# US 2014/0194457 A1 · Carboxamide bioisosteres of opiates

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 2014/0194457 A1
- Document ID: US20140194457A1
- Status: Published application
- Kind: A1
- Application number: 14/206,170
- Filed: 2014-03-12
- Published: 2014-07-10
- Earliest claimed: 2010-03-22
- Assignees: Rensselaer Polytechnic Institute
- Applicants: Rensselaer Polytechnic Institute
- Inventors: Mark P. WENTLAND
- Web page: https://patentgrep.com/patent/US20140194457A1

## CPC

- C07D 489/00: Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: [IMAGE cpc-sch-C07D-0991.gif]
- A61K 31/439: the ring forming part of a bridged ring system, e.g. quinuclidine (8-azabicyclo [3.2.1] octanes A61K31/46)
- A61K 31/4748: forming part of bridged ring systems (strychnine A61K31/475; morphinan derivatives A61K31/485)
- A61K 31/485: Morphinan derivatives, e.g. morphine, codeine
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/10: Laxatives
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/14: Antitussive agents
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/04: Antipruritics
- A61P 19/00: Drugs for skeletal disorders
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 25/08: Antiepileptics; Anticonvulsants
- A61P 25/32: Alcohol-abuse
- A61P 25/34: Tobacco-abuse
- A61P 25/36: Opioid-abuse
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 221/22: Bridged ring systems
- C07D 221/26: Benzomorphans
- C07D 221/28: Morphinans
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 489/08: Oxygen atom
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

A compound of formula I is disclosed. Compounds of formula I are useful as analgesics, anti-inflammatory agents, anti-diarrheal agents, anticonvulsants, antitussives and anti-addiction medications.

## Claims

### Claim 1

A compound of formula I:
wherein
R1 and R2 are each independently selected from hydrogen, halogen, —OH, —CN, —CHO, —OCH3, —OCH2CH3, —OCH(CH3)2, —NO2, —COR10, —COOR10, —SO2R10, —CONR10R11, CSNR10R11, —CONR10NR11R12, —CONR10OR11, —CONR10((C(R12)(R13)tCONR10R11, —CONR10((C(R12)(R13)tCOOR11, —C(═S)R10, —C(═NOR11)R10, C(═NR10)R11, —SO2NR10R11, heterocyclyl, optionally substituted lower alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, and (C1-C6)alkylthio;
or, R1 and R2 together with the atoms to which they are attached, and a fragment selected from —OCH2O—, or —OCH2CH2O—, form a ring,
wherein when Cy is an aromatic group R1 and R2 cannot both be hydrogen;
wherein when Cy is an aromatic group R1 and R2 cannot both be halogen;
R3 is chosen from hydrogen, C1-C8 hydrocarbon, heterocyclyl, aryl and hydroxyalkyl;
R4 is chosen from hydrogen, hydroxyl, amino, lower alkoxy, C1-C20 alkyl and C1-C20 alkyl substituted with hydroxyl or carbonyl;
R5 is lower alkyl;
R6 is lower alkyl;
R7 is chosen from hydrogen, NR10R11 and —OR10; or
together R4, R5, R6 and R7 may form from one, two, three, or four rings, said rings having optional additional substitution;
R8 and R8a are both hydrogen or taken together R8 and R8a are ═O;
R9 is chosen from hydrogen and lower alkyl;
R10, R11, R12 and R13 are each independently hydrogen, optionally substituted lower alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, hydroxyl, —NR100R101 or optionally substituted lower alkoxy, or
R10 and R11, together with the nitrogen atom to which they are attached, form an optionally substituted fused carbocyclic or heterocyclic ring having from 5 to 7 ring members of which up to 3 can be heteroatoms selected from N, O and S;
t is 0, 1, 2, 3, 4, 5, or 6;
R100 and R101 are each independently hydrogen, optionally substituted lower alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, hydroxyl, or optionally substituted lower alkoxy, or
R100 and R101, together with the nitrogen atom to which they are attached, form an optionally substituted fused carbocyclic or heterocyclic ring having from 5 to 7 ring members of which up to 3 can be heteroatoms selected from N, O and S;
Y is a direct bond or —(C(R10)(R11))q-, wherein q is 0, 1, 2, 3, 4 or 5;
L is a direct bond or —(C(R10)(R11))q-; and
Cy is Ar1—B—Ar2, wherein
Ar1 is absent, or an aryl or heteroaryl radical having from 1 to 4 N, O and/or S atoms, which may be unsubstituted or mono-, di- or trisubstituted by halogen, lower alkyl, alkenyl, alkynyl, cycloalkyl, —OR10, —NR10R11, CN, —COR10or —COOR10;
B is a direct bond, —O—, —NR10, —SO2, or —(C(R10)(R11)s-, wherein s is 0, 1, 2, 3, 4 or 5; and
Ar2 is aryl or heteroaryl radical having from 1 to 4 N, O and/or S atoms, which may be unsubstituted or mono-, di- or trisubstituted by halogen, lower alkyl, alkenyl, alkynyl, cycloalkyl, —OR10, —NR10R11, —CN, —COR10or —COOR10,
wherein when Cy is phenyl or biphenyl, R1 is other than —OCH3.

### Claim 2 (depends on 1)

A compound of claim 1 wherein Cy is selected from:
wherein W is selected from [C(R9)2]—, CR8R8a, O, NR9, S and CR9═CR9; and
n is 1, 2, 3, 4 or 5.

### Claim 3 (depends on 1)

A compound of claim 1 of formula III-VI:
wherein, R20, R21 and R22 are each chosen from hydrogen, hydroxyl, amino, lower alkoxy, C1-C20 alkyl and C1-C20 alkyl substituted with hydroxyl or carbonyl; or together, R20, and R21 with the carbon to which they are attached, form —CO, or —CS; or together, R20, and R21 with the carbon(s) to which they are attached, form a ring.

### Claim 4 (depends on 1)

A compound according to claim 1 of formula:

### Claim 5 (depends on 1)

A compound according to claim 1 selected from Table 1:
No
Structure
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
1
47
48

### Claim 6 (depends on 1)

A compound according to claim 1 wherein Cy-R1R2 is of formula
wherein Z is CR10 or N, with the provisos that,
a) at the point of attachment of the distal ring to the proximal ring, Z must be C, and
b) at the points of attachment of R1 and R2, Z will be CR1 and CR2, respectively.

### Claim 7 (depends on 6)

A compound according to claim 6 of formula wherein Cy-R1R2 is of formula:

### Claim 8 (depends on 7)

A compound according to claim 7 wherein one of R1 and R2 is in the para position relative to B and the other of R1 and R2 is hydrogen.

### Claim 9 (depends on 1)

A compound according to claim 1, wherein Ar2 is phenyl and one of R1 or R2 is in the para position relative to B.

### Claim 10 (depends on 9)

A compound according to claim 9 wherein Cy-R1R2 is of formula:

### Claim 11 (depends on 1)

A pharmaceutical formulation comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

### Claim 12 (depends on 1)

A method of preventing or treating a condition or disease associated with binding opioid receptors in a patient in need thereof, comprising the step of administering to said patient a composition comprising an effective amount of a compound according to claim 1.

### Claim 13 (depends on 12)

A method according to claim 12 wherein said disease or condition is chosen from the group consisting of pain, pruritis, diarrhea, irritable bowel syndrome, gastrointestinal motility disorder, obesity, respiratory depression, convulsions, coughing, hyperalgesia, inflammation, osteoarthritis and drug addiction.

### Claim 14 (depends on 13)

A method according to claim 13, wherein the condition is pain and the composition further comprises an effective amount of an opioid.

### Claim 15 (depends on 13)

A method according to claim 13, wherein the condition is osteoarthritis and the composition further comprises an effective amount of an opioid.

### Claim 16

A compound of formula Ia:
wherein
R1 and R2 are each independently selected from hydrogen, halogen, —OH, —CN, —CHO, —OCH3, —OCH2CH3, —OCH(CH3)2, heterocyclyl, optionally substituted lower alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, (C1-C6)alkylthio, —NO2, —COR10, —SO2R10, —CONR10R11, —C(═S)R10, —C(═NOR11)R10, C(═NR10R11 and —SO2NR10R11;
or, R1 and R2 together with the atoms to which they are attached, and a fragment selected from —OCH2O—, or —OCH2CH2O—, form a ring,
with the proviso that R1 and R2 cannot both be hydrogen;
R3 is chosen from hydrogen, C1-C8 hydrocarbon, heterocyclyl, aryl and hydroxyalkyl;
R4 is chosen from hydrogen, hydroxyl, amino, lower alkoxy, C1-C20 alkyl and C1-C20 alkyl substituted with hydroxyl or carbonyl;
R5 is lower alkyl;
R6 is lower alkyl;
R7 is chosen from hydrogen, NR10R11 and —OR10; or
together R4, R5, R6 and R7 may form from one to four rings, said rings having optional additional substitution;
R8 and R8a are both hydrogen or taken together R8 and R8a are ═O;
R9 is chosen from hydrogen and lower alkyl;
R10 and R11 are each independently hydrogen, optionally substituted lower alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, hydroxyl, —NR100R101 or optionally substituted lower alkoxy, or
R10 and R11, together with the nitrogen atom to which they are attached, form an optionally substituted fused carbocyclic or heterocyclic ring having from 5 to 7 ring members of which up to 3 can be heteroatoms selected from N, O and S;
R100 and R101 are each independently hydrogen, optionally substituted lower alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, hydroxyl, or optionally substituted lower alkoxy, or
R100 and R101, together with the nitrogen atom to which they are attached, form an optionally substituted fused carbocyclic or heterocyclic ring having from 5 to 7 ring members of which up to 3 can be heteroatoms selected from N, O and S;
Y is a direct bond or —(C(R10)(R11)) q-, wherein q is 0, 1, 2, 3, 4 or 5; and
Cy is Ar1—B—Ar2, wherein
Ar1 is absent, or an aryl or heteroaryl radical having from 1 to 4 N, O and/or S atoms, which may be unsubstituted or mono-, di- or trisubstituted by halogen, lower alkyl, alkenyl, alkynyl, cycloalkyl, —OR10, —NR10R11, —CN, —COR10or —COOR10;
B is a direct bond, —O—, —NR10, —SO2, or —(C(R10)(R11)s-, wherein s is 0, 1, 2, 3, 4 or 5; and
Ar2 is aryl or heteroaryl radical having from 1 to 4 N, O and/or S atoms, which may be unsubstituted or mono-, di- or trisubstituted by halogen, lower alkyl, alkenyl, alkynyl, cycloalkyl, —OR10, —NR10R11, —CN, —COR10or —COOR10,
wherein when Cy is phenyl or biphenyl, R1 is other than —OCH3.

### Claim 17 (depends on 16)

A compound of claim 16 wherein Cy is selected from:
wherein W is selected from [C(R9)2]—, CR8R8a, O, NR9, S and CR9═CR9; and
n is 1, 2, 3, 4 or 5.

### Claim 18 (depends on 1)

A compound according to claim 1 wherein said R10 and R11 are hydrogen.

### Claim 19 (depends on 1)

A compound according to claim 1 wherein R1 is —OH, —CHO, —CONH2—CON(H)CH2CONH2, —CON(H)CH2CH2CONH2, —CON(H)CH2COOH, or —CON(H)CH2CH2COOH; or R1 and R2 together with the atoms to which they are attached forms a —OCH2O— fused ring.

### Claim 20 (depends on 1)

A compound according to claim 1 wherein R2 is H.