# US 5,703,076 A · Retroviral protease inhibitors

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- Number: US 5,703,076 A
- Document ID: US5703076A
- Status: Granted
- Kind: A
- Application number: 08/449,966
- Filed: 1995-05-25
- Granted: 1997-12-30
- Earliest claimed: 1990-11-19
- Assignees: G. D. Searle & Co.
- Inventors: John J. Talley; Daniel P. Getman; Ko-Chung Lin; Gary A. DeCrescenzo; Donald J. Rogier, Jr.; John N. Freskos
- Web page: https://patentgrep.com/patent/US5703076A

## CPC

- C07K 5/06191: {containing heteroatoms different from O, S, or N}
- A61K 31/17: having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine (isoureas, isothioureas A61K31/155; sulfonylureas A61K31/64)
- A61K 31/195: having an amino group
- A61K 31/197: the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid (carnitine A61K31/205)
- A61K 31/27: of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
- A61K 31/47: Quinolines; Isoquinolines
- A61K 31/4709: Non-condensed quinolines and containing further heterocyclic rings
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- C07C 213/02: by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
- C07C 271/20: to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
- C07C 271/22: to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
- C07C 275/14: being further substituted by nitrogen atoms not being part of nitro or nitroso groups
- C07C 275/18: of a saturated carbon skeleton containing rings
- C07C 275/22: containing rings other than six-membered aromatic rings
- C07C 275/24: containing six-membered aromatic rings
- C07C 275/28: having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C 311/47: Y being a hetero atom
- C07C 317/44: having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
- C07C 317/50: at least one of the nitrogen atoms being part of any of the groups [IMAGE cpc-sch-C07C-0976.gif], X being a hetero atom, Y being any atom
- C07C 323/60: with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
- C07C 329/06: having sulfur atoms of thiocarbonic groups bound to acyclic carbon atoms
- C07C 335/08: of a saturated carbon skeleton
- C07C 335/12: the carbon skeleton containing six-membered aromatic rings
- C07D 213/81: Amides; Imides
- C07D 215/48: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D 215/50: attached in position 4
- C07D 215/54: attached in position 3
- C07D 215/56: with oxygen atoms in position 4
- C07D 217/26: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D 235/06: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D 235/24: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D 239/38: One sulfur atom
- C07D 241/44: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
- C07D 295/13: to an acyclic saturated chain
- C07D 295/15: to an acyclic saturated chain
- C07D 307/85: attached in position 2
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07K 5/0207: {containing the structure -NH-(X)4-C(=0), e.g. 'isosters', replacing two amino acids}
- C07K 5/021: {containing the structure -NH-(X)n-C(=0)-, n being 5 or 6; for n > 6, classification in C07K5/06 - C07K5/10, according to the moiety having normal peptide bonds}
- C07K 5/06026: {the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala}
- C07K 5/06139: {with the first amino acid being heterocyclic}
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- C07C 2601/02: with a three-membered ring
- C07C 2601/04: with a four-membered ring
- C07C 2601/08: the ring being saturated
- C07C 2601/14: The ring being saturated
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- 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)
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Urea-containing hydroxyethylamine compounds are effective as retroviral protease inhibitors, and in particular as inhibitors of HIV protease.

## Claims

### Claim 1

A compound represented by the formula: ##STR208## wherein A represents radicals represented by formula: ##STR209## wherein R.sup.2 represents alkyl, aryl, cycloalkyl, cycloalkylalkyl and aralkyl radicals, which radicals are optionally substituted with a group selected from --OR.sup.9, --SR.sup.9, and halogen radicals,
wherein R.sup.9 represents hydrogen and alkyl radicals;
R.sup.3 represents alkyl, alkenyl, alkynyl, hydoxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl, aralkyl, heteroaralkyl, aminoalkyl and mono- and disubstituted aminoalkyl radicals where said substitutents are selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroalkyl, heterocycloalkyl, and heterocycloalkylalkyl radicals;
X' represents O, C(R.sup.17) where R.sup.17 represents hydrogen and alkyl radicals, and N provided that when X' is O, R.sup.12 is absent;
Y and Y' independents represent O,S and NR.sup.15 wherein R.sup.15 represents radicals as defined for R.sup.3 ;
R.sup.4, R.sup.5, R.sup.11 and R.sup.12 independently represent hydrogen and radicals as defined by R.sup.3, or R.sup.4 and R.sup.5, and/or R.sup.11 and R.sup.12 together with the nitrogen atom to which they are bonded represent heterocycloalkyl and heteroaryl radicals, or R.sup.11 and R.sup.12 together with a carbon atom to which they are attached represent cycloalkyl and aryl radicals;
B represents R.sup.5 and radicals represented by the formula: ##STR210## wherein: R.sup.7 and R.sup.7 ' represent radicals as defined for R.sup.3 and amino acid side chains selected from valine, isoleuceine, glycine, alaninc, allo-isoleucine, asparagine, leucine, glutamine and t-butylglycine;
and R.sup.8 represents an amide derivative of an amino acid;
and R.sup.6 represents hydrogen and alkyl radicals.

### Claim 2 (depends on 1)

A compound of claim 1 represented by the formula: ##STR211## or a pharmaceutically acceptable salt, prodrug or ester thereof, wherein
R.sup.2 represents alkyl, aryl, cycloalkyl and aralkyl radicals;
R.sup.3 represents alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl, aralkyl, heteroaralkyl, aminoalkyl and mono- and disubstituted aminoalkyl radicals where said substiments are selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroalkyl, heterocycloalkyl, and heterocycloalkylalkyl radicals;
R.sup.6 represents hydrogen and alkyl radicals;
R.sup.4, R.sup.5, R.sup.11 and R.sup.12 independently represent radicals as defined for R.sup.3 or, R.sup.4 and R.sup.11, or R.sup.12 together with the nitrogen atom to which they are bonded, represent pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl radicals.
X' represents C(H), O and N provided that when X' is O, R.sup.12 is absent; and
Y and Y' independently represent O and S.

### Claim 3 (depends on 2)

Compound of claim 2 wherein R.sup.2 represents alkyl, cycloalkylalkyl and aralkyl radicals, which radicals are optionally substituted with halogen radicals and radicals represented by the formula --OR.sup.9 and SR.sup.9 wherein R.sup.9 represents hydrogen and alkyl radicals.

### Claim 4 (depends on 2)

Compound of claim 2 wherein R.sup.2 represents alkyl, cycloalkylalkyl and aralkyl radicals.

### Claim 5 (depends on 2)

Compound of claim 2 wherein R.sup.2 represents alkyl radicals.

### Claim 6 (depends on 2)

Compound of claim 2 wherein R.sup.2 represents aralkyl radicals.

### Claim 7 (depends on 2)

Compound of claim 2 wherein R.sup.2 represents cycloalkylalkyl radicals.

### Claim 8 (depends on 2)

Compound of claim 2 wherein R.sup.2 represents CH.sub.3 SCH.sub.2 CH.sub.2 --, n-butyl, iso-butyl, benzyl, 2-naphthylmethyl and cyclohexylmethyl.

### Claim 9 (depends on 2)

Compound of claim 2 wherein R.sup.2 represents n-butyl and iso-butyl radicals.

### Claim 10 (depends on 2)

Compound of claim 2 wherein R.sup.2 represents benzyl and 2-naphthylmethyl.

### Claim 11 (depends on 2)

Compound of claim 2 wherein R.sup.2 represents n-butyl.

### Claim 12 (depends on 2)

Compound of claim 2 wherein R.sup.2 represents cyclohexylmethyl.

### Claim 13 (depends on 2)

Compound of claim 2 wherein R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.11 and R.sup.12 independently represent alkyl, alkenyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl, and heteroaralkyl.

### Claim 14 (depends on 2)

Compound of claim 2 wherein R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.11 and R.sup.12 independently represent alkyl radicals.

### Claim 15 (depends on 2)

Compound of claim 2 wherein R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.11 and R.sup.12 independently represent alkenyl radicals.

### Claim 16 (depends on 2)

Compound of claim 2 wherein R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.11 and R.sup.12 independently represent hydroxyalkyl radicals.

### Claim 17 (depends on 2)

Compound of claim 2 wherein R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.11 and R.sup.12 independently represent cycloalkyl and cycloalkylalkyl radicals.

### Claim 18 (depends on 2)

Compound of claim 2 wherein R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.11 and R.sup.12 independently represent heterocycloalkyl and heterocycloalkylalkyl radicals.

### Claim 19 (depends on 2)

Compound of claim 2 wherein R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.11 and R.sup.12 independently represent aryl and aralkyl radicals.

### Claim 20 (depends on 2)

Compound of claim 2 wherein R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.11 and R.sup.12 independently represent heteroaralkyl radicals.

### Claim 21 (depends on 2)

Compound of claim 2 wherein R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.11 and R.sup.12 independently represent alkyl radicals having from about 2 to about 5 carbon atoms.

### Claim 22 (depends on 2)

Compound of claim 2 wherein R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.11 and R.sup.12 independently represent alkyl radicals having from about 2 to about 5 carbon atoms, cycloalkylalkyl radicals, aralkyl radicals, heterocycloalkyl radicals and heteroaryl radicals.

### Claim 23 (depends on 2)

Compound of claim 2 wherein R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.11 and R.sup.12 independently represent methyl, iopropyl, i-butyl, i-amyl, t-butyl, n-butyl, neo-pentyl, benzyl, para-methoxybenzyl, para-methylbenzyl, 2-naphthylmethyl and cyclohexylmethyl radicals.

### Claim 24 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

### Claim 25 (depends on 2)

A pharmaceutical composition comprising a compound of claim 2 and a pharmaceutically acceptable carrier.

### Claim 26 (depends on 24)

Method of inhibiting a retroviral protease comprising administering a protease inhibiting amount of a composition of claim 24.

### Claim 27 (depends on 26)

Method of claim 26 wherein the retroviral protease is HIV protease.

### Claim 28 (depends on 24)

Method for treating a retroviral infection comprising administering an effective amount of a composition of claim 24.

### Claim 29 (depends on 28)

Method of claim 28 wherein the retroviral infection is an HIV infection.

### Claim 30 (depends on 24)

Method for treating AIDS comprising administering an effective amount of a composition of claim 24.

### Claim 31 (depends on 25)

Method of inhibiting a retroviral protease comprising administering a protease inhibiting amount of a composition of claim 25.

### Claim 32 (depends on 31)

Method of claim 31 wherein the retroviral protease is HIV protease.

### Claim 33 (depends on 25)

Method for treating a retroviral infection comprising administering an effective amount of a composition of claim 25.

### Claim 34 (depends on 33)

Method of claim 33 wherein the retroviral infection is an HIV infection.

### Claim 35 (depends on 25)

Method for treating AIDS comprising administering an effective amount of a composition of claim 25.