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CN-121991035-A - Azetidine tryptamine and method of treating psychotic disorders

CN121991035ACN 121991035 ACN121991035 ACN 121991035ACN-121991035-A

Abstract

The present disclosure includes azetidine tryptamines and methods of treating psychotic disorders with such compounds. Pharmaceutical compositions comprising azetidine primary amines are also provided.

Inventors

  • A.C. Kruger

Assignees

  • 吉尔伽美什制药公司

Dates

Publication Date
20260508
Application Date
20210903
Priority Date
20200904

Claims (9)

  1. 1. A compound having the following general formula I: I is a kind of Wherein the method comprises the steps of Each R 1 -R 6 is independently selected from H, C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl, C 1 -C 5 heteroalkyl, C 2 -C 5 heteroalkenyl, C 2 -C 5 heteroalkynyl, C 1 -C 5 haloalkyl; R 7 -R 10 and R 12 are each independently selected from H, F, cl, br, I, CF 3 、SF 5 、C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 1 -C 10 heteroalkyl, C 2 -C 10 heteroalkenyl, C 2 -C 10 heteroalkynyl, C 1 -C 10 haloalkyl, -CN, -O- (C 1 -C 10 alkyl), -O- (C 1 -C 10 heteroalkyl), -S- (C 1 -C 10 alkyl), -S- (C 1 -C 10 heteroalkyl), -S (O) - (C 1 -C 10 alkyl), -SO 2 -(C 1 -C 10 alkyl), OH, -CO 2 H、-C(O)-NH 2 、-C(O)-NH-(C 1 -C 10 alkyl), -CO 2 -(C 1 -C 10 alkyl, -O-C (O) - (C 1 -C 10 alkyl), -O-P (O) (OH) (OH), NH 2 、-NH-(C 1 -C 10 alkyl), -N (C 1 -C 10 alkyl) (C 1 -C 10 alkyl), NO 2 and OCF 3 , and R 11 is selected from H, C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl, C 1 -C 5 heteroalkyl, C 2 -C 5 heteroalkenyl, C 2 -C 5 heteroalkynyl, C 1 -C 5 haloalkyl; or a pharmaceutically acceptable salt or ester thereof.
  2. 2. A compound according to claim 1 wherein Each R 1 -R 6 is independently selected from H, me, et, n-Pr, i-Pr, cyclopropyl, -ch=ch 2 (vinyl), -CCH (ethynyl), -CH 2 CHCH 2 (allyl); r 7 -R 10 and R 12 are each independently selected from the group consisting of-H, -F, -Cl, -Br-I, -CF 3 、-SF 5 , -Me, -Et, -n-Pr, -I-Pr cyclopropyl, -CHCH 2 (vinyl), -CCH (ethynyl), -CH 2 CHCH 2 (allyl )、-CN、-OMe、-OEt、-SMe、-SEt、-OH、-OAc、-CO 2 H、-C(O)-NH 2 、-CO 2 Me、-O-C(O)-(C 1 -C 5 alkyl), -O-P (O) (OH) (OH), -NH 2 、-NO 2 、-OCF 3 ; and R 11 is selected from the group consisting of-H, -Me, -Et, -n-Pr, -i-Pr, cyclopropyl, -CH 2 CHCH 2 (allyl); or a pharmaceutically acceptable salt or ester thereof.
  3. 3. A compound according to claim 1 wherein R 1 -R 6 is each independently selected from-H, -Me, -Et; R 7 -R 10 and R 12 are each independently selected from -H、-F、-Cl、-Br、-I、-CF 3 、-SF 5 、-Me、-Et、-CN、-OMe、-SMe、-OH、-OAc、-C(O)-NH 2 、-O-P(O)(OH)(OH)、-NH 2 、-NO 2 、-OCF 3 ; and R 11 is selected from-H, -Me, -Et; or a pharmaceutically acceptable salt or ester thereof.
  4. 4. A compound according to claim 1 wherein R 1 -R 6 is each independently selected from-H, -Me, -Et; R 7 -R 10 and R 12 are each independently selected from the group consisting of-H-F, -Cl, -Br, -I, -CF 3 、-Me、-CN、-OMe、-OH、-OAc、-C(O)-NH 2 、-O-P(O)(OH)(OH)、-NH 2 ; and R 11 is-H; or a pharmaceutically acceptable salt or ester thereof.
  5. 5. A compound according to claim 1, wherein the compound is represented by the following formula (I-a): (I-a), Or a pharmaceutically acceptable salt thereof.
  6. 6. A compound according to claim 5, wherein R 7 is selected from the group consisting of-H, -OH, -O- (C 1 -C 10 alkyl) -O-C (O) - (C 1 -C 10 alkyl) and-O-P (O) (OH) (OH).
  7. 7. The compound according to claim 6, wherein R 7 is selected from the group consisting of-H, -OH, -OAc, and-O-P (O) (OH) (OH).
  8. 8. A compound according to claim 5, wherein R 8 is selected from the group consisting of-H, -OH-O- (C 1 -C 10 alkyl) and-O-C (O) - (C 1 -C 10 alkyl).
  9. 9. The compound according to claim 8, wherein R 8 is selected from the group consisting of H, -OH, -OMe and-OAc.

Description

Azetidine tryptamine and method of treating psychotic disorders Technical Field Novel azetidine tryptamines and methods of treating psychotic disorders with such compounds. Pharmaceutical compositions comprising azetidine primary amines are also provided. Background Tryptamine is a diverse class of alkaloids containing the structural framework of the natural alkaloid tryptamine. Tryptamine There are a large number of tryptamine compounds, including naturally occurring compounds as well as synthetic and semisynthetic chemical derivatives having similar structures. Tryptamine is known to have a variety of mental activities and physiological effects. Some tryptamines are agonists of the 5-hydroxytryptamine 2A (5-HT 2A) receptor and/or modulators of other 5-hydroxytryptamine receptors, and are known to have psychotropic activity and/or induce vasoconstriction. In some cases, such compounds induce the illusion of prolonged periods of time. Other tryptamines are modulators of monoamine transporters. The most well known tryptamines are fantasy compounds, including compounds derived from fantasy fungi (entheogenic fungi) (nupharin (psilocybin) and nupharin (psilocin)), DMT, LSD, 5-MeO-DMT, bufogenin and ibogaine. These compounds are known to have a significant impact on thinking, perception and behavior. However, these compounds are currently classified as a first class of drugs (Schedule I drugs) according to the controlled substance method (Controlled Substances Act) because of their high abuse potential, lack of accepted medical use, and lack of established safety. Furthermore, tryptamine is metabolized by a variety of pathways, including monoamine oxidase in some cases, limiting the oral bioavailability of some compounds. Thus, there remains a need for safe and effective tryptamine compounds that can be reliably used to treat psychotic disorders. Disclosure of Invention The present disclosure provides compounds having the following general formula I: I is a kind of Wherein the method comprises the steps of Each R 1-R6 is independently selected from H, C 1-C5 alkyl, C 2-C5 alkenyl, C 2-C5 alkynyl, C 1-C5 heteroalkyl, C 2-C5 heteroalkenyl, C 2-C5 heteroalkynyl, and C 1-C5 haloalkyl; R 7-R10 and R 12 are each independently selected from H, F, cl, br, I, CF 3、SF5、C1-C10 alkyl, C 2-C10 alkenyl, C 2-C10 alkynyl, C 1-C10 heteroalkyl, C 2-C10 heteroalkenyl, C 2-C10 heteroalkynyl, C 1-C10 haloalkyl, -CN, -O- (C 1-C10 alkyl), -O- (C 1-C10 heteroalkyl), -S- (C 1-C10 alkyl), -S- (C 1-C10 heteroalkyl), -S (O) - (C 1-C10 alkyl), -SO 2-(C1-C10 alkyl), OH, -CO 2H、-C(O)-NH2、-C(O)-NH-(C1-C10 alkyl), -CO 2-(C1-C10 alkyl, -O-C (O) - (C 1-C10 alkyl), -O-P (O) (OH) (OH), NH 2、-NH-(C1-C10 alkyl), -N (C 1-C10 alkyl) (C 1-C10 alkyl), NO 2 and OCF 3, and R 11 is selected from H, C 1-C5 alkyl, C 2-C5 alkenyl, C 2-C5 alkynyl, C 1-C5 heteroalkyl, C 2-C5 heteroalkenyl, C 2-C5 heteroalkynyl, and C 1-C5 haloalkyl; or a pharmaceutically acceptable salt or ester thereof. The present disclosure further provides pharmaceutical compositions comprising one or more compounds of the present disclosure. The present disclosure further provides a method of treating a mental disease or disorder in a patient in need thereof, the method comprising administering to the subject a composition comprising an effective amount of a compound of the present disclosure. Drawings The one-way analysis of variance shows that treatment (F (5,54) =19.35, p < 0.0001) has a significant major impact on the total time spent stationary in FST. Dunnett multiple comparison test was used to test whether a group was significantly different from vehicle. All treatments were significantly different from vehicle. * P <.0001 relative to vehicle. Fig. 2. Swimming time in FST. One-way analysis of variance shows that treatment (F (5,54) =9.606, p < 0.0001) has a significant major impact on the total time spent swimming in FST. Dunnett multiple comparison test was used to test whether a group was significantly different from vehicle. * P <.01, P <.0001 with respect to vehicle. Detailed Description In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of the present disclosure. However, it will be understood by those skilled in the art that the present disclosure may be practiced without these specific details. In other instances, well-known methods, procedures, and components have not been described in detail so as not to obscure the present disclosure. Described herein are novel azetidine tryptamines and methods of treating psychotic disorders with such compounds. Pharmaceutical compositions comprising azetidine primary amines are also provided. The compounds provided are more potent as 5-hydroxytryptamine 1A (5-HT 1A) receptor agonists, as compared to their acyclic counterparts, such as tryptamines having N, N-dimethyl substituents. Further, they have better metabolic stability than such N, N-dimethyl count