AU1531092A - Substituted alpha-aminoaldehydes and derivatives - Google Patents
Substituted alpha-aminoaldehydes and derivativesInfo
- Publication number
- AU1531092A AU1531092A AU15310/92A AU1531092A AU1531092A AU 1531092 A AU1531092 A AU 1531092A AU 15310/92 A AU15310/92 A AU 15310/92A AU 1531092 A AU1531092 A AU 1531092A AU 1531092 A AU1531092 A AU 1531092A
- Authority
- AU
- Australia
- Prior art keywords
- substituted
- alkyl
- group
- compound
- mammal
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/56—Amides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
Description
TITLE
Substituted α-Aminoaldehydes and Derivatives
FIELD OF THE INVENTION
This invention relates to substituted α-aminoaldehydes, compositions containing such compounds and methods of using such compounds as antiviral agents.
BACKGROUND OF THE INVENTION
Current treatments for viral diseases usually involve administration of compounds that inhibit viral DNA synthesis. Current treatments for acquired
immunodeficiency syndrome (AIDS) (Dagani, Chem . Eng. News, November 23, 1987 pp. 41-49) involve
administration of compounds such as 2',3'-dideoxycytidine, trisodium phosphonoformate, ammonium 21-tungsto-9-antimoniate, 1-b-D-ribofuranoxyl-1,2,4-triazole-3-carboxamide, 3'-azido-3'-deoxythymidine, and adriamycin all which inhibit viral DNA synthesis;
compounds such as AL-721 and polymannoacetate which may prevent HIV from penetrating the host cell; and
compounds which treat the opportunistic infections caused by the immunosuppression resulting from HIV infection. None of the current AIDS treatments have proven to be totally effective in treating and/or reversing the disease. In addition, many of the
compounds currently used to treat AIDS cause adverse side effects including low platelet count, renal
toxicity and bone marrow cytopenia.
Proteases are enzymes which cleave proteins at specific peptide bonds. Many biological functions are controlled or mediated by proteases and their
complementary protease inhibitors. For example, the protease renin cleaves the peptide angiotensinogen to produce the peptide angiotensin I. Angiotensin I is further cleaved by the protease angiotensin converting
enzyme (ACE) to form the hypotensive peptide angiotensin II. Inhibitors of renin and ACE are known to reduce high blood pressure in vivo. However, no
therapeutically useful renin protease inhibitors have been developed, due to problems of oral availability and in vivo stability.
The genomes of retroviruses encode a protease that is responsible for the proteolytic processing of one or more polyprotein precursors such as the pol and gag gene products. See Wellink, Arch. Virol . 98 1 (1988).
Retroviral proteases most commonly process the gag
precursor into the core proteins, and also process the pol precursor into reverse transcriptase and retroviral protease.
The correct processing of the precursor
polyproteins by the retroviral protease is necessary for the assembly of the infectious virions. It has been shown that in vitro mutagenesis that produces proteasedefective virus leads to the production of immature core forms which lack infectivity. See Crawford, J. Virol . 51, 899 (1985); Katoh et al., Virology 145 280 (1985). Therefore, retroviral protease inhibition provides an attractive target for antiviral therapy. See Mitsuya, Nature 321775 (1987).
Moore, Biochem. Biophys. Res. Commun. , 159 420 (1989) discloses peptidyl inhibitors of HIV protease. Erickson, European Patent Application No. WO 89/10752 discloses derivatives of peptides which are inhibitors of HIV protease.
U.S. Patent No. 4,652,552 discloses methyl ketone derivatives of tetrapeptides as inhibitors of viral proteases. U.S. Patent No. 4,644,055 discloses
halomethyl derivatives of peptides as inhibitors of viral proteases. European Patent Application No.
WO 87/07836 discloses L-glutamic acid gammamonohydroxamate as an antiviral agent.
A small number of aldehyde protease inhibitors are known in the art: GB 2124233 discloses aromatic amino acid aldehyde derivatives that are inhibitors of chymotrypsin; and D.H. Rich (Research Monographs in Cell and Tissue Physiology. J. T. Dingle and J. L. Gordon, Editors, Elsevier, Amsterdam, 1986; p 201) discloses peptide aldehydes that are moderate renin inhibitors. None of these references disclose or suggest that the structurally diverse peptide aldehydes disclosed herein would inhibit HIV protease, would be efficacious in preventing human cells from being infected by HIV, or would be useful as antiviral therapies.
The ability to inhibit a protease provides a method for blocking viral replication and therefore a treatment for diseases, and AIDS in particular, that may have fewer side effects and be more efficacious when compared to current treatments. The topic of this patent
application is substituted α-aminoaldehydes and
derivatives, which compounds are capable of inhibiting viral protease and which compounds are believed to serve as a means of combating viral diseases such as AIDS.
The aldehydes and derivatives of this invention provide significant improvements over protease inhibitors that are known in the art. A large number of compounds have been reported to be renin inhibitors, but have suffered from lack of adequate bio-availability and are thus not useful as oral therapeutic agents, particularly if oral administration is desired. This poor activity has been ascribed to the unusually high molecular weight of renin inhibitors, to inadequate solubility properties, and to the presence of a number of peptide bonds, which are vulnerable to cleavage by mammalian proteases. The α-aminoaldehydes and derivatives described herein have a
distinct advantage in this regard, in that many do not contain peptide bonds, are of low molecular weight, and can be either hydrophobic or hydrophilic yet still inhibit the viral protease enzyme.
Additionally, many compounds that inhibit renin do not inhibit HIV protease. The structure-activity requirements of renin inhibitors differ from those of HIV protease inhibitors. The aldehydes and derivatives of the invention are particularly useful as HIV protease inhibitors.
Other HIV protease inhibitors have been reported, but to date very few have shown activity against viral replication in human cells. This lack of cellular activity is probably due in part to the factors
discussed above for renin inhibitors. Unlike other HIV protease inhibitors, aldehydes and derivatives disclosed herein show potent inhibition of viral replication in human cells.
An additional advantage of the aldehydes and derivatives disclosed herein is that they are very easy to prepare. Many can be prepared in one or two steps from commercially available starting materials. This facile preparation results in low cost for reagents and equipment, which in turn increases the likelihood of lower costs for the final product when compared to other AIDS drugs.
SUMMARY OF THE INVENTION
There is provided by this invention a compound of the formula:
or a pharmaceutically acceptable salt, prodrug, chiral, diastereomeric or racemic form thereof wherein:
R1, R2, R3 and R4 are independently selected from the group consisting of:
hydrogen, C1-C8 alkyl substituted with 0-3 R5, C2-C8 alkenyl substituted with 0-3 R5, C3-C8 alkynyl substituted with 0-3 R5, C3-C8 cycloalkyl substituted with 0-3 R5, C6-C10 bicycloalkyl substituted with 0-3 R5, aryl substituted with 0-3 R6, a C6-C14 carbocyclic residue substituted with 0-3 R6, a heterocyclic ring system composed of 5 to 10 atoms including at least one nitrogen, oxygen or sulfur atom substituted with 0-2 R6, or any naturally occurring amino acid;
R2A, R3A and R4A are independently selected from the following group consisting of:
hydrogen, C1-C4 alkyl, or benzyl;
each R5 is selected from the group consisting of:
keto, halogen, cyano, -NR7R8, -CO2R7, -OC(=O)R7, -OR7, C2-C6 alkoxyalkyl, -S(O)mR7, -NHC(=NH)NHR7,
-C(=NH)NHR7, -C(=O)NR7R8f -NR8C(=O)R7-, NR8C(=O)OR8, OC(=O)NR7R8, -NR8SO2NR7R8, -NR8SO2R7, -SO2NR7R8, C1-C4 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, C3-C6
cycloalkylmethyl, a C5-C14 carbocyclic residue
substituted with 0-3 R6, aryl substituted with 0-3 R6, or a heterocyclic ring system composed of 5 to 10 atoms including at least one nitrogen, oxygen or sulfur atom, substituted with 0-2 R6;
R6, when a substituent on carbon, is selected from the group consisting of:
phenyl, benzyl, phenethyl, phenoxy, benzyloxy,
halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, C7-C10 arylalkyl, alkoxy, -NR7R8, C2-C6 alkoxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1- C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, -S(O)mR7, -SO2NR7R8, -NHSO2R8, or R6 may be a 3- or 4- carbon chain attached to adjacent carbons on the ring to form a fused 5- or 6- membered ring, said 5- or 6- membered ring being optionally substituted on the aliphatic carbons with halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, or NR7R8, or when R6 is attached to a
saturated carbon atom it may be carbonyl or
thiocarbonyl;
R6, when a substituent on nitrogen, is selected from the group consisting of:
phenyl, benzyl, phenethyl, hydroxy, C1-C4 alkoxy, nitro, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, -NR7R8, C2-C6 alkoxyalkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonyl; -S(O)mR7, -SO2NR7R8, or R6 may be a 3- or 4- carbon chain attached to adjacent atoms on the ring to form a fused 5- or 6- membered ring, said 5- or 6- membered ring being
optionally substituted on the aliphatic carbons with halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, or NR7R8; R7 is H, phenyl, benzyl or C1-C6 alkyl;
R8 is H or C1-C4 alkyl;
or R7R8 can join to form (CH2)4, (CH2)5,
(CH2CH2N(R9)CH2CH2), or (CH2CH2OCH2CH2) ;
R9 is H or CH3;
R11 is H, phenyl, benzyl or C1-C6 alkyl;
R12 is H or C1-C4 alkyl;
m is 0, 1 or 2;
n is 0 or 1;
W is selected from the group consisting of:
-NR12C(=Q)NR12-, -C(=Q)NR12-, -C(=Q)O-, -NR12C(=Q)O-, -OC(=Q)NR12-, -NR12C(=Q)-, -C(=Q)-, -C(=Q)CH2-,
-NR12SO2NR12-, -NR12SO2-, -SO2NR12-, -SO2-, -QCH2-, -Q-, -CH2NR12-, -CH2CH2-, -CH-CH-, -CH(OH)CH(OH)-,
-CH(OH)CH2-, -CH2CH(OH)-, -CH(OH)-, -NH-NH-,
-C(=O)NH-NH-, -C(Cl)=N-, -C(-OR11)-N-, -C(-NR11R12)=N-, -OP(=O) (Q1)O-, -P(=O) (Q1)O-, -SO2NHC(=O)NH-;
X is selected from the group consisting of:
-C(=Q)NR12-, -C(=Q)O-, -C(=Q)-, -CH2C(=Q)-,
-CH2C(=Q)CH2-, -C(=Q)CH2-, -SO2NR12-, -SO2-, -CH2QCH2-, -CH2O-, -CH2NR12-, -CH2CH2-, -CH-CH-, -CH(OH)CH(OH)-, -CH(OH)CH2-, -CH2CH(OH)-, -CH(OH)-, -C(=O)NH-NH-,
-C(-OR11)=N-, -C(-NR11R12)=N-, -C(Cl)=N-;
Y is selected from the group consisting of:
-C(=Q)NR12-, -SO2NR12-, -CH2NR12-, -C(Cl)=N-,
-C(-OR11)=N-, -C(-NR11R12)=N-, -NR12C(=O)NR12-,
-OC(=O)NR12-;
Q is selected from oxygen or sulfur; and
Q1 is selected from oxygen, sulfur, NR8 or a direct bond.
The compounds herein described may have asymmetric centers. All chiral, diastereomeric and racemic forms are included in the present invention. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention.
When any variable (for example, R1 through R10, R2A,
R3A and R4A, m, n, p, Q, W, X, Y, Z, etc.) occurs more than one time in any constituent or in formula (I), its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations
of substituents and/or variables are permissible only if such combinations result in stable compounds.
As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms;
"alkoxy" represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge;
"cycloalkyl" is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl; and "biycloalkyl" is intended to include saturated bicyclic ring groups such as
[3.3.0]bicyclooctane, [4.3.0] bicyclononane,
[4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, and so forth. "Alkenyl" is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl and the like; and "alkynyl" is intended to include hydrocarbon chains of either a straight or branched
configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl, propynyl and the like. "Halo" as used herein refers to fluoro, chloro, bromo and iodo; and "counterion" is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate and the like.
As used herein, "aryl" or "aromatic residue" is intended to mean phenyl or naphthyl; "carbocyclic" is intended to mean any stable 5- to 7- membered monocyclic or bicyclic or 7- to 14-membered bicyclic or tricyclic carbon ring, any of which may be saturated, partially unsaturated, or aromatic.
As used herein, the term heterocycle is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ring which is
either saturated, unsaturated, or aromatic and which consists of carbon atoms and from 1 to 4 heteroatoms selected from the group consisting of N, O and S and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen may optionally be
quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable.
Examples of such heterocycles include, but are not limited to, pyridyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl,
benzothiophenyl, indolyl, indolenyl, quinolinyl,
isoquinolinyl or benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl,
tetrahydroisoquinolinyl, decahydroquinolinyl or
octahydroisoquinolinyl.
The term "substituted", as used herein, means that an one or more hydrogen on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
By "stable compound" or "stable structure" is meant herein a compound that is sufficiently robust to survive: isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
As used herein, "pharmaceutically acceptable salts" and "prodrugs" refer to derivatives of the disclosed compounds that are modified by making acid or base salts, or by modifying functional groups present in the compounds
in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Examples include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; acetate, formate and benzoate derivatives of alcohols and amines; and the like.
Preferred Embodiments
[A] Preferred compounds of the present invention are compounds of formula (I) wherein:
R1, R2, R3 and R4 are independently selected from the group consisting of:
hydrogen, C1-C8 alkyl substituted with 0-3 R5, C2-C8 alkenyl substituted with 0-3 R5, C3-C8 cycloalkyl
substituted with 0-3 R5, C6-C10 bicycloalkyl substituted with 0-3 R5, aryl substituted with 0-3 R6, a C6-C14 carbocyclic residue substituted with 0-3 R6, or a
heterocyclic ring system composed of 5 to 10 atoms including at least one nitrogen, oxygen or sulfur atom substituted with 0-2 R6;
R2A, R3A and R4A are hydrogen;
R5, R6, R7, R8, and R9 are as defined above;
R11 is H;
R12 is H;
m is 0, 1 or 2;
n is 0 or 1;
W is selected from the following:
-NR12C(=Q)NR12-, -C(=Q)NR12-, -C(=Q)O-, -NR12C(=Q)O-, -OC(=Q)NR12-, -NR12C(=Q)-, -C(=Q)-, -C(=Q)CH2-,
-NRl2SO2NR12-, -NR12SO2-, -SO2NR12-, -SO2-, -QCH2-, -Q-, -CH2NR12-, -CH2CH2-, -CH=CH-, -CH(OH)CH(OH)-,
-CH(OH)CH2-, -CH2CH(OH)-, -CH(OH)-, -OP(=O)(Q1)O-,
-P(=O) (Q1)O-, or -SO2NHC(=O)NH-;
X is selected from the group consisting of:
-C(=Q)NR12-, -C(=Q)O-, -C(=Q)-, -CH2C(=Q)-,
-CH2C(=Q)CH2-, -C(=Q)CH2-, -SO2NR12-, -SO2-, -CH2QCH2-, -CH2Q-, -CH2NR12-, -CH2CH2-, -CH=CH-, -CH(OH)CH(OH)-,
-CH(OH)CH2-, -CH2CH(OH)-, -CH(OH)-;
Y is selected from the group consisting of:
-C(=Q)NR12-, -SO2NR12-, -CH2NR12-, -NR12C(=O)NR12-,
-OC(=O)NR12-;
Q is oxygen or sulfur; and
Q1 is oxygen, sulfur, NR12 or a direct bond.
[B] More preferred compounds of the present Invention are compounds in the preferred scope ([A] above) wherein:
W is selected from the group consisting of:
-NR8C(=Q)NR12-, -C(=Q)NR12-, -C (=Q) O-, -NR12C (=Q)O-,
-OC(=Q)NR12-, -NR12SO2NR12-, -SO2NR12-, -Q-, -CH2NR12-, -OP(=O) (Q1)O-, -P(=O) (Q1)O-, -SO2NHC(=O)NH-;
X is selected from the group consisting of:
-C(=Q)NR12-, -C(=Q)O-, -SO2NR12-, -CH2Q-, or -CH2NR12-;
Y is selected from the group consisting of:
-C(=Q)NR12-, -SO2NR12-, or -CH2NR12-;
Q is oxygen; and
Q1 is oxygen.
[C] Further preferred compounds of the present invention are compounds in the more preferred Scope ([B] above) wherein:
R1 is C1-C8 alkyl substituted with 0-3 R5;
R2, R3 and R4 are independently selected from the group
consisting of hydrogen, C1-C8 alkyl substituted with 0-3 R5, or C2-C8 alkenyl substituted with 0-3 R5;
each R5 is selected from the group consisting of:
keto, halogen, cyano, -NR7R8 , -CO2R7, -OC (=O) R7 , -OR7 , C2-C6 alkoxyalkyl, -S(O)mR7, -NHC(=NH)NHR7, -C(=NH)NHR7, -C(=O)NR7R8, -NR8C(=O)R7-, NR8C(=O)OR8, -OC(=O)NR7R8,
-OC(=O)NR7R8, -NR8SO2NR7R8, -NR8SO2R7, -SO2NR7R8, C1-C4 alkyl, C2-C4 alkenyl, C3-C5 cycloalkyl, C3-C5
cycloalkylmethyl, a C5-C14 carbocyclic residue
substituted with 0-3 R6, aryl substituted with 0-3 R6, or a heterocyclic ring system, composed of 5 to 10 atoms including at least one nitrogen, oxygen or sulfur atom, substituted with 0-2 R6;
each R6, when a substituent on carbon, is selected from the group consisting of:
phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C3-C6 cycloalkyl, C3- C6 cycloalkylmethyl, C7-C10 arylalkyl, alkoxy, -NR7R8, C2-C6 alkoxyalkyl, methylenedioxy, ethylene&ioxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4
alkylcarbonylamino, -S(O)mR7, -SO2NR7R8, -NHSO2R8, or R6 may be a 3- or 4- carbon chain attached to adjacent carbons on the ring to form a fused 5- or 6-membered ring, said 5- or 6- membered ring being optionally substituted on the aliphatic carbons with halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, or NR7R8, or when R6 is attached to a saturated carbon atom it may be carbonyl or thiocarbonyl; and
each R6, when a substituent on nitrogen, is selected from the group consisting of:
phenyl, benzyl, phenethyl, hydroxy, C1-C4 alkoxy, nitro, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, -NR7R8, C2-C6 alkoxyalkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, C1-C4
alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4
alkylcarbonyl; -S(O)mR7, -SO2NR7R8, or R6 may be a 3- or 4- carbon chain attached to adjacent atoms on the ring to form a fused 5- or 6-membered ring, said 5- or 6- membered ring being optionally substituted on the
aliphatic carbons with halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, or NR7R8;
R7 is H, benzyl or C1-C6 alkyl;
R8 is H or C1-C4 alkyl;
or R7R8 can join to form (CH2)4, (CH2)5,
(CH2CH2N(R9)CH2CH2), or (CH2CH2OCH2CH2) ;
R9 is H or CH3; and
W is selected from the group consisting of:
-NR8C(=Q)NR12-, -NR12C(=Q)O-, -OC(=Q)NR12-,
-NR12SO2NR12-, -SO2NR12-, -CH2NR12-, or -SO2NHC(=O)NH-.
[D] Still further preferred compounds of the present invention are compounds within the further preferred scope ([C] above) wherein:
R1 is C1-C4 alkyl substituted with:
a C5-C12 carbocyclic residue substituted with 0-2 R6, aryl substituted with 0-2 R6, or a heterocyclic ring system composed of 5 to 10 atoms including at least one nitrogen, oxygen or sulfur atom, substituted with 0-2 R6; R2 and R3 are independently selected from hydrogen, or C1-C4 alkyl substituted with 0-2 R5;
R4 is C1-C4 alkyl substituted with:
a C5-C12 carbocyclic residue substituted with 0-2 R6, aryl substituted with 0-2 R6, or a heterocyclic ring system composed of 5 to 10 atoms including at least one nitrogen, oxygen or sulfur atom substituted with 0-2 R6; each R5 is selected independently from the group consisting of:
keto, halogen, cyano, -NR7R8, -CO2R7, -OR7, C2-C6
alkoxyalkyl, -S(O)mR7, -C(=O)NR7R8, -NR8C(=O)R7-,
NR8C(=O)OR8, NR8SO2R7, -SO2NR7R8, C1-C4 alkyl, C2-C4 alkenyl, or C3-C6 cycloalkyl;
each R6, when a substituent on carbon, is selected from the group consisting of:
phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, C2-C6 alkoxyalkyl, methylenedioxy, C1-C2 haloalkyl, C1-C4 alkoxycarbonyl.
C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, or -NHSO2R8;
each R6, when a substituent on nitrogen, is C1-C4 alkyl, phenyl, benzyl or phenethyl;
R7 is H or C1-C2 alkyl;
R8 is H or C1-C2 alkyl;
or R7R8 can join to form (CH2)4, (CH2)5,
(CH2CH2N(R9)CH2CH2), or (CH2CH2OCH2CH2) ; and
W is selected from the following:
-NR8C(=Q)NR12-, -NR12C(=Q)O, -OC(=Q)NR12, -SO2NR12-, -CH2NR12-.
X is selected from the group consisting of:
-C(=Q)NR12-, -C(=Q)O-, -SO2NR12-, -CH2Q-, or -CH2NR12-. [E] Even further preferred compounds of the present invention are those compounds within the still further preferred scope ([D] above) wherein:
R1 is C1-C4 alkyl substituted with:
aryl substituted with 0-2 R6, or a heterocyclic ring system, composed of 5 to 10 atoms including at least one nitrogen, oxygen or sulfur atom, substituted with 0-1 R6; R3 is C1-C4 alkyl substituted with 0-1 R5;
R4 is C1-C4 alkyl substituted with:
a C5-C12 carbocyclic residue substituted with 0-2 R6 or aryl substituted with 0-2 R6;
each R5 is selected independently from the group consisting of:
halogen, -NR7R8, -CO2R7, -OR7, -NR8C(=O)R7-, NR8C(=O)OR8, NR8SO2R7, -SO2NR7R8, C1-C4 alkyl, or C3-C6 cycloalkyl; each R6, when a substituent on carbon, is selected
independently from the group consisting of:
benzyloxy, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C2 haloalkyl, C1-C4 alkylcarbonylamino or -NHSO2R8;
each R6, when a substituent on nitrogen, is C1-C2 alkyl or benzyl;
m is 2;
n is 0;
W is -NR8C(=Q)NR12-, -OC (=Q)NR12- or -SO2NR12-; and
Y is -C(=Q)NR12-, or -CH2NR12-.
[F] Specifically preferred are the following compounds:
Detailed Description of the Invention Compounds of formula (I) can be prepared in a number of ways well known to one skilled in the art of organic synthesis. Preferred methods include but are not limited to those described below:
Compounds wherein Z is H, n is zero, and Y is
-C(=Q)NR12-, and the other variables are as described above, can be prepared by reaction of the amine (II) with a carboxylic acid or derivative (III):
wherein P is hydrogen or optionally an alcohol protecting group1, R10 is hydrogen or an aliphatic or substituted aromatic group, and the carboxylic acid or ester is activated to nucleophilic attack by methods well known in the art2, with the preferred method employing 1,1'-carbonyldiimidazole as the activating agent, THF as solvent, and 0-40°C as temperature, and P=H. If a
protecting group is necessary, the preferred group is the 2-methoxyethoxymethyl group3.
Removal of the protecting group if employed, followed by oxidation (see below), provides aldehydes (V) and (VI). Examples of compounds that can be made from the above procedures are described in Table 1 and Table 2:
[B] Thioamides of structure (VII) and (VIII) can be made from the above protected hydroxyamides (IV) followed by treatment with a thionation reagent4, and deprotection followed by oxidation to the aldehyde. A preferred thionation reagent is Lawesson's reagent, and a preferred protecting group is the 2-methoxyethoxymethyl group2.
Examples of compounds that can be made by this or very similar methods are shown in Table. 3 and Table 4:
wherein Act is an activating group, preferably chloride, and P is optionally a protecting group.
Removal of the protecting group if employed, followed by oxidation (see below), provides aldehydes (XI) and
(XII). Examples of compounds that can be made by this or very similar methods are shown in Table 5 and Table 6:
Wherein LG is a leaving group such as halogen or OSO2R, as is described in the art6. The preferred method employs a tosylate or iodide as leaving group, and a secondary amine as the nucleophile, i.e., R12 is not hydrogen. A preferred method for the preparation of compounds wherein R12 is hydrogen is simply by LiAlH4 reduction of the amides in
Table I, if hydride-sensitive functionality is not present. A final preferred method is the reaction of amines (II) with aldehydes (XXXIII), followed by reduction of the imine by catalyic hydrogenation or by borohydride reduction of the intermediate imine.
Removal of the protecting group, if employed, followed by oxidation (see below), provides aldehydes (XV) and (XVI).
Examples of compounds that can be prepared by these methods are shown in Table 7:
[E] When Y is -C(Cl)=N-, -C(-OR11)=N-; or
-C(-NR11R12)=N-;
the compounds of the invention can be advantageously prepared by reaction of secondary amides or thioamides (XVII) with halogenating agents to produce imidoyl halides (X)7. The synthesis of amides and thioamides (XVII) is described above (II, R12 = H). See Section [A]. The imidoyl halides so produced can then be reacted with alcohols to produce imidates (XIX)8; or with amines to produce amidines (XX)9, as shown. Preferred halogenating reagents include phosphorous pentachloride and phosphorous oxychloride.
Cleavage of the protecting group and oxidation to the aldehyde as described below produces (XXI), with the indicated Y values. Examples of compounds that can be produced by these or very similar methods are shown in Table V:
When Y is -NR12C(=O)NR12-, the compounds of the invention can be prepared by reacting amine (II) with a derivatizing agent to form the isocyanate or carbamate, followed by reaction with a primary or secondary amine, optionally in the presence of a base10.
When Y is -OC(=O)NR12, the compounds of the invention can be prepared by reacting amine (II) with a derivatizing agent to form the isocyanate, followed by reaction with an alcohol in the presence of a base10.
Cleavage of the protecting group and oxidation to the aldehyde as described below produces (XXIII) , with the indicated Y values . Examples of compounds that can be produced by these or very similar methods are shown in Table 11 and Table 12 :
The product of the above reactions, alcohol or protected alcohol (XXVIII),
can be readily oxidized to aldehyde11 (I), following deprotection if necessary1, by techniques that are well known in the art. Preferred methods include pyridinium dichromate, pyridinium chlorochrornate, pyridine/sulfur trioxide, and activated dimethyl sulfoxide. The preferred method employs dimethylsulfoxide/oxalyl chloride12, also known as Swern oxidation, in dichloromethane or
tetrahydrofuran/dichloromethane at -60°C, followed by treatment with a base such as triethylamine.
While the preferred method of oxidation is gentle and specific, there are functional groups within the
contemplated scope that may not survive such oxidation. Examples of these are primary alcohols, amines, indoles, sulfides, thiols. If necessary, these groups can be protected prior to oxidation of the aldehyde.
Alternatively, the reductive conditions described below may be used to prepare the aldehyde when oxidative conditions cause difficulties with certain functional groups.
Amine (VIII) can be reacted with any of the above electrophiles, (III, IX or XIII) to form N-methoxyamide (XXIX). It is known that (XXIX) can be reduced cleanly to aldehyde by stoichiometric lithium aluminum hydride13, provided that sensitive functionality is not present.
Finally, there are functional groups within the contemplated scope that will survive neither lithium aluminum hydride nor oxidation. In this occasion,
reduction of aminoester (XXX) with one equivalent of diisobutyl aluminum hydride at low temperature14, followed by quenching at low temperature, can provide an alternative to the above conditions.
Preparation of Intermediates
The compounds of the invention can be obtained by reacting an amino alcohol or amino acid derivative (II), (XXIX) or (XXX) , with the appropriate left portion of the molecule, that is, carboxylic acid (III), activated sulfonic acid (IX) and alkyl halide or tosylate (XIII). Methods of preparation of these intermediates are described below.
[G] α-Aminoalcohols, acids and derivatives are well known in the art. Protected aminoalcohols (II) can be obtained from commercially available or prepared amino alcohols (P =H) by employing standard protecting group chemistry as described in Reference (1). However, in most cases the alcohol does not need protection, and (II, P = H) can be used directly in condensation reactions with (III), (IX) and (XIII). Many amino alcohols are commercially
available15; aminoalcohols with values of R4 that are not available can be easily synthesized by reduction of α-amino acids or esters (XXX) . A preferred method is the direct reduction of amino acids employing borane•methyl sulfide in the presence of BF3 etherate16. A plethora of α-amino acids or esters are available17, both natural and unnatural, and simple variations of known preparative methods18 will provide amino acids with any R4 value of interest.
N-methoxyamides (XXIX) can be prepared by techniques known in the art.14
[E] Substituted carboxylic acids (III) can be prepared as follows:
1] when n is O and W is -NR12C(=Q)NR12"' -C(=Q)NR12-, -OC(=Q)NR12-, -NR12SO2NR12-, -SO2NR12-, -NR12- or
-SO2NHC(=O)NH- then (III) can be prepared simply by reacting the amino group of an α-amino acid or ester (XXXI) with one of the following: R1CO2H (XXXII), R1NHR12 (XXXIII), R1OH (XXXIV), R1LG (XXXV) , or RSO2Act (XXXVI)
under the condition described above in sections [A] through [D]. α-amino acid or ester (XXXI) are
commercially available or can be prepared as described in section [G]. (XXXII) through (XXXVI) are for the most part commercially available or can be obtained by
modifications of commercially available starting materials using methods that are well known to one skilled in the art.
2] When W is -C(Cl)=N-, -C(-OR7)-N-, -C(-NR7R12)=N- these compounds can be obtained by reacting the amides or thioamides produced above under the conditions described in section [E].
3] When X is O and W is -C(=Q)O-, -NR8C(=Q)O-; -O-;
-OP(=O) (QR11)O-; -P(=O) (Q1)O-;
then carboxylic acids or esters (III) can be prepared by a number of techniques that are well known in the art.
Preferred is the reaction of a-hydroxy esters or acids (XXXVII) with:
(a) R1-LG under conditions for condensing alcohols with alkyl halides or tosylates19, preferably in the presence of a base, preferably NaH, in a solvent.
preferably a polar aprotic solvent such as pyridine or DMF, where LG is preferably bromide or tosylate;
(b) R1CO2R10 under the well-known conditions suitable for condensing alcohols and acids or esters20, wherein R10 is preferably H , the preferred activating agent is thionyl chloride, and the preferred solvent is dimethyIformamide;
(c) R1NR12C(=O)OR7 or R1N=C=O, under the conditions described in section [F] ;
(d) R1P(=O) (Q1)OR10, under conditions suitable for condensing alcohols and phosphonic acids or esters, wherein R10 is preferably H, the preferred activating agent is thionyl chloride, and the preferred solvent is dimethyIformamide.
The intermediates R1LG, R1CO2R10 R1NR12C(=O)OR7, R1N=C=OR1 and P(=O)(Q1)OR10 are available commercially or by simple modifications to commercially available materials well known to one skilled in the art.
4] When n is O and W is -QCH2-, then (III) can be
prepared by means known in the art. Preferred is the reaction of hydoxypropionic acid or ester (XXXVIII):
with a molecule R1LG (see section [H.3]).
5] When n is 0 and W is -NR12C(=Q), then (III) can be prepared by means known in the art. Preferred is the reaction of malonic half acid (XXXIX) with a group R1NHR12 (see section [H.3]). Many malonic acid derivatives are available commercially; the preparation of other compounds can be accomplished by procedures well known in the art.
The preferred method is the alkylation of the dianion of (XXXIX, R10 = H) with an alkyl chloroformate or dialkyl carbonate21. Many carboxylic acid derivatives (XXXIX) are available commercially; the preparation of other compounds is well known in the art22.
6] When n is O and W is -CHOH-, then (III) can be
prepared by means known in the art. Preferred is the reaction of carboxylic acid (XXXX) with a group R1 CHO (see above) via the well-known aldol condensatic. to form alcohol (XXXXI)23. Preferred is the method employing a bulky R10 group to avoid problems of self-condensation, and the preferred base is lithium diisopropyl amide.
7] When n is O and W is -C(=Q)-, then (III) can be prepared by means known in the art. Preferred is the oxidation of alcohols (XXXXI) prepared in [H.6], above. Preferred oxidation reagents are pyridinium chlorochromate, pyridinium dichromate, or DMSO/oxalyl chloride.
Thionation, preferably with Lawesson's reagent, can provide the thiocarbonyl.
8] When n is O and W is -CHOHCH2-, then (III) can be prepared by means known in the art. Preferred is the reaction of epoxides R1(CH2OCH2) with an organometallic derivative of ester or acid (XXXX)24, preferably the cuprate25. The product is ß-hydroxycarboxyl derivative (XXXXII). Epoxides R1(CH2OCH2) can be prepared by the reaction of R1CHO, see above, with reagents known in the art. The prefered reagent for formation of epoxides from such aldehydes is dimethylsufoxonium methylide26.
Many aldehydes R1CHO are commercially available.
Others can be prepared by standard oxidation of
commercially available alcohols R1CH2OH (see section
[B.3]).
Values of n = O and W = -C(=Q)CH2- are produced by oxidation of (XXXXII) to the carbonyl, followed by
thionation to the thiocarbonyl, as described in [H.7]. 9] When n is O and W is -CH=CH-, then (III) can be prepared by means known in the art. Preferred is the well-known Wittig reaction of ylides R1=P(Ar)3 with an aldehyde
(XXXXIII)27. Said ylides can be prepared by the reaction of R1LG, see [H.3], with reagents (Ar)33P under conditions known in the art, preferably employing the condensation of triphenylphosphine and a primary alkyl bromide, followed by treatment with sodium hydride. The malonaldehydes
substituted with R3 can be prepared from the malonic acid derivatives discussed above, preferably by diborane/methyl sulfide reduction of the malonic half acid to the alcohol, followed by oxalyl chloride/dimethyl sulfoxide oxidation to the aldehyde.
10] When n is O and W is -CH2CH2-, then (III) can be prepared by means known in the art. Preferred is the catalytic hydrogenation of the olefins (XXXXIV) produced in [H.9], above28. Advantageous reagents are 10% palladium on carbon with ethanol or ethanol/THF as solvent under 50-100 PSI hydrogen gas.
11] When n is O and W is -CH(OH)CH(OH)- then (III) can be prepared by means known in the art. Preferred is the osmylation of olefins (XXXXIV) produced in [H.9], above. Advantageous reagents are catalytic osmium tetroxide in the presence of N-methylmorpholine-N-oxide29.
12] When n is O and W is -NHNH-, then (III) can be
prepared by means known in the art. Preferred is the reaction of aldehyde (XXXXIII), prepared as described in
[H.9] above, with sym-dimthylhydrazine followed by
hydrazine to form hydrazone (XLV)30. Alkylation of (XLV), preferably with an alkyl bromide or tosylate, followed by hydride or catalytic reduction of the substituted
hydrazone, preferably with sodium borohydride,provides disubstituted hydrazine (XLVI).
13] When n is O and W is -C(=O)NHNH-, then (III) can be prepared by means known in the art. Preferred is the acylation of hydrazone (XLV) with activated carboxylic acid R1COAct, wherein Act is preferably chloride. Hydride or catalytic reduction of the substituted hydrazone,
preferably with sodium borohydride, provides substituted hydrazide (XLVII).
The carbonyl compounds produced above can be reacted with thionation reagents as described in the art and as discussed in section [B] when values of Q = S are desired. When (III) is produced as an ester and needs to be
converted to an acid for reaction with (II), standard saponification or de-esterification as known in the art31 can be employed. Some of the above values of R may have
functional groups that are sensitive to the reaction conditions described in section [H]. Should this be the case, standard protecting group chemistry1 will obviate any difficulties.
[I] Substituted sulfonic acids and derivatives (IX) can be prepared as follows.
1] when n is O and W is -NR12C(=Q)NR12-, -C(=Q)NR12-;
-OC(=Q)NR12-, -NR12SO2NR12-, -SO2NR12-, -NR12-, or - SO2NHC(=O)NH- then (III) can be prepared simply by reacting an the amino group of α-amino sulfonic acid, amide or ester (XXXXVI, J =
H, OR7,NR11R12)
with one of the following R1CO2H (XXXII), R1NHR12 (XXXIII), R1OH (XXXIV), R1LG (XXXV); or RSO2Act (XXXVI)
under conditions described above in sections [A] through [D]. The preferred method employs the t-butyl
sulfonamide, (XXXXVI, J = NH-t-Bu), which is readily formed, protects the sulfonic acid from unwanted side reactions, and is readily cleaved with aqueous hypochlorite ion.
α-Aminosulfonic acids are readily available by the reaction of aldehydes R3CHO and amines R12NH2 in the presence of sodium bisulfite.32 This procedure is general
for aromatic or aliphatic amines and aldehydes and proceeds in good yields. The preparation of R1 derivatives (XXXI) through (XXXVI) are commercially available or can be prepared as described in section [H]. Cleavage of the t-butylsulfonamide or other protecting can yield the sulfonic acid or directly provide the sulfonyl chloride (IX, Act - Cl) on treatment with aqueous hypochlorite.
2] When W is -C(Cl)=N-, -C(-OR7)=N-, or -C(-NR7R8)=N-, these compounds can be obtained by reacting the amides or thioamides produced in section [I.1], above, under the conditions described in section E.
3] When X is O and W is -C(=Q)O-, -NR12C(=Q)O-, -O-,
-OP(=O) (QR11)O-, or -P(=O)(Q1) O-,
then sulfonic acids or esters (IX) can be prepared by a number of techniques that are well known in the art.
Preferred is the reaction of α-hydroxy sulfonamides
(XXXXVII, J = e.g. N-t-Bu)
with:
(a) R1LG under conditions for condensing alcohols with alkyl halides or tosylates19, preferably in the presence of a base, preferably NaH, in a solvent, preferably a polar aprotic solvent such as pyridine, where LG is preferably tosylate;
(b) R1CO2R10 under conditions suitable for condensing alcohols and acids or esters20, wherein R10 is
preferably H, the preferred activating agent is thionyl chloride, and the preferred solvent is
dimethyIformamide;
(c) R1NR12C (=O)OR7 or R1N=C=O, under the conditions described in section [F];
(d) R1P (=O)(Q1)OR10, under conditions suitable for condensing alcohols and phosphonic acids or esters, wherein R10 is preferably H, the preferred activating agent is thionyl chloride, and the preferred solvent is dimethylformamide.
The intermediates R1LG, R1CO2R10 R1NR12C(=O)OR7, R1N=C=OR1 and P(=O)(Q1)OR10 are available commercially or by simple modifications to commercially available materials well known to one skilled in the art.
α-Hydroxysulfonic acids derivatives (XXXXVII) are available by techniques well known in the art. The
preferred method reacts bisulfite or sulfur dioxide with aldehydes R3CHO to form the sulfonic acid. Conversion to the sulfonyl chloride and then the sulfonamide follows standard procedures33. Many aldehydes R3CHO are
commercially available, others can be made by simple modification of commercially available alcohols, acids, and the like.
4] When n is O and W is -QCH2-, then sulfonic acids (IX) can be prepared by means known in the art. Preferred is the reaction of ß-hydroxysulfonic acid derivative
(XXXXVIII)
with a molecule R1LG (see section [H.3]). The ß- hydroxysulfonamide (XXXXVII, J = NH-t-Bu) is more preferred as a protected derivative for ease of use, as discussed above.
5] When n is O and W is -NR12C (=Q) , then sulfonic acids (IX) can be prepared by means known in the art. Preferred
is the reaction of ß-carboxysulfonic acid derivative
(XXXXIX)
with a group R1NHR12 (see section [H.3]). The preparation of other compounds can be accomplished by procedures well known in the art. The preferred method is the alkylation of the anion of (XXXXIXA) with alkyl chloroformates or dialkyl carbonates.20
6] When n is O and W is -CHOH-, then (IX) can be prepared by means known in the art. Preferred is the reaction of sulfonamide (L) with a group R1CHO (see above) in the presence of base to form alcohol (LI). Preferred is the method employing J = NH-t-Bu, and the preferred base is sodium hydride. Another advantageous method is the reaction of sulfite ion with epoxides, R1-(CHOCH)-R3 34. Many sulfonic acids (L) are available commercially; the preparation of other compounds is well known in the art. The preferred method is the reaction of alkyl halides R1X with sulfite ion35. Derivitization to values of J other than hydrogen is also well known35.
7] When n is O and W is -C(=Q)-, then (IX) can be
prepared by means known in the art. Preferred is the
oxidation of alcohols (LII) prepared in [I.6], above. Preferred oxidation reagents are pyridinium
chlorochromate, pyridinium dichromate, or DMSO/oxalyl chloride. Thionation, preferably with Lawesson's reagent, can provide the thiocarbonyl.
8] When n is O and W is -CHOHCH2-, then (IX) can be prepared by means known in the art. Preferred is the reaction of epoxides R1(CH2OCH2) with the dianion of sulfonamide (L), preferably the dianion formed by
treatment with two equivalents of a base such as lithium diisopropyl amide. The product is ß-hydroxysulfonyl derivative (LIII). Epoxides R1(CH2OCH2) can be prepared by the methods described in section [H.8].
Values of n = O and W = -C(=Q)CH2- are produced by
oxidation of (LIII) to the carbonyl, followed by
thionation to the thiocarbonyl, as described in [H.7]. 9] When n is O and W is -CH=CH-, then (IX) can be
prepared by means known in the art. Preferred is the well-known Wittig reaction of ylides R1=P(Ar)3 with an aldehyde (LIV), as described in section [H.9]. The sulfonaldehydes substituted with R3 can be prepared from
the sulfonic acid derivatives discussed above, preferably by diborane/methyl sulfide reduction of the sulfonamide to the alcohol, followed by oxalyl chloride/dimethyl
sulfoxide oxidation to the aldehyde.
10] When n is O and W is -CH2CH2-, then (IX) can be prepared by means known in the art. Preferred is the catalytic hydrogenation of the olefins (LV) produced in
[I.9], above. Advantageous reagents are 10% palladium on barium sulfate with ethanol or ethanol/THF as solvent under 50-100 PSI hydrogen gas.
11] When n is O and W is -CH(OH)CH(OH)- then (IX) can be prepared by means known in the art. Preferred is the osmylation of olefins (LV) produced in [1.9], above.
Advantageous reagents are catalytic osmium tetroxide in the presence of N-methylmorpholine-N- oxide, as discussed in section [H.11].
12] When n is O and W is -NHNH-, then (IX) can be
prepared by means known in the art. Preferred is the reaction of aldehyde (LIV), prepared as described in [1.9] above, with sym-dimethylhydrazine followed by hydrazine and reduction to form the disubstituted hydrazine, as described in section [H.12].
13] When n is O and W is -C(=O)NHNH-, then (III) can be prepared by means known in the art. Preferred is the
acylation of the intermediate hydrazone as described in section [H.13].
The carbonyl compounds produced above can be reacted with thionation reagents as described in the art and as discussed in section [B] when values of Q = S are desired. When (III) is produced as an ester and needs to be
converted to an acid for reaction with (II), standard saponification or de-esterification as known in the art can be employed, as discussed at the end of section [H]. Some of the above values of R may have functional groups that are sensitive to the reaction conditions described in section [I]. Should this be the case, standard protecting group chemistry1 will obviate any difficulties.
[J]. Leaving-group substituted derivatives (XIII) can be prepared by means known to one skilled in the art.
The preferred method employs the reduction of
carboxylic acid (III, R10 = H; preparation described in section [H])
to the alcohol, preferably via diborane/methyl sulfide, followed by activation of the alcohol, preferably as the tosylate or mesylate, or displacement with halogen,
preferably to form the bromide. The preferred reagent for
the latter reaction is phosphorous tribromide. Another preferred technique is the displacement of tosylate or bromide so formed with sodium iodide/dimethyl sulfoxide, and employing the alkyl iodide as the electrophile.
Some of the above values of R may have functional groups that are sensitive to the reaction conditions described in section [I]. Should this be the case, standard protecting group chemistry1 will obviate any difficulties.
* * * * * * * * * * * * * * * * * * * *
Procedure I: Preparation of I ntermediates
N-Carbobenzyloxyalanine (6.63 g, 29.7 mmol; Sigma Chemical Company) was dissolved in 30 mL THF in a 100 mL oven-dried flask under N2 and stirred at room temperature while adding 1,1'-carbonyl diimidazole (4.82 g, 29.7 mmol; Aldrich
Chemical Company) neat. Copious bubbling occurred,
indicating CO2 formation. The mixture was stirred 30 minutes and (s)-2-amino-1-phenylpropanol (4.5 g, 29.7 mmol; Sigma Chemical Company) was added neat. Stirring was continued for 18 hours.
The mixture was poured into a separatory funnel and the flask rinsed with dichloromethane. 100 mL of
dichloromethane was added, and 50 mL saturated aqueous disodium-L-tartaric acid. The funnel was shaken, the aqueous layer removed, the organic layer washed with saturated bicarbonate and brine, and dried with magnesium sulfate. Filtration and solvent removal yielded a white solid. Recrystallization by dissolving in hot ethyl acetate, filtering, and adding hexane until cloudy provided 6.76 g (64%) white crystals with properties consistent with alcohol (III).
Melting Point: 120-121°C
NMR (300 MHz, CDCI3) ; 8, ppm: 7.1-7.5 (m, 10 H); 6.45
(broad d, 1H, NH) ; 5 .35 (d, 1H, NH) ; 5 .1 (broad s , 2H,
OCH2Ph) ; 4 .1-4.2 (m, 2H, alanine α-CH) ; 3. 6 (m, 2H, CH2OH) ;
2.85 (m, 2H, phenylalaninol ß-CH2); 1.2-1.4 (d, 3H,
methyl). Using the above conditions, the following a-aminoalcohols were prepared:
D :
Melting Point: 158-160°C
NMR (300 MHz, CDCI3): 7.1-7.6 (m, 10 H) ; 6.2 (broad d, 1H, NH); 5.25 (d, 1H, NH); 5.1 (broad s, 2H, 0CH2Ph); 4.2 (m, 1H, isoleucine α-CH); 3.95 (dd, 1H, isoleucine α-CH); 3.6
(m, 2H, CH2OH); 2.85 (m, 2H, phenylalaninol ß-CH2); 1.85 (m, 2H, isoleucine methylene) 1.3 (m, 1H, isoleucine
methine); 0.8-1.1 (m, 6H, methyls).
E.
Melting point: 159-160°C
NMR (300 MHz, DMSO-d6; mixture of isomers; major isomer): 7.6-7.9 (m, 2H, NH); 7.1-7.3 (M, 5H, aromatic); 4.75 (dd, 1H, valine α-CH); 3.8-4.2 (m, 2H, phenylalaninol α-CH,
OH); 3.2-3.4 (m, 2H, CH2OH) ; 2.6-2.9 (m, 2H, phenylalaninol ß-CH2); 1.85 (3H, acetyl); 0.8 (6H, dd, valine methyls).
F.
Melting Point 173-180°C
NMR (300 MHz, DMSO-d6) : (m, 7.65, 1H, NH) ; 7.2-7.4 (11H, m, aromatic and NH); 5.05 (2H, m, OCH2); 3.9 (m, 1H, CH2OH); 3.8 (dd, 1H, isoleucine α-CH); 3.35-3.5 (m, 2H, CH2OH); 2.6-2.9 (m, 2H, phenylalaninol ß-CH2) ; 1.6 (m, 2H,
isoleucine methylene)1.3 (m, 1H, isoleucine methine); 0.8- 1.1 (m, 6H, methyls) .
G.
Melting point 147.5-149.5°C
NMR (300 MHz, DMSO-d6): 7.65 (d, 1H, NH); 7.2-7.4 (6H, m, aromatic and NH); 5.05 (2H, m, OCH2); 4.7 (dd, 1H,
isoleucine α-CH); 3.8 (m, 1H, methionine α-CH); 3.25-3.4
(m, 2H, CH2OH); 2.3-2.5 (m, 2H, methione g-CH2); 1.9 (s, 3H, SCH3); and 0.7-1.9, aliphatics.
H:
NMR (300 MHz, CDCI3): 7.2-7.2 (m, 10H, aromatic); 6.2 (d, 1H, NH); 5.1-5.2 (m, 3H, OCH2, NH) ; 4.15 (m, 1H,
phenylalaninol α-CH) 3.95 (dd, 1H, valine α-CH); 3.5-3.7 (m, 2H, CH2OH); 2.8-2.9 (m, 2H, phenylalaninol ß-CH2); 2.1 (m, 1H, valine ß-CH); 0.9 (d, 3H, methyl); 0.8 (d, 3H, methyl). Procedure II: Synthesis of Aldehydes
A nitrogen-filled, oven-dried 500 mL flask was charged with 35 mL CH2CI2 and 2.90 g oxalyl chloride (25.25 mmol) under N2 and cooled to -60. Dry dimethylsulfoxide (2.42 g, 33.6 mmol) in 40 mL CH2CI2 was added over about 10 min.
The mixture was stirred 15 min at -60, and alcohol C (6.00 g, 16.8 mmol) was added in 100 mL 1:1 THF/CH2CI2.
After stirring 25 min at -60, triethylamine (6.8 g, 67.2 mmol) was added in 20 mL CH2Cl2.
Stirred 30 min at -60 and quenched with 20% aqueous KHSO4 (150 mL) at -60. A white solid formed as water froze.
Added 180 mL hexane and warmed to RT. Separated aqueous layer and washed with ether. Combined organic layers, filtered off white solid (presumably unreacted, insoluble starting alcohol) and washed with sat. aq. NaHCO3, water and brine, and dried over MgSO4. Yield: 5.12 g white solid. Analytically pure sample can be obtained by
recrystallization from EtOAc/hexane, but the aldehyde is very readily epimerized at the α-carbon, and a small amount of the S,R isomer is generally observed after workup or other manipulation.
Melting Point: 125-126°C
NMR (300 MHz, CDCI3): 9.6 (br s, 1H, CHO); 7.1-7.4 (m, 10H, aromatic); 6.5 (br, 1H, NH); 5.1-5.2 (m, 3H, NH and OCH2); 4.65 (m, 1H, phenylalaninal α-CH); 4.25 (m, 1H, alanine α-CH); 3.15 (m, 2H, phenylalaninal ß-CH2); 1.35 (d, 3H, CH3).
Using the above procedure, the following aminoaldehydes were prepared:
J:
Melting Point 116-117°C NMR (300 MHz, CDCI3): 9.6 (br s, 1H, CHO); 7.1-7.5 (m, 10H, aromatic); 6.45 (br d, 1H, NH); 5.1-5.2 (m, 3H, NH and OCH2); 4.65 (m, 1H, phenylalaninal α-CH); 4.1 (m, 1H,
isoleucine α-CH); 3.15 (m, 2H, phenylalaninal ß-CH2); 1.85
(m, 2H, isoleucine methylene) 1.4 (m, 1H, isoleucine ß- CH2); 0.8-1.1 (m, 6H, methyls) .
MS (FAB) : M+H (measured) 397.21; (calculated) 397.17
K:
NMR (300 MHz, CDCl3) : 9.6 (br s, 1H, CHO); 7.1-7.4 (m, 10H, aromatic); 6.4 (br d, 1H, NH) ; 5.1-5.2 (m, 3H, NH and OCH2); 4.75 (m, 1H, phenylalaninal α-CH); 4.0 (m, 1H, valine α-CH); 3.15 (m, 2H, phenylalaninal ß-CH2); 2.1 (m, 1H, valine ß-CH); 0.8-1.0 (m, 6H, methyls).
MS (FAB): M+H (measured) 383.13; (calculated) 383.20
L:
NMR (300 MHz, CDCI3) : 9.6 (br s, 1H, CHO)
M:
NMR (300 MHz, CDCI3) : 9.6 (br s, 1H, CHO); 7.1-7.5 (m, 10H, aromatic); 6.45 (br d, 1H, NH) ; 5.1-5.2 (m, 3H, NH and OCH2); 4.7 (m, 1H, 4-chlorophenylalaninal α-CH); 4.1 (m.
1H, isoleucine α-CH); 3.1 (m, 2H, 4-chlorophenylalaninal ß- CH2); 1.85 (m, 2H, isoleucine methylene) 1.4 (m, 1H, isoleucine ß-CH2); 0.8-1.1 (m, 6H, methyls).
N:
NMR (300 MHz, DMSO-d6; mixture of isomers; major isomer): 9.4 (s, 1H, CHO).
Biological Tests
Standard procedures were used for detecting and comparing the activity of the compounds of this invention. The results are summarized in Table IV.
Procedure III: Cell Free Proteaae Inhibition Assay
Materials: HIV gag polyprotein corresponding to all of pl7 and 78 amino acids of p24, produced by in vitro translation using rabbit reticulocyte lysate and mRNA prepared in vitro from plasmid encoding full length gag polyprotein linerized with the restriction enzyme Pst 1. (See S. Erickson-Viitanen et al.. Aids Research and Human Retroviruses, 5 (6), 577
(1989) for plasmid construction, and basis for assay).
Source of protease: Either (A) crude E. coll lysate of bacteria harboring a plasmid containing HIV protease under the control of the lac prombtor, used at a final concentration of 0.5 mg/ml, or (B) inclusion bodies of E. coli harboring plasmid containing HIV protease under the control of the T7 promotor (Cheng et al., Gene, in press (1990). Such inclusion bodies were solubilized in 8 M
urea, 50 mM Tris pH 8.0. Protease activity was recovered by dilution of the inclusion bodies 20-fold in buffer containing 50 mM Sodium Acetate, pH 5.5, ImM EDTA, 10% glycerol and 5% ethylene glycol. This protease source was used at a final concentration of 0.00875 mg/ml.
Inhibitory compounds were dissolved in sufficient DMSO to make a 2.5 mM stock concentration. All further
dilutions were done in DMSO.
Set Up Into sterile test tubes were placed the
following:
1 uL inhibitor dilutions
14 ul HIV protease in Phosphate Buffered Saline (20 mM Sodium Phosphate, 0.15.M NaCl, pH 6.5).
5 ul of in vitro translation products.
Reactions were incubated at 30°C, then quenched by the addition of Sample buffer. See U. K. Laemmli, Nature, 1970, 227:680-685.
One fourth of each sample was analyzed on an 8-16% gradient denaturing acrylamide gel (Novex, Inc), according to Laemmli. Following electrophoresis, gels were fixed, impregnated with Enhance (Du Pont NEN, Boston, MA) and dried according to manufacturers instructions (NEN). Dried fluorographs were exposed to film and/or quantitated using an Ambis radioanalytic scanner.
Each group of test compounds was compared to the values obtained for pepstatin, a well known inhibitor of acid proteases. Inhibitory concentration for 50%
inhibition (IC50) is determined from plots of log
concentration inhibitor versus % inhibition of protease activity.
Biological Activity: IC50 is the concentration
necessary for reducing the activity of the enzyme by 50%.
HIV YIELD REDUCTION CELL ASSAY
Materials:
MT-2, a human T-cell line, was cultured in RPMI medium supplemented with 5% (v/v) heat inactivated fetal calf serum (FCS), L-glutamine and gentamycin. Human
immunodeficiency virus strains, HIV(3B) and HIV(Rf) were propagated in H-9 cells in RPMI with 5% FCS. Poly-L-lysine (Sigma) coated cell culture plates were prepared according to the method of Harada et al. (Science 1985 229:563-566). MTT, 3-(4,5-dimethyl-thiazol-2yl)-2,5-diphenyltetrazolium bromide, was obtained from Sigma.
Method:
Test compounds were dissolved in dimethylsulfoxide to 5 mg/ml and serially diluted into RPMI medium to ten times the desired final concentration. MT-2 cells (5 × 10E5/ml) in 2.3 ml were mixed with 0.3 ml of the appropriate test compound solution and allowed to sit for 30 minutes at room temperature. HIV(3b) or HIV(Rf) (~5 × 10E5 plaque forming units/ml) in 0.375 ml was added to the cell and compound mixtures and incubated for one hour at 36°C. The mixtures were centrifuged at 1000 rpm for 10 minutes and the
supernatants containing unattached virus were discarded. The cell pellets were suspended in fresh RPMI containing the appropriate concentrations of test compound and placed in a 36°C, 4% CO2 incubator. Virus was allowed to
replicate for 3 days. Cultures were centrifuged for 10 minutes at 1000 rpm and the supernatants containing cell free progeny virus were removed for plaque assay.
The virus titers of the progeny virus produced in the presence or absence of test compounds were determined by plaque assay. Progeny virus suspensions were serially diluted in RPMI and 1.0 ml of each dilution was added to 9 ml of MT-2 cells in RPMI. Cells and virus were incubated for 3 hours at 36°C to allow for efficient attachment of the virus to cells. Each virus and cell mixture was
aliquoted equally to two wells of a six well poly-L-lysine coated culture plate and incubated overnight at 36°C, 4% CO2. Liquid and unattached cells were removed prior to the addition of 1.5 ml of RPMI with 0.75% (w/v) Seaplaque agarose (FMC Corp) and 5% FCS. Plates were incubated for 3 days and a second RPMI/agarose overlay was added. After an additional 3 days at 36°C, 4% CO2, a final overlay of phosphate-buffered saline with 0.75% Seaplaque agarose and Img MTT/ml was added. The plates were incubated overnight at 36°C. Clear plaques on a purple background were counted and the number of plaque forming units of virus was
calculated for each sample. The antiviral activity of test compounds was determined by the percent reduction in the virus titer with respect to virus grown in the absence of any inhibitors.
HIV Low Multiplicity Assay
Materials:
MT-2, a human T-cell line, was cultured in RPMI medium supplemented with 5% (v/v) heat inactivated fetal calf serum (FCS), L-glutamine and gentamycin (GIBCO).
Human immunodeficiency virus strains HIV(3b) and HIV (Rf) were propagated in H-9 cells in RPMI with 5% FCS. XTT, benzene-sulfonic acid, 3,3'-[1-[(phenyl-amino)carbonyl]-3,4-tetrazolium]bis(4-methoxy-6-nitro)-, sodium salt, was obtained from Starks Associates, Inc.
Method:
Test compounds were dissolved in dimethyl-suIfoxide to 5 mg/ml and serially diluted into RPMI medium to ten times the desired final concentration. MT-2 cells (5 × 10E4/0.1 ml) were added to each well of a 96 well culture plate and 0.02 ml of the appropriate test compound solution was added to the cells such that each compound concentration was present in two wells. The cells and compounds were allowed to sit for 30 minutes at room temperature. HIV(3b) or HIV(Rf) (~5 × 10E5 plaque forming units/ml) was diluted in
medium and added to the cell and compound mixtures to give a multiplicity of infection of 0.01 plaque forming
unit/cell. The mixtures were incubated for 7 days at 36°C, during which time the virus replicated and caused the death of unprotected cells. The percentage of cells protected from virus induced cell death was determined by the degree of metabolism of the tetrazolium dye, XTT. In living cells, XTT was metabolized to a colored formazan product which was quantitated spectrophotometrically at 450 nm. The amount of colored formazan was proportional to the number of cells protected from virus by the test compound. The concentration of compound protecting either 50% (IC50) or 90% (IC90) with respect to an uninfected cell culture was determined.
Examples I, J, K, L, M and N show activity in ther above tests. Examples J and K show cell free enzyme inhibition IC50's of less than 5 μg/mL in the HIV low multiplicity assay.
Footnotes
1 Greene, Protective Groups in Organic Synthesis. Wiley, New York, 1981, pp. 14-71
2 Bodanszky and Bodanszky, The Practice of Peptide
Synthesis, Springer-Verlag, Brlin, 1984, Chapter II, pp. 89-150
3 Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1981, p. 19
4 Pedersen, Scheibye, Nilsson and Lawesson, Bull. Chim.
Soc. Beiges 87, 223 (1978)
5 March, Advanced Organic Chemistry, Wiley, New York, 1985, p 445
6 March, Advanced Organic Chemistry, Wiley, New York, 1985, p. 798
7 Gautier, Miocque and Farnoux, in The Chemistry of
Amidines and Imidates, Patai, Ed., Wiley, London, 1975, pp. 297-301
8 Gautier, Miocque and Farnoux, in The Chemistry of
Amidines and Imidates, Patai, Ed., Wiley, London, 1975, pp. 398-405
9 Gautier, Miocque and Farnoux, in The Chemistry of
Amidines and Imidates. Patai, Ed., Wiley, London, 1975, pp. 297-301
10 Satchell and Satchell, Chem. Soc. Rev.. 4, 231-250
(1975)
11 March, Advanced Organic Chemistry, Wiley, New York,
1985, pp. 1057-1060
12 For a recent review, see Tidwell, Synthesis 857 (1990)
13 Fehrentz and Castro, Synthesis 676 (1990)
14 Kawamura et al., Chem. Pharm. Bull . 17, 1902 (1969)
15 For example, see the Aldrich Catalog Handhook of Fine
Chemicals, 1990
16 Smith and Gawley, Organic Synthesis, Vol. 63 p. 136
17 For example, see the Sigma Chemical Company Catalog, 1990
18 References for the preparation of thousands of natural and unnatural amino acids can be found in The Peptides.
5, E. Gross, Ed., Academic Press, New York, 1983 (pp. 341-429)
19 March, Advanced Organic Chemistry, Wiley, New York,
1985, pp. 342-344
20 Buehler and Pearson, Survey of Organic Synthesis 2, John Wiley, New York, 1977 pp. 715-719
21 Krapcho, Jahngen and Kashdan, Tetrahedron Lett. 2721 (1974)
22 Buehler and Pearson, Survey of Organic Synthesis 2, John Wiley, New York, 1977 pp. 655-781
23 March, Advanced Organic Chemistry, Wiley, New York,
1985, p. 835
24 Kharasch and Rheinmuth, Grignard Reactions of Nonmetallic Substances. Prentice-Hall, Englewood Cliffs,
New Jersey, 1954, pp. 961-1012; Schrumpf et al.,
J. Chem. Res . , Synop . 162 (1982)
25 Huynh, Derguini-Boumechal, and Linstrumelle,
Tetrahedron Lett . 1503 (1979)
26 March, Advanced Organic Chemistry. Wiley, New York,
1985, pp. 864-866, and references therein
27 March, Advanced Organic Chemistry, Wiley, New York,
1985, pp. 845-854, and references therein
28 Techniques for catalytic hydrogenation conditions and choice of catalyst are described in detail in House, Modern Synthetic Reactions. 2nd Ed., Benjamin/Cummings,
Menlo Park, California, 1972, pp. 1-34
29 NanRheenen, Kelly and Cha, Tetrahedron Lett . , 1973
(1976); Ray and Matteson, Tetrahedron Lett . , 449 (1980)
30 March, Advanced Organic Chemistry. Wiley, New York,
1985, p. 605, and references therein
31 Buehler and Pearson, Survey of Organic Synthesis 2,
John Wiley, New York, 1977 p. 658, and references therein
Nellakantan and Hartung, J . Org. Chem. 24, 1943
(1959) ; Frankel and Moses, Tetrahedron 9, 289 (1960) ; Chem. Ind. 1942 (1967)
March, Advanced Organic Chemistry. Wiley, New York,
1985, pp. 444-445, and references therein
Yoneda, Griffin and Carlyle, J. Org. Chem. 40, 375 (1975) Gilbert, Sulfonation and Related Reactions,
Interscience, New York, 965, pp. 136-148, 161-163
Claims (1)
- WHAT IS CLAIMED IS:1. A compound of the formula:or a pharmaceutically acceptable salt, prodrug, chiral, diastereomeric or racemic form thereof wherein:R1, R2, R3 and R4 are independently selected from the group consisting of:hydrogen, C1-C8 alkyl substituted with 0-3 R5, C2-C8 alkenyl substituted with 0-3 R5, C3-C8 alkynyl substituted with 0-3 R5, C3-C8 cycloalkyl substituted with 0-3 R5, C6-C10 bicycloalkyl substituted with 0-3 R5, aryl substituted with 0-3 R6, a C6-C14 carbocyclic residue substituted with 0-3 R6, a heterocyclic ring system composed of 5 to 10 atoms including at least one nitrogen, oxygen or sulfur atom substituted with 0-2 R6, or any naturally occurring amino acid;R2A, R3A and R4A are independently selected from the following group consisting of:hydrogen, C1-C4 alkyl, or benzyl;each R5 is selected from the group consisting of:keto, halogen, cyano, -NR7R8, -CO2R7, -OC(=O)R7, -OR7, C2-C6 alkoxyalkyl, -S(O)mR7, -NHC(=NH)NHR7,-C(=NH)NHR7, -C(=O)NR7R8, -NR8C(=O)R7-, NR8C(=O)OR8,OC(=O)NR7R8, -NR8SO2NR7R8, -NR8SO2R7, -SO2NR7R8, C1-C4 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, C3-C6cycloalkylmethyl, a C5-C14 carbocyclic residuesubstituted with 0-3 R6, aryl substituted with 0-3 R6, or a heterocyclic ring system composed of 5 to 10 atoms including at least one nitrogen, oxygen or sulfur atom, substituted with 0-2 R6;R6, when a substituent on carbon, is selected from the group consisting of:phenyl, benzyl, phenethyl, phenoxy, benzyloxy,halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, C7-C10 arylalkyl, alkoxy, -NR7R8, C2-C6 alkoxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1- C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, -S(O)mR7, -SO2NR7R8, -NHSO2R8, or R6 may be a 3- or 4- carbon chain attached to adjacent carbons on the ring to form a fused 5- or 6- membered ring, said 5- or 6- membered ring being optionally substituted on the aliphatic carbons with halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, or NR7R8, or when R6 is attached to asaturated carbon atom it may be carbonyl orthiocarbonyl;R6, when a substituent on nitrogen, is selected from the group consisting of:phenyl, benzyl, phenethyl, hydroxy, C1-C4 alkoxy, nitro, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, -NR7R8, C2-C6 alkoxyalkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonyl; -S(O)mR7, -SO2NR7R8, or R6 may be a 3- or 4- carbon chain attached to adjacent atoms on the ring to form a fused 5- or 6- membered ring, said 5- or 6- membered ring beingoptionally substituted on the aliphatic carbons with halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, or NR7R8; R7 is H, phenyl, benzyl or C1-C6 alkyl;R8 is H or C1-C4 alkyl;or R7R8 can join to form (CH2)4, (CH2)5,(CH2CH2N(R9)CH2CH2), Or (CH2CH2OCH2CH2) ; R9 is H or CH3;R11 is H, phenyl, benzyl or C1-C6 alkyl;R12 is H or C1-C4 alkyl;m is 0, 1 or 2;n is 0 or 1;W is selected from the group consisting of:-NR12C(=Q)NR12-, -C(=Q)NR12-, -C(=Q)O-, -NR12C(=Q)O-, -OC(=Q)NR12-, -NR12C(=Q)-, -C(=Q)-, -C(=Q)CH2-,-NR12SO2NR12-, -NR12SO2-, -SO2NR12-, -SO2-, -QCH2-, -Q-, -CH2NR12-, -CH2CH2-, -CH-CH-, -CH(OH)CH(OH)-,-CH(OH)CH2-, -CH2CH(OH)-, -CH(OH)-, -NH-NH-,-C(=O)NH-NH-, -C(Cl)=N-, -C(-OR11)=N-, -C(-NR11R12)=N-, -OP(=O)(Q1)O-, -P(=O) (Q1)O-, -SO2NHC(=O)NH-;X is selected from the group consisting of:-C(=Q)NR12-, -C(=Q)O-, -C(=Q)-, -CH2C(=Q)-,-CH2C(=Q)CH2-, -C(=Q)CH2-, -SO2NR12-, -SO2-, -CH2QCH2-, -CH2Q-, -CH2NR12-, -CH2CH2-, -CH-CH-, -CH(OH)CH(OH)-, -CH(OH)CH2-, -CH2CH(OH)-, -CH(OH)-, -C(-O)NH-NH-,-C(-OR11)=N-, -C(-NR11R12)-N-, -C(Cl)=N-;Y is selected from the group consisting of:-C(=Q)NR12-, -SO2NR12-, -CH2NR12-, -C(Cl)=N-,-C(-OR11)=N-, -C(-NR11R12)=N-, -NR12C(=O)NR12-,-OC(=O)NR12-;Q is selected from oxygen or sulfur; andQ1 is selected from oxygen, sulfur, NR8 or a direct bond.2. A compound of Claim 1 wherein:R1, R2, R3 and R4 are independently selected from the group consisting of:hydrogen, C1-C8 alkyl substituted with 0-3 R5, C2-C8 alkenyl substituted with 0-3 R5, C3-C8 cycloalkyl substituted with 0-3 R5, C6-C10 bicycloalkyl substituted with 0-3 R5, aryl substituted with 0-3 R6, a C6-C14 carbocyclic residue substituted with 0-3 R6, or a heterocyclic ring system composed of 5 to 10 atoms including at least one nitrogen, oxygen or sulfur atom substituted with 0-2 R6;R2A, R3A and R4A are hydrogen;R5, R6, R7, R8, and R9 are as defined above;R11 is H;R12 is H;m is 0, 1 or 2;n is 0 or 1;W is selected from the following:-NR12C(=Q)NR12-, -C(=Q)NR12-, -C(=Q)O-, -NR12C(=Q)O-, -OC(=Q)NR12-, -NR12C(=Q)-, -C(-Q)-, -C(=Q)CH2-,-NR12SO2NR12-, -NR12SO2-, -SO2NR12-, -SO2-, -QCH2-, -Q-, -CH2NR12-, -CH2CH2-, -CH=CH-, -CH(OH) CH(OH) -,-CH(OH)CH2-, -CH2CH(OH)-, -CH(OH)-, -OP(=O)(Q1)O-,-P(-O) (Q1)O-, or -SO2NHC(=O)NH-;X is selected from the group consisting of:-C(=Q)NR12-, -C(=Q)O-, -C(=Q)-, -CH2C(=Q)-,-CH2C(=Q)CH2-, -C(=Q)CH2-, -SO2NR12-, -SO2-, -CH2QCH2-, -CH2Q-, -CH2NR12-, -CH2CH2-, -CH-CH-, -CH(OH)CH(OH)-, -CH(OH)CH2-, -CH2CH(OH)-, -CH(OH)-;Y is selected from the group consisting of:-C(=Q)NR12-, -SO2NR12-, -CH2NR12-, -NR12C (=O)NR12-,-OC(=O)NR12-;Q is oxygen or sulfur; andQ1 is oxygen, sulfur, NR12 or a direct bond.3. A compound of Claim 1 wherein:W is selected from the group consisting of:-NR8C(=Q)NR12-; -C(=Q)NR12-, -C(=Q)O-, -NR12C(=Q)O-, -OC(=Q)NR12-, -NR12SO2NR12-, -SO2NR12-, -Q-, -CH2NR12-, -OP(=O)(Q1)O-, -P(=O)(Q1)O-, -SO2NHC(=O)NH-;X is selected from the group consisting of:-C(=Q)NR12-, -C(=Q)O-, -SO2NR12-, -CH2Q-, or -CH2NR12-;Y is selected from the group consisting of:-C (=Q) NR)2-, -SO2NR12-, or -CH2NR12-; Q is oxygen; andQ1 is oxygen.4. A compound of Claim 1 wherein:R1 is C1-C8 alkyl substituted with 0-3 R5;R2, R3 and R4 are independently selected from the groupconsisting of hydrogen, C1-C8 alkyl substituted with 0-3 R5, or C2-C8 alkenyl substituted with 0-3 R5;each R5 is selected from the group consisting of:keto, halogen, cyano, -NR7R8, -C02R7, -OC(=O)R7, -OR7,C2-C6 alkoxyalkyl, -S(O)mR7, -NHC(=NH)NHR7, -C(=NH)NHR7,-C(=O)NR7R8, -NR8C(=O)R7-, NR8C (=O) OR8, -OC («0)NR7R8, -OC(=O)NR7R8, -NR8SO2NR7R8, -NR8SO2R7, -SO2NR7R8, C1-C4 alkyl, C2-C4 alkenyl, C3-C5 cycloalkyl, C3-C6cycloalkylmethyl, a C5-C14 carbocyclic residuesubstituted with 0-3 R6, aryl substituted with 0-3 R6, or a heterocyclic ring system, composed of 5 to 10 atoms including at least one nitrogen, oxygen or sulfur atom, substituted with 0-2 R6;each R6, when a substituent on carbon, is selected from the group consisting of:phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C3-C5 cycloalkyl, C3- C6 cycloalkylmethyl, C7-C10 arylalkyl, alkoxy, -NR7R8, C2-C6 alkoxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4alkylcarbonylamino, -S(O)mR7, -SO2NR7R8, -NHSO2R8, or R6 may be a 3- or 4- carbon chain attached to adjacent carbons on the ring to form a fused 5- or 6-membered ring, said 5- or 6- membered ring being optionally substituted on the aliphatic carbons with halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, or NR7R8, or when R6 is attached to a saturated carbon atom it may be carbonyl or thiocarbonyl; and each R6, when a substituent on nitrogen, is selected from the group consisting of:phenyl, benzyl, phenethyl, hydroxy, C1-C4 alkoxy, nitro, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, -NR7R8, C2-C6 alkoxyalkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, C1-C4alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4alkylcarbonyl; -S(O)mR7, -SO2NR7R8, or R6 may be a 3- or 4- carbon chain attached to adjacent atoms on the ring to form a fused 5- or 6-membered ring, said 5- or 6- membered ring being optionally substituted on the aliphatic carbons with halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, or NR7R8.;R7 is H, benzyl or C1-C6 alkyl;R8 is H or C1-C4 alkyl;or R7R8 can join to form (CH2)4, (CH2)5,(CH2CH2N(R9)CH2CH2), or (CH2CH2OCH2CH2) ;R9 is H or CH3; andW is selected from the group consisting of:-NR8C(=Q)NR12-, -NR12C(=Q)O-, -OC(=Q)NR12-,-NR12SO2NR12-, -SO2NR12-, -CH2NR12-, or -SO2NHC(=O)NH-.5. A compound of Claim 1 wherein:R1 is C1-C4 alkyl substituted with:a C5-C12 carbocyclic residue substitut d with 0-2 R6, aryl substituted with 0-2 R6, or a heterocyclic ring system composed of 5 to 10 atoms including at least one nitrogen, oxygen or sulfur atom, substituted with 0-2 R6; R2 and R3 are independently selected from hydrogen, or C1-C4 alkyl substituted with 0-2 R5;R4 is C1-C4 alkyl substituted with:a C5-C12 carbocyclic residue substituted with 0-2 R6, aryl substituted with 0-2 R6, or a heterocyclic ring system composed of 5 to 10 atoms including at least one nitrogen, oxygen or sulfur atom substituted with 0-2 R6; each R5 is selected independently from the group consisting of:keto, halogen, cyano, -NR7R8, -CO2R7, -OR7, C2-C6 alkoxyalkyl, -S(O)mR7, -C(=O)NR7R8, -NR8C(=O)R7-,NR8C(=O)OR8, NR8SO2R7, -SO2NR7R8, C1-C4 alkyl, C2-C4 alkenyl, or C3-C6 cycloalkyl;each R6, when a substituent on carbon, is selected from the group consisting of:phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, C2-C6 alkoxyalkyl, methylenedioxy, C1-C2 haloalkyl, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, or -NHSO2R8;each R6, when a substituent on nitrogen, is C1-C4 alkyl, phenyl, benzyl or phenethyl;R7 is H or C1-C2 alkyl;R8 is H or C1-C2 alkyl;or R7R8 can join to form (CH2)4, (CH2)5,(CH2CH2N(R9)CH2CH2) , or (CH2CH2OCH2CH2) ; andW is selected from the following:-NR8C(=Q)NR12-, -NR12C(=Q)O, -OC(=Q)NR12, -SO2NR12-,-CH2NR12- .X is selected from the group consisting of:-C(=Q)NR12-, -C(=Q)O-, -SO2NR12-, -CH2Q-, or -CH2NR12- .6. A compound of Claim 1 wherein:R1 is C1-C4 alkyl substituted with:aryl substituted with 0-2 R6, or a heterocyclic ring system, composed of 5 to 10 atoms including at least one nitrogen, oxygen or sulfur atom, substituted with 0-1 R6; R3 is C1-C4 alkyl substituted with 0-1 R5;R4 is C1-C4 alkyl substituted with:a C5-C12 carbocyclic residue substituted with 0-2 R6 or aryl substituted with 0-2 R6; each R5 is selected independently from the group consisting of:halogen, -NR7R8, -CO2R7, -OR7, -NR8C(=O)R7-, NR8C(=O)OR8,NR8SO2R7, -SO2NR7R8, C1-C4 alkyl, or C3-C6 cycloalkyl; each R6, when a substituent on carbon, is selectedindependently from the group consisting of:benzyloxy, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C2 haloalkyl, C1-C4 alkylcarbonylamino, or -NHSO2R8;each R6, when a substituent on nitrogen, is C1-C2 alkyl or benzyl;m is 2;n is 0;W is -NR8C(=Q)NR12-, -OC(=Q)NR12- or -SO2NR12-; andY is -C(=Q)NR12-, or -CH2NR12-.The compounds of Claim 1 which are:8. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound of Claim 1. 9. A pharmaceutical composition comprising apharmaceutically acceptable carrier and an effective amount of a compound of Claim 2.10. A pharmaceutical composition comprising apharmaceutically acceptable carrier and an effective amount of a compound of Claim 3.11. A pharmaceutical composition comprising apharmaceutically acceptable carrier and an effective amount of a compound of Claim 4.12. A pharmaceutical composition comprising apharmaceutically acceptable carrier and an effective amount of a compound of Claim 5.13. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound of Claim 6. 14. A pharmaceutical composition comprising apharmaceutically acceptable carrier and an effective amount of at least one of the compounds of Claim 8.15. A method of treating a virus in a mammalcomprising administering to a mammal in need of such treatment an antiviral effective amount of a compound of Claim 1.16. A method of treating a virus in a mammalcomprising administering to a mammal in need of such treatment an antiviral effective amount of a compound of Claim 2.17. A method of treating a virus in a mammalcomprising administering to a mammal in need of such treatment an antiviral effective amount of a compound of Claim 3.18. A method of treating a virus in a mammalcomprising administering to a mammal in need of such treatment an antiviral effective amount of a compound of Claim 4.19. A method of treating a virus in a mammalcomprising administering to a mammal in need of such treatment an antiviral effective amount of a compound of Claim 5.20. A method of treating a virus in a mammalcomprising administering to a mammal in need of such treatment an antiviral effective amount of a compound ofClaim 6.21. A method of treating a virus in a mammal comprising administering to a mammal in need of such treatment an antiviral effective amount of at least one of the compounds of Claim 8.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US65944291A | 1991-02-22 | 1991-02-22 | |
| US659442 | 1991-02-22 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| AU1531092A true AU1531092A (en) | 1992-09-15 |
Family
ID=24645418
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU15310/92A Abandoned AU1531092A (en) | 1991-02-22 | 1992-02-21 | Substituted alpha-aminoaldehydes and derivatives |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP0572547A1 (en) |
| JP (1) | JPH06506921A (en) |
| AU (1) | AU1531092A (en) |
| CA (1) | CA2104602A1 (en) |
| WO (1) | WO1992014696A2 (en) |
| ZA (1) | ZA921279B (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5679688A (en) * | 1992-03-11 | 1997-10-21 | Narhex Limited | Quinaldoyl-amine derivatives of oxo-and hydroxy-substituted hydrocarbons |
| US5888992A (en) * | 1992-03-11 | 1999-03-30 | Narhex Limited | Polar substituted hydrocarbons |
| US6071895A (en) * | 1992-03-11 | 2000-06-06 | Narhex Limited | Polar-substituted hydrocarbons |
| US6258806B1 (en) | 1992-03-11 | 2001-07-10 | Narhex Limited | Amine derivatives of oxo- and hydroxy- substituted hydrocarbons |
Families Citing this family (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5413999A (en) * | 1991-11-08 | 1995-05-09 | Merck & Co., Inc. | HIV protease inhibitors useful for the treatment of AIDS |
| US5559256A (en) * | 1992-07-20 | 1996-09-24 | E. R. Squibb & Sons, Inc. | Aminediol protease inhibitors |
| US5386215A (en) * | 1992-11-20 | 1995-01-31 | Massachusetts Institute Of Technology | Highly efficient planar antenna on a periodic dielectric structure |
| AU667995B2 (en) * | 1993-02-15 | 1996-04-18 | Bayer Aktiengesellschaft | New pseudopeptides having an antiviral action |
| JP2848232B2 (en) * | 1993-02-19 | 1999-01-20 | 武田薬品工業株式会社 | Aldehyde derivatives |
| DE4311835A1 (en) * | 1993-04-07 | 1994-10-13 | Boehringer Ingelheim Int | Method for inhibiting gene transcription |
| US5977074A (en) * | 1993-10-01 | 1999-11-02 | Merrell Pharmaceuticals, Inc. | Inhibitors of β-amyloid protein production |
| AU687449B2 (en) * | 1993-10-01 | 1998-02-26 | Aventis Inc. | Inhibitors of beta-amyloid protein production |
| US5804560A (en) * | 1995-01-06 | 1998-09-08 | Sibia Neurosciences, Inc. | Peptide and peptide analog protease inhibitors |
| US6017887A (en) * | 1995-01-06 | 2000-01-25 | Sibia Neurosciences, Inc. | Peptide, peptide analog and amino acid analog protease inhibitors |
| US6214800B1 (en) | 1995-10-25 | 2001-04-10 | Senju Pharmaceutical Co., Ltd. | Angiogenesis inhibitor |
| ES2193615T3 (en) | 1995-10-25 | 2003-11-01 | Senju Pharma Co | .NIVER OF ANGIOGENESIS. |
| ES2293651T3 (en) * | 1995-11-28 | 2008-03-16 | Cephalon, Inc. | INHIBITORS OF CYSTEINE AND SERINE PROTEASES DERIVED FROM AMINO ACIDS D. |
| US5744339A (en) * | 1996-08-30 | 1998-04-28 | Cephalon, Inc. | Thiomethylene group-containing aldehyde cysteine and serine protease inhibitors |
| WO2000024704A1 (en) * | 1998-10-23 | 2000-05-04 | Senju Pharmaceutical Co., Ltd. | Process for producing peptidyl aldehydes |
| EP3725797A1 (en) * | 2008-03-26 | 2020-10-21 | Novozymes A/S | Stabilized liquid enzyme compositions |
Family Cites Families (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS50137951A (en) * | 1974-04-27 | 1975-11-01 | ||
| JPS5839149B2 (en) * | 1976-06-08 | 1983-08-27 | 三共株式会社 | peptide derivative |
| US5142056A (en) * | 1989-05-23 | 1992-08-25 | Abbott Laboratories | Retroviral protease inhibiting compounds |
| JPS5754157A (en) * | 1980-09-19 | 1982-03-31 | Nippon Kayaku Co Ltd | L-argininal derivative and its preparation |
| WO1984000365A1 (en) * | 1982-07-19 | 1984-02-02 | Nat Res Dev | Synthetic peptides and their preparation |
| GB8312339D0 (en) * | 1983-05-05 | 1983-06-08 | Austen B M | Peptides |
| JPS61103897A (en) * | 1984-10-26 | 1986-05-22 | Suntory Ltd | Preparation of anti-carpaine |
| JPH0794418B2 (en) * | 1987-08-03 | 1995-10-11 | 和光純薬工業株式会社 | New manufacturing method |
| JPH075634B2 (en) * | 1987-10-30 | 1995-01-25 | 日東紡績株式会社 | Tripeptides and antiplasmin agents containing the same |
| JPH0629229B2 (en) * | 1987-11-05 | 1994-04-20 | サントリー株式会社 | Cysteine proteinase inhibitor |
| IL89900A0 (en) * | 1988-04-12 | 1989-12-15 | Merck & Co Inc | Hiv protease inhibitors useful for the treatment of aids and pharmaceutical compositions containing them |
| EP0361341A3 (en) * | 1988-09-28 | 1991-07-03 | Miles Inc. | Therapeutics for aids based on inhibitors of hiv protease |
| JP2701932B2 (en) * | 1989-04-10 | 1998-01-21 | サントリー株式会社 | Protease inhibitor |
| GB8909836D0 (en) * | 1989-04-28 | 1989-06-14 | Boots Co Plc | Therapeutic agent |
-
1992
- 1992-02-21 JP JP4507279A patent/JPH06506921A/en active Pending
- 1992-02-21 AU AU15310/92A patent/AU1531092A/en not_active Abandoned
- 1992-02-21 ZA ZA921279A patent/ZA921279B/en unknown
- 1992-02-21 EP EP92907442A patent/EP0572547A1/en not_active Withdrawn
- 1992-02-21 WO PCT/US1992/001077 patent/WO1992014696A2/en not_active Application Discontinuation
- 1992-02-21 CA CA002104602A patent/CA2104602A1/en not_active Abandoned
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5679688A (en) * | 1992-03-11 | 1997-10-21 | Narhex Limited | Quinaldoyl-amine derivatives of oxo-and hydroxy-substituted hydrocarbons |
| US5888992A (en) * | 1992-03-11 | 1999-03-30 | Narhex Limited | Polar substituted hydrocarbons |
| US5942504A (en) * | 1992-03-11 | 1999-08-24 | Narhex Limited | Amine derivatives of oxo- and hydroxy- substituted hydrocarbons |
| US6071895A (en) * | 1992-03-11 | 2000-06-06 | Narhex Limited | Polar-substituted hydrocarbons |
| US6258806B1 (en) | 1992-03-11 | 2001-07-10 | Narhex Limited | Amine derivatives of oxo- and hydroxy- substituted hydrocarbons |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH06506921A (en) | 1994-08-04 |
| CA2104602A1 (en) | 1992-08-23 |
| ZA921279B (en) | 1993-08-23 |
| WO1992014696A2 (en) | 1992-09-03 |
| WO1992014696A3 (en) | 1993-02-18 |
| EP0572547A1 (en) | 1993-12-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU1531092A (en) | Substituted alpha-aminoaldehydes and derivatives | |
| KR0184866B1 (en) | Retroviral protease inhibiting compounds | |
| WO1991018866A2 (en) | 1,4-diamino-2,3-dihydroxybutanes | |
| CA1198118A (en) | Derivatives of cycloalka[c]pyrrolcarboxylic acids, a process for their preparation, agents containing these compounds, and their use, and new cycloalka[c]pyrrolcarboxylic acidsas intermediates, and a process for their preparation | |
| EP0765873B1 (en) | Cyclic ureas and analogues useful as retroviral protease inhibitors | |
| US5296604A (en) | Proline derivatives and compositions for their use as inhibitors of HIV protease | |
| JPH04217949A (en) | Amino acid derivative | |
| FR2609289A1 (en) | NOVEL COMPOUNDS WITH ACTIVITY OF COLLAGENASE INHIBITORS, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS COMPRISING THE SAME | |
| TW201200508A (en) | Processes and intermediates | |
| KR20000049047A (en) | Sulfonamide Interleukin-1beta Converting Enzyme Inhibitors | |
| NZ198826A (en) | Bicyclic compounds and pharmaceutical compositions | |
| JPS6323897A (en) | Taftsin analog, manufacture and medicinal composition | |
| JP4068639B2 (en) | Compound having anti-HCV action and process for producing the same | |
| EP0691961B1 (en) | Substituted caprolactams and derivatives thereof useful for treatment of hiv disease | |
| GB1595168A (en) | Expoxysuccinic acid derivatives | |
| JPS6251A (en) | Cis, endo-2-azabicyclo(3,3,0)octane-3-carboxylic acid derivative and manufacture | |
| US4087520A (en) | Lowering blood pressure with new L-3-(3,4-dihydroxyphenyl)-2-methyl-alanine peptides | |
| US4965283A (en) | Amino acid esters, process for the preparation thereof and use thereof | |
| RO104347B1 (en) | Production method of amids acids cyclomethylen - 1,2 - dicarboxylic | |
| WO1994008977A1 (en) | Substituted caprolactams and derivatives thereof useful for treatment of aids | |
| CA2181308A1 (en) | Improving the tolerability of pharmaceutically active beta-amino acids | |
| AU8205491A (en) | 1,4-diamino-2,3-dihydroxybutanes | |
| JPS59130268A (en) | Novel 2-azabicyclo(2,2,1)heptane derivative | |
| US4446151A (en) | Decarboxylase-inhibiting fluorinated pentane diamine derivatives | |
| CA1204775A (en) | Decarboxylase-inhibiting fluorinated alkane diamine derivatives |