# US 2021/0276987 A1 · Pharmaceutical agents for use in smoking and tobacco cessation

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- Number: US 2021/0276987 A1
- Document ID: US20210276987A1
- Status: Published application
- Kind: A1
- Application number: 17/257,160
- Filed: 2019-07-03
- Published: 2021-09-09
- Earliest claimed: 2018-07-03
- Assignees: Washington State University
- Applicants: Washington State University
- Inventors: Philip Lazarus; Travis Denton; Gang Chen; Pramod Srivastava; Alec Wynd; Zuping Xia; Christy Watson
- Web page: https://patentgrep.com/patent/US20210276987A1

## CPC

- A61P 25/34: Tobacco-abuse
- C07D 409/14: containing three or more hetero rings
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 35/00: Antineoplastic agents
- C07D 207/44: having three double bonds between ring members or between ring members and non-ring members
- C07D 213/38: having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
- C07D 213/61: Halogen atoms or nitro radicals
- C07D 213/68: attached in position 4
- C07D 217/12: with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D 239/26: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 405/04: directly linked by a ring-member-to-ring-member bond
- C07D 405/14: containing three or more hetero rings
- C07D 409/04: directly linked by a ring-member-to-ring-member bond
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

The present disclosure describes novel compounds and compositions that reduce nicotine mediated cravings in humans. In embodiments, the novel compounds blocking CYP2A6-meditated nicotine metabolism thereby reducing the need for additional nicotine. Leading to a desirable treatment option in reducing nicotine craving which does not exacerbate the sympathetic response rate caused by the abused substance and which has favorable pharmacodynamics effects.

## Claims

### Claim 1

A compound of Formula I,
wherein,
A is a heterocycle comprising X, N, and one to 5 carbon atoms, and N is at position 1 on the heterocycle;
X is C, N, O, or S and X is at any position on the heterocycle that is not occupied by N or a carbon atom bonded to M;
M is a linker and M is bonded to the carbon atom on the heterocycle at position n, wherein n is 2, 3, 4, 5, or 6;
R is one or more substituents on A, and at least one R is at position n+1;
each R is the same or different and is independently alkyl, cycloalkyl, aminoalkyl, aralkyl, alkoxy, alkoxyalkyl, cycloalkenyl, alkynyl, cycloalkynyl, acyl, acylalkyl, acyloxy, acyloxyalkyl, heterocycle, aryl, heteroaryl, heteroaralkyl, heteroaralkyloxy, aroyl, aroylalkyl, aryloxy, aryloxyalkyl, halogen, haloalkyl, cyano, cyanoalkyl, nitro, nitroalkyl, carboxyl, carboxylalkyl, amino, aminoalkyl, aminocarbonyl, aminocarbonylalkyl, carbamoylalkyl, carbamoylalkoxy, iminoalkyl, imidoalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkylamino, alkylaminoalkyl, dialkylamino, dialkylaminoalkyl, arylamino, arylaminoalkyl, hydroxy, hydroxyalkyl, isocyano, isocyanoalkyl, isothiocyano, isothiocyanoalkyl, oximinoalkoxy, morpholino, morpholinoalkyl, azido, azidoalkyl, formyl, formylalkyl, alkylthio, alkylthioalkyl, alkylsulfinyl, alkylsulfinylalkyl, alkylsulfonyl, alkylsulfonylalkyl, aminosulfonyl, arylsulfonyl, N-alkyl-N-arylaminosulfonyl, heteroatom, or heteroatom-containing group, and wherein each is optionally substituted by one or more substituents; and
R5 and R6 are the same or different and are independently alkyl, cycloalkyl, aminoalkyl, aralkyl, alkoxy, alkoxyalkyl, cycloalkenyl, alkynyl, cycloalkynyl, acyl, acylalkyl, acyloxy, acyloxyalkyl, heterocycle, aryl, heteroaryl, heteroaralkyl, heteroaralkyloxy, aroyl, aroylalkyl, aryloxy, aryloxyalkyl, hydrogen, halogen, haloalkyl, cyano, cyanoalkyl, nitro, nitroalkyl, carboxyl, carboxylalkyl, amino, aminoalkyl, aminocarbonyl, aminocarbonylalkyl, carbamoylalkyl, carbamoylalkoxy, iminoalkyl, imidoalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkylamino, alkylaminoalkyl, dialkylamino, dialkylaminoalkyl, arylamino, arylaminoalkyl, hydroxy, hydroxyalkyl, isocyano, isocyanoalkyl, isothiocyano, isothiocyanoalkyl, oximinoalkoxy, morpholino, morpholinoalkyl, azido, azidoalkyl, formyl, formylalkyl, alkylthio, alkylthioalkyl, alkylsulfinyl, alkylsulfinylalkyl, alkylsulfonyl, alkylsulfonylalkyl, aminosulfonyl, arylsulfonyl, N-alkyl-N-arylaminosulfonyl, heteroatom, or heteroatom-containing group, wherein each is optionally substituted by one or more substituents.

### Claim 2 (depends on 1)

The compound of claim 1, wherein M is,

### Claim 3 (depends on 1)

The compound of claim 1, wherein,
A is a 5- or 6-membered heterocycle; and
R is a lower alkyl, aryl, heteroaryl, cycloalkyl, cycloakenyl, cycloalkynyl, or spirocyclic.

### Claim 4 (depends on 1)

The compound of claim 1, wherein A is pyridine, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, pyrimidine, pyridazine, pyrazine, thiophene, or furan.

### Claim 5 (depends on 1)

The compound of claim 1, wherein A is a pyridine and R is positioned para to N.

### Claim 6 (depends on 1)

The compound of claim 1, wherein the compound has Formula II,
R1 is halogen, alkyl, aryl, aralkyl, heteroaryl, alkenyl, alkynyl, cycloalkyl, heterocycle, or heteroatom-containing group, wherein the alkyl, aryl, aralkyl, heteroaryl, alkenyl, alkynyl, cycloalkyl, heterocycle, or heteroatom-containing group is optionally substituted by one or more substituents;
R2, R3, and R4 are the same or different and are independently halogen, hydrogen, alkyl, aryl, aralkyl, heteroaryl, alkenyl, alkynyl, cycloalkyl, heterocycle, or heteroatom-containing group, wherein the alkyl, aryl, aralkyl, heteroaryl, alkenyl, alkynyl, cycloalkyl, heterocycle, or heteroatom-containing group is optionally substituted by one or more substituents;
X is N or C;
M is an independently
and
R5 and R6 are the same or different and are independently hydrogen, halogen, alkyl, aryl, aralkyl, heteroaryl, alkenyl, alkynyl, cycloalkyl, heterocycle, heteroatom-containing group, or a protecting group, wherein alkyl, aryl, aralkyl, heteroaryl, alkenyl, alkynyl, cycloalkyl, heterocycle, heteroatom-containing group, or protecting group is optionally substituted by one or more substituents.

### Claim 7 (depends on 6)

The compound of claim 6, wherein,
R1 is a lower alkyl; and
each of R2, R3, and R4 is hydrogen.

### Claim 8 (depends on 1)

A salt or solvate of the compound of claim 1, or a solvate of the salt of the compound of claim 1.

### Claim 9 (depends on 1)

A composition, wherein the composition comprises the compound, or a salt or solvate of claim 1 and a carrier.

### Claim 10 (depends on 9)

The composition of claim 9, wherein the composition is a pharmaceutical composition and the carrier is a pharmaceutically acceptable carrier.

### Claim 11 (depends on 10)

A method of treating, preventing, or reducing the risk of developing a disease or disorder, wherein the method comprises administering a therapeutically effective amount the pharmaceutical composition of claim 10 to the subject.

### Claim 12 (depends on 11)

The method of claim 11, wherein treating, preventing, or reducing the risk of developing a disease or disorder comprises blocking CYP2A6- and/or UGT2B10-mediated nicotine metabolism.

### Claim 13 (depends on 11)

The method of claim 11, wherein the disease or disorder is nicotine addiction, cancer, alcoholism, neurodegenerative disease, psychiatric disorder, cardiovascular disease, blindness, cataracts, periodontitis, pneumonia, chronic obstructive pulmonary disease, asthma, diabetes, reduced fertility, ectopic pregnancy, erectile dysfunction, rheumatoid arthritis, or alcoholism.

### Claim 14 (depends on 13)

The method of claim 13,
wherein the cancer is oropharyngeal cancer, laryngeal cancer, esophageal cancer, tracheal cancer, bronchial cancer, lung cancer, acute myeloid leukemia, stomach cancer, liver cancer, pancreatic cancer, kidney cancer, ureter cancer, cervical cancer, bladder cancer, or colorectal cancer;
wherein the psychiatric disorder is anxiety disorders such as post-traumatic stress disorder, bipolar disorder, generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, separation anxiety, social anxiety disorder, or attention deficit disorder; or
wherein the cardiovascular disease is stroke, myocardial infarction, aortic aneurysm, or atherosclerosis.

### Claim at position 15

-17. (canceled)

### Claim 18 (depends on 10)

A method of treating a subject that would benefit from blocking CYP2A6- and/or UGT2B10-meditated nicotine metabolism, wherein the method comprises administering a therapeutically effective amount of the pharmaceutical composition of claim 10 to a subject in need thereof.

### Claim 19 (depends on 10)

A method of blocking CYP2A6- and/or UGT2B10-mediated nicotine metabolism, wherein the method comprises administering the pharmaceutical composition of claim 10 to cells associated with cells overexpressing CYP2A6- and/or UGT2B10-mediated nicotine metabolism and assaying for nicotine metabolites.

### Claim 20 (depends on 19)

The method of claim 19, wherein the cells are an in vitro sample of cells or an in vivo sample of cells.

### Claim 21 (depends on 19)

The method of claim 19, wherein the cells are human liver microsomes.

### Claim 22 (depends on 10)

A method of blocking CYP2A13 and/or CYP2A6 activation of pro-carcinogens, wherein the method comprises administering the pharmaceutical composition of claim 10 to a subject in need thereof.

### Claim 23 (depends on 22)

The method of claim 22, wherein the subject is diagnosed with cancer or is at risk of developing cancer.

### Claim 24 (depends on 23)

The method of claim 23, wherein the subject has lung cancer or has a risk of developing lung cancer.

### Claim at position 23

-27. (canceled)