# US 2024/0197741 A1 · External anti-inflammatory coupling compound drug, and preparation method therefor and use thereof

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- Number: US 2024/0197741 A1
- Document ID: US20240197741A1
- Status: Published application
- Kind: A1
- Application number: 18/413,842
- Filed: 2024-01-16
- Published: 2024-06-20
- Earliest claimed: 2021-07-20
- Assignees: Coval Biopharma (Shanghai) Co., Ltd.
- Applicants: Coval Biopharma (Shanghai) Co., Ltd.
- Inventors: Lichun FENG; Weijiang ZHANG; Guolong WU; Hao ZHANG; Dafeng LI
- Web page: https://patentgrep.com/patent/US20240197741A1

## CPC

- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 31/4985: Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- C07D 487/02: in which the condensed system contains two hetero rings
- C07D 487/14: Ortho-condensed systems
- C07D 519/00: Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

An external anti-inflammatory drug compound, and a preparation method therefor and the use thereof. The structural formula of the compound is A-Y—B, wherein A is a group after dehydrogenation of an amine compound having JAK inhibitory activity, Y is a direct connection or —(CH2)—O— or, and B is a group formed by means of dehydroxylation of a carboxy-containing carboxylic acid compound B1, or a group formed by means of dehydrogenation of a hydroxy-containing compound B2. The compound has the special effects of having a strong transdermal property, controlled drug release, high efficacy, etc.

## Claims

### Claim 1

An anti-inflammatory compound, or a stereoisomer, tautomer, nitrogen oxide thereof, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof, having a structure shown in general formula (I):
A-Y—B (I)
wherein, A is a group after dehydrogenation of an amine compound having JAK inhibitory activity;
Y is a direct connection; or —(CH2)—O— or —(CH2)—;
B is a group formed by means of dehydroxylation of a carboxy-containing carboxylic acid compound B1, or a group formed by means of dehydrogenation of a hydroxy-containing compound B2; and
wherein, in the case where the carboxylic acid B1 is dehydroxylated to form a group, the Y group is a direct connection or —(CH2)—O—; or in the case where the hydroxy-containing compound B2 is dehydrogenated to form a group, the Y group is —(CH2)—.

### Claim 2 (depends on 1)

The anti-inflammatory compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof of claim 1, having a structure shown in general formulas (II) or (IIa):
wherein R1 is selected from pyrazolyl or pyrrolyl unsubstituted or substituted with Ra; or —N(CH3)—Cy; Ria represents a pyrrole ring substituted by a halogen-substituted C1-C6 alkylaminoacyl group and/or by a C1-C6 alkyl group;
Cy is a five- or six-membered carbocyclic ring or a five- or six-membered nitrogen-containing heterocyclic ring unsubstituted or substituted by Rb; Ra and Rb are each independently groups containing at least one or two groups selected from a group consisting of an acyl group, a dithioyl group, a cyano group, an amino group or a C1-C6 alkyl-substituted amino group, and a four-, five-, or six-membered nitrogen-containing heterocyclic group, or the nitrogen-containing heterocyclic group substituted with C1-C6 alkyl;
R2 in both general formulas (II) and (IIa) is —B, i.e. is a group formed by means of dehydroxylation of a carboxy-containing carboxylic acid compound B1 and is selected from R4—Ar—R3—CO—,
wherein, R3 is selected from C1-C6 alkylene; —NH—, R5NH—, or C1-C6 alkylene substituted with a C1-C6 alkoxyamide group; or a direct connection, i.e. the Ar group is directly linked to —CO—; Ar is an aromatic ring group and
R4 is halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl containing C1-C6 cycloalkanoyl, C1-C6 alkylamido or aryl fused heterocyclic amido, C1-C6 carbonyloxy, halogen substituted benzoyl, C1-C6 alkyl or halogen substituted or unsubstituted phenoxy, C1-C6 alkyl or halogen substituted or unsubstituted phenyl or aryl fused heterocyclic ring, C1-C6 alkyl or halogen substituted or unsubstituted phenylamino, or R4 can also be absent; wherein the C1-C6 alkoxy can also form a bridged ring with Ar.

### Claim 3 (depends on 2)

The anti-inflammatory compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof of claim 2, wherein Cy is substituted cyclohexyl or substituted piperidinyl.

### Claim 4 (depends on 1)

The compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof of claim 1, wherein the compound is a coupling compound resulting from a condensation reaction of an amine compound A with a carboxylic acid compound B1.

### Claim 5 (depends on 1)

The compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof of claim 1, wherein A- is a group after dehydrogenation of an amine compound selected from a group consisting of any one of the following groups: tofacitinib, baricitinib, oclacitinib, ruxolitinib, upadacitinib and delgocitinib:

### Claim 6 (depends on 2)

The anti-inflammatory compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof of claim 2, wherein —B1 is a group after dehydroxylation of a carboxylic acid moiety selected from a group consisting of ibuprofen, (S)-(+)-ibuprofen, naproxen, fenoprofen, flurbiprofen, loxoprofen, ketoprofen, diclofenac, etodolac, actarit, indomethacin, N-Boc-L-phenylglycine, aspirin, indobufen, mefenamic acid and tolfenamic acid:

### Claim 7 (depends on 6)

The anti-inflammatory compound, or the stereoisomer, tautomer, N-oxide, metabolite, prodrug, pharmaceutically acceptable salt or solvate thereof of claim 6, wherein the compound is a coupled compound obtained by condensation reaction of an amine compound A selected from the group consisting of tofacitinib, baricitinib, oclacitinib, upadacitinib, ruxolitinib and delgocitinib with a carboxylic acid compound B1 selected from the group consisting of ibuprofen, (S)-(+)-ibuprofen, naproxen, fenoprofen, flurbiprofen, loxoprofen, ketoprofen, etodolac, actarit and indomethacin.

### Claim 8 (depends on 6)

The anti-inflammatory compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof of claim 6, wherein the compound is any one of the following specific compounds:

### Claim 9 (depends on 6)

The anti-inflammatory compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof of claim 6, wherein the compound is any one of the following specific compounds:

### Claim 10 (depends on 6)

The anti-inflammatory compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof of claim 6, wherein the compound is any one of the following specific compounds:

### Claim 11 (depends on 1)

The anti-inflammatory compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof of claim 1, having a structure shown in general formulas (III):
wherein R1 has the same meaning as R1 in general formula (II); Ria has the same meaning as R1a in formula (IIa); R2′ in formula (III) and formula (IIIa) are both Y—B, B is B1 in formula (II) or (IIa), or B is B2; wherein the group —B1 is a group formed by dehydroxylation of a carboxylic acid compound B1 and Y— is (CH2)—O—; the group —B2 is a group formed by dehydrogenation of a hydroxyl-containing compound B2 and Y— is —(CH2)—; the group —B1 has the same meaning as the R2 group in formula (II) or in formula (IIa); the group —B2 is Rd—CO—NH—Rd, wherein Rc is a 4-hydroxy-benzothiazine dioxide-3-yl represented by the following structural formula (a), (wherein the phenyl ring may be substituted by halogen or C1-C6 alkyl), or a 4-hydroxy-Re substituted thienothiazine dioxide-3-yl represented by the following structural formula (b), wherein —CO—NH—Rd is bonded at the 3-position of the thiazine ring,
wherein Rd is thiazole, isothiazole, oxazole, isoxazole, or pyridine or the group thereof substituted with C1-C6 alkyl or halogen; Re is C1-C6 alkyl or halogen; a arrow next to Re in formula (b) indicates that its substitution position on the thiophene ring may be any carbon-linked hydrogen atom capable of undergoing substitution.

### Claim 12 (depends on 11)

The anti-inflammatory compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof of claim 11, wherein —B1 is a group after dehydroxylation of any one of carboxylic acids selected from a group consisting of the following groups:
ibuprofen, (S)-(+)-ibuprofen, naproxen, fenoprofen, flurbiprofen, loxoprofen, ketoprofen, diclofenac, etodolac, actarit, indomethacin, N-Boc-L-phenylglycine, aspirin, indobufen, mefenamic acid and tolfenamic acid:
—B2 is a group after dehydrogenation of a hydroxyl-containing compound of one of the following specific compounds:

### Claim 13 (depends on 11)

The anti-inflammatory compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof of claim 11, obtained by a preparation method comprising the step of:
1) reacting A-CH2—OH compound with an acyl chloride of B or directly with the B compound;
wherein the A-CH2—OH compound is prepared by the following step 1): reacting the amine compound A to form the A-CH2—OH compound, wherein A- is a group after dehydrogenation of an amine compound selected from a group consisting of any one of the following groups: tofacitinib, baricitinib, oclacitinib, ruxolitinib, upadacitinib and delgocitinib:

### Claim 14 (depends on 13)

The anti-inflammatory compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof of claim 13, wherein the compound is any one of the following specific compounds:

### Claim 15 (depends on 1)

Use of the anti-inflammatory compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof of claim 1, for anti-inflammatory symptom.

### Claim 16 (depends on 1)

An anti-inflammatory drug preparation or drug composition including the anti-inflammatory compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof of claim 1.

### Claim 17 (depends on 3)

The anti-inflammatory compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof of claim 3, wherein the substituted cyclohexyl group is a cyclohexyl group substituted with an amino group and a dithio group, and the substituted piperidinyl group is a piperidinyl group substituted with an acyl group or a dithio group and —CN.

### Claim 18 (depends on 2)

The anti-inflammatory compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof of claim 2, wherein Ra and Rb are each independently groups which consist of one group of acyl or dithioacyl and at least one group selected from a group consisting of cyano, amino or C1-C6 alkyl substituted amino and a four-, five-, or six-membered nitrogen-containing heterocyclyl, or the nitrogen-containing heterocyclyl substituted with C1-C6 alkyl, wherein the C1-C6 alkyl is substitutable by halogen.

### Claim 19 (depends on 11)

The anti-inflammatory compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof of claim 11, Rd is a thiazole or isoxazole substituted with methyl; or unsubstituted pyridyl.

### Claim 20 (depends on 2)

The anti-inflammatory compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof of claim 2, Ar is an aromatic ring group selected from a benzene ring; a naphthalene ring or an aryl heterocyclic ring; and a benzene ring, a naphthalene ring, or an aryl heterocyclic ring or an aryl fused heterocyclic ring substituted with one or more groups selected from halogen, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 acyl group, or a C1-C6 alkoxy group.