# US 5,705,522 A · Compounds having anti-inflammatory and anti-viral activity, compositions of these, alone and in combination with reverse transcriptase inhibitors

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- Number: US 5,705,522 A
- Document ID: US5705522A
- Status: Granted
- Kind: A
- Application number: 08/600,525
- Filed: 1996-02-13
- Granted: 1998-01-06
- Earliest claimed: 1995-09-15
- Assignees: Compagnie de Developpement Aguettant S.A.
- Inventors: Farid Hamedi-Sangsari; Fabienne Nugier; Thierry Vallet; Jacques Grange; Jorge Vila
- Web page: https://patentgrep.com/patent/US5705522A

## CPC

- C07C 259/06: having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/12: Antivirals
- C07D 207/46: with hetero atoms directly attached to the ring nitrogen atom
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

A new family of compounds having anti-inflammatory, anti-viral, and brocho-dilating activity having the following linear and cyclic formulas: ##STR1## and compositions of these, which alone, and in combination with reverse transcriptase inhibitors thereby resulting in an additive or synergistic effect, are useful in inhibiting or suppressing viruses including those exhibiting retroviral replication, or in treating viruses including a retrovirus such as HIV in a human cell population and methods of using these compositions, compounds, and salts thereof.

## Claims

### Claim 1

A compound having the following linear or cyclic formulas: ##STR10## wherein R.sup.1 is an alkyl group of from 1 to 4 carbon atoms optionally mono-, -di, or tri-substituted with halogen; each of R.sup.2, R.sup.3, and R.sup.4 is hydrogen, or a straight or branched alkyl radical containing 1 to 8 carbon atoms, an alkenyl radical containing 2 to 8 carbon atoms, an alkynyl radical containing 2 to 8 carbon atoms, a cycloalkyl radical containing 3 to 6 carbon atoms, a cycloalkenyl radical containing from 4 to 6 carbon atoms or a bicycloalkyl radical containing 7 to 11 carbon atoms, these radicals optionally being substituted by at least one substituent selected from halogen, hydroxyl, alkyloxy containing 1 to 4 carbon atoms, dialkyl amino, in which each alkyl contains 1 to 4 carbon atoms, phenyl alkyl in which the alkyl contains 1 to 4 carbon atoms, cyclo alkyl containing 3 to 6 carbon atoms, optionally substituted phenyl, cyano, carboxyl, or alkyloxy carbonyl in which the alkyl contains 1 to 4 carbon atoms; n is an integer from 0 to 6; for formula I and n=1 for formula II and salts thereof.

### Claim 2 (depends on 1)

The compound according to claim 1 wherein R.sup.1 is CH.sub.3, each of R.sup.2, R.sup.3, and R.sup.4 is hydrogen and n is 1.

### Claim 3 (depends on 1)

The compound according to claim 1 wherein R.sup.1 is CF.sub.3, each of R.sup.2, R.sup.3, and R.sup.4 is hydrogen and n is 1.

### Claim 4 (depends on 1)

The method of treatment with a compound according to claim 1 to inhibit production or spread of a virus comprising exposing a cell population including said virus to a compound according to claim 1.

### Claim 5 (depends on 1)

The method of treatment with a compound according to claim 1 to limit the spread of a virus comprising exposing a cell population including said virus to a compound according to claim 1.

### Claim 6 (depends on 1)

The method of treatment with a compound according to claim 1 to block the production of a virus comprising exposing a cell population including said virus to a compound according to claim 1.

### Claim 7 (depends on 1)

The method of treatment with a compound according to claim 1 to block the production or limit spread of a virus comprising exposing a cell population including said virus to a synergistic combination of at least one reverse transcriptase inhibitor and at least one compound according to claim 1.

### Claim 8 (depends on 1)

The method of treatment with a compound according to claim 1 for inhibiting the spread of a virus comprising exposing a cell population including said virus to a synergistic combination of at least one reverse transcriptase inhibitor and at least one compound according to claim 1.

### Claim 9 (depends on 1)

The method of treatment with a compound according to claim 1 to block the production of a virus comprising exposing a cell population including said virus to a synergistic combination of at least one reverse transcriptase inhibitor and at least one compound according to claim 1.

### Claim 10 (depends on 4)

The method of claim 4 wherein the virus is a retrovirus.

### Claim 11 (depends on 5)

The method of claim 5 wherein the virus is a retrovirus.

### Claim 12 (depends on 6)

The method of claim 6 wherein the virus is a retrovirus.

### Claim 13 (depends on 7)

The method of claim 7 wherein the virus is a retrovirus.

### Claim 14 (depends on 8)

The method of claim 8 wherein the virus is a retrovirus.

### Claim 15 (depends on 9)

The method of claim 9 wherein the virus is a retrovirus.

### Claim 16 (depends on 4)

The method of claim 4 wherein the virus is HIV-1, HIV-2, HTLV-1, HTLV-2, SIV, HSV, HBV OR HCV.

### Claim 17 (depends on 5)

The method of claim 5 wherein the virus is HIV-1, HIV-2, HTLV-1, HTLV-2, SIV, HSV, HBV OR HCV.

### Claim 18 (depends on 6)

The method of claim 6 wherein the virus is HIV-1, HIV-2, HTLV-1, HTLV-2, SIV, HSV, HBV OR HCV.

### Claim 19 (depends on 7)

The method of claim 7 wherein the virus is HIV-1, HIV-2, HTLV-1, HTLV-2, SIV, HSV, HBV OR HCV.

### Claim 20 (depends on 8)

The method of claim 8 wherein the virus is HIV-1, HIV-2, HTLV-1, HTLV-2, SIV, HSV, HBV OR HCV.

### Claim 21 (depends on 9)

The method of claim 9 wherein the virus is HIV-1, HIV-2, HTLV-1, HTLV-2, SIV, HSV, HBV OR HCV.

### Claim 22 (depends on 4)

The method of claim 4 wherein the compound is D-acetamido-N-hydroxy succinamic acid (DANHSA); D-acetamido-N-hydroxy succinimide; D-trifluoroacetamido-N-hydroxy succinamic acid (DTFANHSA); D-trifluroacetamido-N-hydroxy succinimide; and salts thereof.

### Claim 23 (depends on 5)

The method of claim 5 wherein the compound is D-acetamido-N-hydroxy succinamic acid (DANHSA); D-acetamido-N-hydroxy succinimide; D-trifluoroacetamido-N-hydroxy succinamic acid (DTFANHSA); D-trifluroacetamido-N-hydroxy succinimide; and salts thereof.

### Claim 24 (depends on 6)

The method of claim 6 wherein the compound is D-acetamido-N-hydroxy succinamic acid (DANHSA); D-acetamido-N-hydroxy succinimide; D-trifluoroacetamido-N-hydroxy succinamic acid DTFANHSA); D-trifluroacetamido-N-hydroxy succinimide; and salts thereof.

### Claim 25 (depends on 7)

The method of claim 7 wherein the compound is D-acetamido-N-hydroxy succinamic acid (DANHSA); D-acetamido-N-hydroxy succinimide; D-trifluoroacetamido-N-hydroxy succinamic acid (DTFANHSA); D-trifluroacetamido-N-hydroxy succinimide; and salts thereof and the at least one reverse transcriptase inhibitor is a dideoxynucleoside.

### Claim 26 (depends on 8)

The method of claim 8 wherein the compound is D-acetamido-N-hydroxy succinamic acid (DANHSA); D-acetamido-N-hydroxy succinimide; D-trifluoroacetamido-N-hydroxy succinamic acid (DTFANHSA); D-trifluroacetamido-N-hydroxy succinimide; and salts thereof; and the at least one reverse transcriptase inhibitor is a dideoxynucleoside.

### Claim 27 (depends on 9)

The method of claim 9 wherein the compound is D-acetamido-N-hydroxy succinamic acid (DANHSA); D-acetamido-N-hydroxy succinimide; D-trifluoroacetamido-N-hydroxy succinamic acid (DTFANHSA); D-trifluroacetamido-N-hydroxy succinimide; and salts thereof and the at least one reverse transcriptase inhibitor is a dideoxynucleoside.

### Claim 28 (depends on 25)

The method of claim 25 wherein the dideoxynucleoside is selected from the group consisting of AZT, ddC, ddA, ddG, ddI, ddT, 3TC and d4T.

### Claim 29 (depends on 26)

The method of claim 26 wherein the dideoxynucleoside is selected from the group consisting of AZT, ddC, ddA, ddG, ddI, ddT, 3TC and d4T.

### Claim 30 (depends on 27)

The method of claim 27 wherein the dideoxynucleoside is selected from the group consisting of AZT, ddC, ddA, ddG, ddI, ddT, 3TC and d4T.

### Claim 31

A method of treating HIV infected and AIDS patients comprising administering to the patients a compound of the following linear or cyclic formula: ##STR11## wherein R.sup.1 is an alkyl group of from 1 to 4 carbon atoms optionally mono-, -di, or tri-substituted with halogen; each of R.sup.2, R.sup.3, and R.sup.4 is hydrogen, or a straight or branched alkyl radical containing 1 to 8 carbon atoms, an alkenyl radical containing 2 to 8 carbon atoms, an alkynyl radical containing 2 to 8 carbon atoms, a cycloalkyl radical containing 3 to 6 carbon atoms, a cycloalkenyl radical containing from 4 to 6 carbon atoms or a bicycloalkyl radical containing 7 to 11 carbon atoms, these radicals optionally being substituted by at least one substituent selected from halogen, hydroxyl, alkyloxy containing 1 to 4 carbon atoms, dialkyl amino, in which each alkyl contains 1 to 4 carbon atoms, phenyl alkyl in which the alkyl contains 1 to 4 carbon atoms, cyclo alkyl containing 3 to 6 carbon atoms, optionally substituted phenyl, cyano, carboxyl, or alkyloxy carbonyl in which the alkyl contains 1 to 4 carbon atoms; n is an integer from 0 to 6 for formula I and n=1 for formula II; and salts thereof, in combination with at least one reverse transcriptase inhibitor.

### Claim 32 (depends on 31)

The method according to claim 31 wherein the compound is D-acetamido-N-hydroxy succinamic acid (DANHSA); D-acetamido-N-hydroxy succinimide; D-trifluoroacetamido-N-hydroxy succinamic acid (DTFANHSA); D-trifluroacetamido-N-hydroxy succinimide; and salts thereof; and the reverse transcriptase inhibitor is a dideoxynucleoside selected from the group consisting of AZT, ddC, ddA, ddG, ddI, ddT, 3TC and d4T.

### Claim 33 (depends on 32)

The method of claim 32 wherein the dideoxynucleoside is ddI, AZT, ddC or 3TC.

### Claim 34 (depends on 1)

The method of inhibiting or treating Human Immunodeficiency Viruses (HIV) infection, comprising the step of administering to a subject in need thereof an effective amount of a pharmaceutically acceptable composition comprising a synergistic combination of a compound according to claim 1 and at least one reverse transcriptase inhibitor.

### Claim 35 (depends on 34)

The method of claim 34 wherein the compound is D-acetamido-N-hydroxy succinamic acid (DANHSA); D-acetamido-N-hydroxy succinimide; D-trifluoroacetamido-N-hydroxy succinamic acid (DTFANHSA); D-trifluroacetamido-N-hydroxy succinimide; and salts thereof; and the reverse transcriptase inhibitor is ddI, AZT, ddC or 3TC.

### Claim 36 (depends on 1)

The method of inhibiting or blocking Human immunodeficiency Viruses comprising the steps of:
(a) administering to a subject in need thereof an effective amount of a pharmaceutically acceptable composition comprising a compound according to claim 1; and
(b) co-administering an effective amount of a pharmaceutical composition comprising a reverse transcriptase inhibitor.

### Claim 37 (depends on 36)

The method of claim 36 wherein the compound is D-acetamido-N-hydroxy succinamic acid (DANHSA); D-acetamido-N-hydroxy succinimide; D-trifluoroacetamido-N-hydroxy succinamic acid (DTFANHSA); D-trifluroacetamido-N-hydroxy succinimide; and salts thereof; and the reverse transcriptase inhibitor is ddI, AZT, ddC or 3TC.

### Claim 38 (depends on 1)

The compound according to claim 1 having a cyclic structure wherein R.sup.1 is CH.sub.3, each R.sup.2 and R.sup.3 is hydrogen.

### Claim 39 (depends on 1)

The compound according to claim 1 having a cyclic structure wherein R.sup.1 is CF.sub.3, each of R.sup.2 and R.sup.3 is hydrogen.

### Claim 40 (depends on 1)

The compound according to claim 1, wherein said compound is selected from the group consisting of D-acetamido-N-hydroxy succinamic acid (DANHSA), D-acetamido-N-hydroxy succinimide, D-trifluoroacetamido-N-hydroxy succinamic acid (DTFANHSA), D-trifluoroacetamido-N-hydroxy succinimide; and salts thereof.

### Claim 41

A D-compound of the formulae: ##STR12## wherein R.sup.1 is an alkyl group of from 1 to 4 carbon atoms optionally mono-, -di, or tri-substituted with halogen; each of R.sup.2, R.sup.3, and R.sup.4 is hydrogen, or a straight or branched alkyl radical containing 1 to 8 carbon atoms, an alkynyl radical containing 2 to 8 carbon atoms, an alkenyl radical containing 2 to 8 carbon atoms, a cycloalkyl radical containing 3 to 6 carbon atoms, a cycloalkenyl radical containing from 4 to 6 carbon atoms or a bicycloalkyl radical containing 7 to 11 carbon atoms, these radicals optionally being substituted by at least one substituent selected from halogen, hydroxyl, alkyloxy containing 1 to 4 carbon atoms, dialkyl amino, in which each alkyl contains 1 to 4 carbon atoms, phenyl alkyl in which the alkyl contains 1 to 4 carbon atoms, cyclo alkyl containing 3 to 6 carbon atoms, optionally substituted phenyl, cyano, carboxyl, or alkyloxy carbonyl in which the alkyl contains 1 to 4 carbon atoms; n is an integer from 0 to 6 for formula I and n=1 for formula II; and salts thereof.

### Claim 42

A method of treating asthma comprising administering to patients in need of treatment an effective amount of a compound of the following linear or cyclic formula: ##STR13## wherein R.sup.1 is an alkyl group of from 1 to 4 carbon atoms optionally mono-, -di, or tri-substituted with halogen; each of R.sup.2, R.sup.3, and R.sup.4 is hydrogen, or a straight or branched alkyl radical containing 1 to 8 carbon atoms, an alkenyl radical containing 2 to 8 carbon atoms, an alkynyl radical containing 2 to 8 carbon atoms, a cycloalkyl radical containing 3 to 6 carbon atoms, a cycloalkenyl radical containing from 4 to 6 carbon atoms or a bicycloalkyl radical containing 7 to 11 carbon atoms, these radicals optionally being substituted by at least one substituent selected from halogen, hydroxyl, alkyloxy containing 1 to 4 carbon atoms, dialkyl amino, in which each alkyl contains 1 to 4 carbon atoms, phenyl alkyl in which the alkyl contains 1 to 4 carbon atoms, cyclo alkyl containing 3 to 6 carbon atoms, optionally substituted phenyl, cyano, carboxyl, or alkyloxy carbonyl in which the alkyl contains 1 to 4 carbon atoms; n is an integer from 0 to 6 for formula I and n=1 for formula II; and salts thereof.