim 17 or claim 18, or a pharmaceutically acceptable salt thereof.

compounds of formula IV

, or a salt thereof, comprising:
wherein R ¹ consists of C ₁ -C ₂₀ haloalkyl, C ₁ -C ₂₀ hydroxyalkyl, deuterated C ₁ -C ₂₀ alkyl, tritiated C ₁ -C ₂₀ alkyl, and C ₂ -C ₂₀ alkenyl selected from the group,
The method comprises a thioester of formula II

culturing the modified recombinant host cell in a medium comprising
wherein ^R4 is selected from the group consisting of coenzyme A (CoA) moieties, pantetheine moieties, and cysteamine moieties;
The modified recombinant host cell is
iii. a thioester of formula II and malonyl-CoA to a tetraketide of formula III

a first polynucleotide encoding a synthase that converts to
iv. a second polynucleotide encoding a 2-alkyl-4,6-dihydroxybenzoate cyclase that converts a tetraketide of formula III to a compound of formula IV; and
said modified recombinant host cell is cultured under conditions in which the products encoded by said first and said second polynucleotides are expressed to produce a compound of Formula IV;
Method.

R ¹ is selected from the group consisting of C ₁ -C ₁₀ haloalkyl, C ₁ -C ₁₀ hydroxyalkyl, deuterated C ₁ -C ₁₀ alkyl, tritiated C ₁ -C ₁₀ alkyl, and C ₂ -C ₁₀ alkenyl 22. The method of claim 21, wherein

22. The method of claim 21, wherein said synthase is olivetolate synthase.

22. The method of claim 21, wherein said 2-alkyl-4,6-dihydroxybenzoate cyclase is a truncated olivetolate cyclase.

22. The method of claim 21, wherein ^R4 is a CoA moiety.

said host cell is a starting material of formula IIa

to a thioester of formula II, further comprising a third polynucleotide encoding an acyl-CoA synthetase, and
step (a) comprises culturing the host cell under conditions in which the product encoded by the third polynucleotide is expressed to produce the thioester of Formula II;
22. The method of claim 21.

27. The method of claim 26, wherein said acyl-CoA synthetase is revS or CsAAE3.

22. The method of claim 21, wherein ^R4 in the thioester of Formula II is a pantetheine moiety or a cysteamine moiety.

The compound of formula IV is converted to the compound of formula V

or a salt thereof ^, wherein R3 is a prenyl moiety.

Compounds of formula V are decarboxylated to give compounds of formula Va

30. The method of claim 29, further comprising the step of obtaining

The compound of formula IV is decarboxylated to give the compound of formula IVa.

22. The method of claim 21, further comprising the step of obtaining

The compound of formula IVa is converted to the compound of formula Va

32. The method of claim 31 ^, further comprising converting to where R3 is a prenyl moiety.

said host cell further comprising a fourth polynucleotide encoding a prenyltransferase enzyme that converts the compound of Formula IV to a compound of Formula V, and wherein converting step (b) is encoded by said fourth polynucleotide; 30. The method of claim 29, comprising culturing said host cell under conditions in which the product of formula V is expressed to produce the compound of formula V.

said host cell further comprising a fourth polynucleotide encoding a prenyltransferase enzyme that converts the compound of formula IVa to the compound of formula Va, and wherein converting step (b) is encoded by said fourth polynucleotide 33. The method of claim 32, comprising culturing said host cell under conditions in which said product is expressed to produce a compound of Formula Va.

34. The method of claim 33, wherein said prenyltransferase is geranyl pyrophosphate:olivetolate geranyltransferase.

The converting step (b) comprises forming a reaction mixture comprising (1) a compound of formula IV, (2) geraniol, activated geraniol, or citral, and (3) an organic solvent, and a compound of formula V 30. The method of claim 29, comprising maintaining the reaction mixture under conditions sufficient for

The converting step (b) comprises forming a reaction mixture comprising (1) a compound of formula IVa, (2) geraniol, activated geraniol, or citral, and (3) an organic solvent, and a compound of formula Va 33. The method of claim 32, comprising maintaining the reaction mixture under conditions sufficient for