Search Images Maps Play YouTube News Gmail Drive More »
Sign in
Screen reader users: click this link for accessible mode. Accessible mode has the same essential features but works better with your reader.

Patents

  1. Advanced Patent Search
Publication numberUSH725 H
Publication typeGrant
Application numberUS 07/019,469
Publication dateJan 2, 1990
Filing dateFeb 26, 1987
Priority dateFeb 26, 1987
Publication number019469, 07019469, US H725 H, US H725H, US-H-H725, USH725 H, USH725H
InventorsEric M. Gordon
Original AssigneeE. R. Squibb & Sons, Inc.
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Ureido amino and imino acids, compositions and methods for use
US H725 H
Abstract
Compounds of the formula ##STR1## wherein X is various amino or imino acids and esters are disclosed. These compounds are useful due to their angiotensin converting enzyme inhibition activity and depending upon the definition of X may also be useful as analgesics due to their enkephalinase inhibition activity.
Images(19)
Previous page
Next page
Claims(6)
What is claimed is:
1. A compound of the formula
or a pharmaceutically acceptable salt thereof wherein
R1 is hydrogen, lower alkyl, ##STR71## --(CH2)m -cycloalkyl, --(CH2)2 --NH2, --(CH2)3 --NH2, --(CH2)4 --NH2 ;
n is one or two;
R2 is ##STR72## R3 and R4 are independently selected from hydrogen, lower alkyl, ##STR73## R24 is hydrogen, ##STR74## R25 is hydrogen, lower alkyl, ##STR75## --(CH2)m -cycloalkyl, or ##STR76## R26 is lower alkyl, --(CH2)q -cycloalkyl, ##STR77## m is zero or an integer from 1 to 4, r is an integer from 1 to 7,
q is an integer from 1 to 4,
R7 is hydrogen or lower alkyl;
R5 is lower alkyl of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons, lower alkylthio of 1 to 4 carbons, chloro, bromo, fluoro, trifluoromethyl or hydroxy,
R6 is hydrogen, lower alkyl, benzyl, benzhydryl, alkali metal salt ion, alkaline earth metal salt ion ##STR78## or --(CH2)2 Si(CH3)3 ; and p is one, two or three provided that p is more than one only if Rs is methyl, methoxy, chloro, bromo or fluoro.
2. A compound of claim 1 wherein
n is one;
R1 is --CH3 or --(CH2)4 --NH2 ;
R2 is ##STR79## R3 is ##STR80## R4 is methyl, n-butyl, or --(CH2)4 --NH2, and R24 is hydrogen, ##STR81##
3. The compound of claim 1 wherein
R1 is methyl;
R2 is ##STR82## R3 is ##STR83## R4 is --CH2)4 --NH2 R6 is hydrogen; and
R24 is ##STR84##
4. The compound of claim 11 having the name 1-[[[(S)-3-[[N2 -(cyclobutylcarbonyl)-L-lysyl]-amino-2-oxo-4-phenylbutylmethylamino]carbonyl]-L-proline, 1.5 hydrochloride.
5. The compound of claim 1 wherein
R1 is methyl;
R2 is ##STR85## R3 is ##STR86## R4 is --(CH2)4 --NH2 ; R6 is hydrogen;
R24 is ##STR87##
6. The compound of claim 1 having the name 1-[[[(S)-3-[[N2 -(Cyclobutylcarbonyl)-L-lysyl]-amino-2-hydroxy-4-phenylbutyl]methylamino]carbonyl]-L-proline, 1.5 hydrochloride.
Description
FIELD OF THE INVENTION

The present invention relates to ureido amino and imino acid compounds and more particularly concerns such compounds, compositions including such compounds and methods for their use.

BACKGROUND OF THE INVENTION

Almquist et al., "Synthesis and Biological Activity of a Ketomethylene Analogue of a Tripeptide Inhibitor of Angiotensin Converting Enzyme",J. Med. Chem., 1980, 23, 1392-1398, discloses the ketomethylene compound the formula ##STR2## This and related compounds are also disclosed by Almquist et al. in U.S. Pat. No. 4,329,473.

Natarajan et al. in U.S. Pat. No. 4,621,092 disclose compounds of the formula ##STR3## These compounds are useful as hypotensive agents due to their angiotensin converting enzyme inhibition activity and depending upon the definition of X may also be useful as analgesics due to their enkephalinase inhibition activity.

Godfrey, Jr. et al. in U.S. Pat. No. 4,604,402 disclose compounds of the formula ##STR4## These compounds are useful as hypotensive agents due to their angiotensin converting enzyme inhibition activity and depending upon the definition of X may also be useful as analgesics due to their enkephalinase inhibition activity.

SUMMARY OF THE INVENTION

In accordance with the present invention novel ureido imino and amino acid compounds useful, for example, as hypotensive agents are disclosed. The various ureido-keto and hydroxy-substituted ureido compounds have the general formula ##STR5## wherein R1 is hydrogen, lower alkyl, halo substituted lower alkyl, ##STR6##

n is one or two,

R2 is ##STR7##

R3 and R4 are independently selected from hydrogen, lower alkyl, ##STR8##

R24 is hydrogen, ##STR9##

R25 is hydrogen, lower alkyl, ##STR10##

m is zero or an integer from 1 to 4,

r is an integer from 1 to 7,

q is an integer from 1 to 4,

X is an animo or imino acid or ester of the formula ##STR11##

R7 is hydrogen, lower alkyl, halogen, hydroxy, ##STR12## a 1- or 2-naphthyl of the formula ##STR13## a substituted 1- or 2-naphthyl of the formula ##STR14## a 1- or 2-naphthyloxy of the formula ##STR15## a substituted 1- or 2-naphthyloxy of the formula ##STR16## a 1- or 2-naphthylthio of the formula ##STR17## or a substituted 1- or 2-naphthylthio of the formula ##STR18##

R8 is lower alkyl, halogen, ##STR19## --O--lower alkyl, a 1- or 2-naphthyloxy of the formula ##STR20## a substituted 1- or 2-naphthyloxy of the formula ##STR21## a 1- or 2-naphthylthio of the formula ##STR22## or a substituted 1- or 2-naphthylthio of the formula ##STR23##

R9 is lower alkyl, keto, ##STR24##

R10 is halogen or Y-R16.

R11, R'11, R12 or R'12 are independently selected from hydrogen and lower alkyl or R'11, R12 and R'12 are hydrogen and R11 is ##STR25##

R13 is lower alkyl of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons, lower alkylthio of 1 to 4 carbons, chloro, bromo, fluoro, trifluoromethyl, hydroxy, phenyl, phenoxy, phenythio, or phenylmethyl.

R5 is lower alkyl of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons, lower alkylthio of 1 to 4 carbons, chlorl, bromo, fluoro, trifluoromethyl or hydroxy.

R6 is hydrogen, lower alkyl, benzyl, benzhydryl, alkali metal salt ion, alkaline earth metal salt ion, ##STR26## or --(CH2)2 Si(CH3)3.

p is one, two or three provided that p is more than one only if R13 or R5 is methyl, methoxy, chloro, bromo or fluoro.

R14 is hydrogen, lower alkyl, ##STR27##

R15 is hydrogen or lower alkyl of 1 to 4 carbons.

Y is oxygen or sulfur.

R16 is lower alkyl of 1 to 4 carbons, ##STR28## or the R16 groups join to complete an unsubstituted 5- or 6-membered ring or said ring in which one or more of the carbons has a lower alkyl of 1 to 4 carbons of a di(lower alkyl of 1 to 4 carbons) substituent.

R17 is hydrogen, lower alkyl, cycloalkyl, or phenyl.

R18 is hydrogen, lower alkyl, lower alkoxy, or phenyl.

v is zero, one, or two

R19 is lower alkyl or ##STR29##

R20 is hydrogen, lower alkyl, ##STR30##

R21 is hydrogen, lower alkyl, ##STR31##

R22 is lower alkyl, benzyl, or phenethyl.

R23 is hydrogen, lower alkyl, benzyl, or phenethyl.

DETAILED DESCRIPTION OF THE INVENTION

This invention is directed to the various novel ureido-keto and hydroxy-substituted ureido imino and amino acid compounds of formula I above, and compositions and methods of using compositions containing the novel compounds.

The term lower alkyl used in defining various symbols refers to straight or branched chain radicals having up to seven carbons. The preferred lower alkyl groups are up to four carbons with methyl and ethyl most preferred. Similarly the terms lower alkoxy and lower alkythio refer to such lower alkyl groups attached to an oxygen or sulfur.

The term cycloalkyl refers to saturated rings of 3 to 7 carbon atoms with cyclopentyl and cyclohexyl being most preferred.

The term halogen refers to chloro, bromo and fluoro.

The term halo substituted lower alkyl refers to such lower alkyl groups described above in which one or more hydrogens have been replaced by chloro, bromo or fluoro groups such as trifluoromethyl, which is preferred, pentafluoroethyl, 2,2,2-trichloroethyl, chloromethy, bromomethyl, etc.

The symbols ##STR32## represent that the alkylene bridge is attached to an available carbon atom.

R2 is ##STR33## and n=1, a compound of the formula ##STR34## is reacted with a chlorocarbonate of the formula ##STR35## in the presence of a base, such as triethylamine or diisopropylethylamine followed by diazomethane to provide a compound of the formula ##STR36##

Compound IV is reacted with amine of the formula ##STR37## (the benzyl function acting as a nitrogen protecting group) in the presence of a base such as triethylamine and then treated with p-toluenesulfonic acid (pTSA) to provide ##STR38## Hydrogenation (for example, by treating with hydrogen in the presence of a palladium on carbon catalyst) to remove the benzyl protecting group yields ##STR39## which is thereafter reacted with the acid chloride of the formula ##STR40## wherein R6 in the definition of X is an easily removable ester protecting group such as benzhydryl or benzyl; in the presence of N-methyl morpholine and an aprotic solvent, e.g. methylene chloride to provide ##STR41##

Treatment of compound IX with hydrochloric acid in the presence of an organic solvent, such as ethyl acetate, affords an intermediate of the formula ##STR42## wherein R6 in the definition of X is still an ester protecting group.

An acid of the formula ##STR43## (wherein prot is an amino protectin such as benzyloxycarbonyl) is reacted with

R24 --halo                                            (XII)

in the presence of an acid scavenger, e.g. bis(trimethylsilyl)trifluoroacetamide and acetonitrile to provide a compound of the formula ##STR44##

Compound XIII is thereafter reacted with the compound of formula X in the presence of a base, e.g. triethylamine and a peptide coupling reagent to produce a compound having the formula ##STR45##

Compounds of formula I wherein R2 is ##STR46## are thereafter obtained by hydrogenation of the compound of formula XIV to remove the protecting groups. For example, hydrogenation with hydrochloric acid in the presence of a palladium on carbon catalyst when Re is benzyl or benzhydryl affords the hydrochloride salt of the compound of formula I wherein R2 is and R6 is hydrogen.

Compounds of formula I wherein R2 is ##STR47## can be obtained by treating compounds of formula I wherein R2 is ##STR48## (the preparation of which has been described above) with a conventional reducing agent such as sodium borohydride, sodium cyanoborohydride, diisobutyl aluminum hydride, lithium tri-t-butoxy aluminum hydride and the like.

In the above reactions if any or all of R1, R2 and R4 are ##STR49## then the hydroxyl, amino, imidazolyl, mercaptan or guanidinyl function should be protected during the reaction. Suitable protecting groups include benzyloxycarbonyl, t-butoxycarbonyl, benzyl, benzhydryl, trityl, etc., and nitro in the case of guanidinyl. The protecting group is removed by hydrogenation, treatment with acid, or other known methods following completion of the reaction sequence.

The ester products of formula I wherein R6 is lower alkyl, benzyl or benzhydryl can be chemically treated such as with sodium hydroxide in aqueous dioxane or with trimethylsilylbromide to yield the products of formula I wherein R6 is hydrogen. The benzyl and benzhydryl esters can also be hydrogenated, for example by treating with hydrogen in the presence of a palladium on carbon catalyst.

The ester products of formula I wherein R6 is ##STR50## may be obtained by employing the acid chloride of formula VIII in the above reactions with such ester group already in place. Such ester reactants can be prepared by treating the corresponding amino or imino acid of the formula

HX                                                         XV

wherein R6 is hydrogen with an acid chloride such as ##STR51## so as to protect the N-atom. The protected amino or imino acid is then reacted in the presence of a base with a compound of the formula ##STR52## wherein L is a leaving group such as chlorine, bromine, tolylsulfonyl, etc., followed by removal of the N-protecting group such as by treatment with acid or hydrogenation.

The ester products of formula I wherein R6 is ##STR53## can also be obtained by treating the product of formula I wherein R6 is hydrogen with a molar excess of the compound of formula XVI.

When the compounds of formula I contain a reactive sulfur atom within the amino acid portion of the molecule, i.e. X is ##STR54## for example, then the above described procedures are somewhat altered to avoid the use of hydrogenation to remove the N-protecting groups. For example, the N-protecting group used should be those which are compatible with acid removal such as benzyloxycarbonyl, t-butyl and the like.

The compounds of formula I wherein R6 is hydrogen form salts with a variety of inorganic or organic bases. The nontoxic, pharmaceutically acceptable salts are preferred, although other salts are also useful in isolating or purifying the product. Such pharmaceutically acceptable salts include metal salts such as sodium, potassium or lithium, alkaline earth metal salts such as calcium or magnesium, and salts derived from amino acids such as arginine, lysine, etc. The salts are obtained by reacting the acid form of the compound with an equivalent of the base supplying the desired ion in a medium in which the salt precipitates or in aqueous medium and then lyophilizing.

Similarly, the compounds of formula I, especially wherein Rs is an ester group, form salts with a variety of inorganic and organic acids. Again, the non-toxic pharmaceutically acceptable salts are preferred, although other salts are also useful in isolating or purifying the product. Such pharmaceutically acceptable salts include those formed with hydrochloric acid, methanesulfonic acid, sulfuric acid, maleic acid, etc. The salts are obtained by reacting the product with an equivalent amount of the acid in a medium in which the salt precipitates.

As shown above, the amino or imino acid portion of the molecule of the products of formula I is in the L-configuration. Several asymmetric centers are also present in the balance of the molecule as represented by the * in formula I. Thus the compounds of formula I can exist in diastereoisomeric forms or in mixtures thereof. The above described processes can utilize racemates, enantiomers or diastereomers as starting materials. When diastereomeric products are prepared, they can be separated by conventional chromatographic or fractional crystallization methods.

The products of formula I wherein the imino acid ring is monosubstituted give rise to cis-trans isomerism. The configuration of the final product will depend upon the configuration of the R7, R8 and R9 substituent in the starting material of formula XV.

The compounds of formula I, and the pharmaceutically acceptable salts thereof, are hypotensive agents. They inhibit the conversion of the decapeptide angiotensin I to angiotensin II and, therefore, are useful in reducing or relieving angiotensin related hypertension. The action of the enzyme renin on angiotensinogen, a pseudoglobulin in blood, produces angiotensin I. Angiotensin I is converted by angiotensin converting enzyme (ACE to angiotensin II. The latter is an active pressor substance which has been implicated as the causative agent in several forms of hypertension in various mammalian species, e.g. humans. The compounds of this invention intervene in the angiotensinogen→(renin)→angiotensin I→angiotensin II sequence by inhibiting angiotensin converting enzyme and reducing or eliminating the formation of the pressor substance angiotensin II. Thus by the administration of a composition containing one (or a combination) of the compounds of this invention, angiotensin dependent hypertension in a species of mammal (e.g. humans) suffering therefrom is alleviated. A single dose, or preferably two to four divided daily doses, provided on a basis of about 0.1 to 100 mg, preferably about 1 to 50 mg, per kilogram of body weight per day is appropriate to reduce blood pressure. The substance is preferably administered orally, but parenteral routes such as the subcutaneous, intramuscular, intravenous or intraperitoneal routes can also be employed.

The compounds of this invention can also be formulated in combination with a diuretic for the treatment of hypertension. A combination product comprising a compound of this invention and a diuretic can be administered in an effective amount which comprises a total daily dosage of about 30 to 600 mg, preferably about 30 to 330 mg of a compound of this invention, and about 15 to 300 mg, preferably about 15 to 200 mg of the diuretic, to a mammalian species in need thereof. Exemplary of the diuretics contemplated for use in combination with a compound of this invention are the thiazide diuretics, e.g. chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlothiazide, trichloromethiazide, polythiazide or benzthiazide as well as ethacrynic acid, ticrynafen, chlorthalidone, furosemide, musolimine, bumetanide, triamterene, amiloride and spironolactone and salts of such compounds.

The compounds of formula I can be formulated for use in the reduction of blood pressure in compositions such as tablets, capsules or elixirs for oral administration, or in sterile solutions or suspensions for parenteral administration. About 10 to 500 mg of a compound of formula I is compounded with physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavor, etc., in a unit dosage form as called for by accepted pharmaceutical practice. The amount of active substance in these compositions or preparations is such that a suitable dosage in the range indicated is obtained.

The compounds of formula I wherein X is ##STR55## also possess enkephalinase inhibition activity and are useful as analgesic agents. Thus, by the administration of a composition containing one or a combination of such compounds of formula I or a pharmaceutically acceptable salt thereof, pain is alleviated in the mammalian host. A single dose, or preferably two to four divided daily doses, provided on a basis of about 0.1 to about 100 mg per kilogram of body weight per day, preferably about 1 to about 50 mg per kilogram per day, produces the desired analgesic activity. The composition is preferably administered orally but parenteral routes such as subcutaneous can also be employed.

Preferred compounds of this invention with respect to the amino or imino acid part of the structure are those wherein ##STR56##

R7 is hydrogen, hydroxy, chloro, fluoro, lower alkyl of 1 to 4 carbons, cyclohexyl, amino, --O-lower alkyl wherein lower alkyl is of 1 to 4 carbons, --S-lower alkyl wherein lower alkyl is of to 4 carbons, ##STR57##

m is zero, one or two.

R13 is methyl, methoxy, chloro, fluoro, bromo, methylthio, or hydroxy.

t is 2 or 3.

R21 is hydrogen, straight or branched chain lower alkyl of 1 to 4 carbons, ##STR58##

R20 is ##STR59##

R6 is hydrogen, sodium ion, potassium ion, calcium ion, lithium ion, or ##STR60##

R17 is hydrogen, straight or branched chain lower alkyl or 1 to 4 carbons, cyclohexyl, or phenyl.

R18 is hydrogen or straight or branched chain lower alkyl of 1 to 4 carbons.

Most preferred are those wherein:

X is ##STR61##

R6 is hydrogen, sodium ion, potassium ion, calcium ion, or lithium ion.

Preferred compounds of this invention with respect to the ureido part of the structure are those wherein R1 is a straight or branched chain lower alkyl of 1 to 4 carbon atoms, --(CH2)r --NH2 or ##STR62##

n is 1;

R2 is ##STR63##

R3 is a branched chain lower alkyl of 1 to 4 carbon atoms, ##STR64##

R4 is hydrogen, straight or branched chain lower alkyl of 1 to 4 carbons, --(CH2)r --NH2, ##STR65##

R24 is hydrogen, ##STR66##

r is an integer from 3 to 5

m is one or two.

R5 is methyl, methoxy, methylthio, chloro, bromo, fluoro, or hydroxy.

R17 is hydrogen, straight or branched chain lower alkyl of 1 to 4 carbons, cyclohexyl, or phenyl.

R18 a is hydrogen or straight or branched chain lower alkyl of 1 to 4 carbons.

Most preferred are those wherein:

n is one;

R1 is --CH3 or --(CH2)4 --NH2 ;

R2 is; ##STR67##

R3 is ##STR68##

R4 is methyl, n-butyl, or --(CH2)4 --NH2.

R24 is hydrogen,

The present invention will now be described by the following examples, however the invention is not meant to be limited to the details therein.

EXAMPLE 1 1-[[[(S)-3-[[N2 -(Cyclobutylcarbonyl)-L-lysyl]-amino]-2-oxo-4-phenylbutyl]methyl-amino]carbonyl]-L-proline, 1.5 hydrochloride A. N2 -(Cyclobutylcarbonyl)-N6 -[(phenylmethoxy)-carbonyl]-L-lysine

N6 -[(Phenylmethoxy)carbonyl]-L-lysine (4.73 g, 16.9 mmole) was suspended in 50 ml of acetonitrile and thereafter bis(trimethylsilyl)trifluoroacetamide (18.5 ml, 17.92 g, 69.6 mmol) was added. After stirring the mixture for 45 minutes under argon, it became homogeneous. After cooling to 5 C., a solution of cyclobutane carboxylic acid chloride (2.02 g, 17 mmol) in 10 ml of tetrahydrofuran was added dropwise over 15 minutes. The reaction mixture was stirred for 2 hours and then partitioned between ethyl acetate and water. The ethyl acetate layer was concentrated to an oil, dissolved in a saturated bicarbonate solution and washed with ethyl acetate. The aqueous layer was acidified to pHz with concentrated hydrochloric acid and extracted with ethyl acetate. This ethyl acetate extract was dried over sodium sulfate and concentrated in vacuo to give the title A compound (5.46 g, 15.5 mmol).

B. (S)-[3-Chloro-2-oxo-1-(phenylmethyl)propyl]-carbamic acid, 1,1-dimethylethyl ester

To a stirred solution of benzyloxy carbonyl-L-phenylalanine (26.5 g, 100 mmol) in tetrahydrofuran (150 ml) at -20 was added isobutylchloroformate (13 ml, 100 mmol). N-methylmorpholine (11 ml, 100 mmol) was then added in drops. The solution was stirred between -15 and -20 for fifteen minutes and was filtered. Tetrahydrofuran (25 ml) was used for the washings. This was added to a cold (ice bath) etheral solution of diazomethane in drops. After the addition was over, the ice bath was removed and the reaction mixture was stirred at ambient temperature for 2 hours. Nitrogen was blown over the solution and the volume was reduced to 400 ml. The reaction mixture was then stirred in an ice bath and hydrochloric acid in acetic acid (2N, 55 ml) was added in drops. After the addition was over, the ice bath was removed and the reaction mixture stirred for fifteen minutes at room temperature. The reaction mixture was evaporated in vacuo and the residue on attempted dissolution in ether afforded 6.2 g of the title B compound. The mother liquor on concentration and after crystallization from ether/hexane afforded another 17.65 g of the title B compound.

C. (S)-[3-[Methyl(phenylmethyl)amino]-2-oxo-1-(phenylmethyl)propyl]carbamic acid, 1,1-dimethylethyl ester, p-toluenesulfonate salt

A solution of the compound of part B (6.45 g, 21.65 mmole), benzylmethylamine (2.78 ml, 21.55 mmole), NaHCO3 (2.18 g, 26 mmole) and sodium iodide (1.62 g, 10.83 mmole) in dimethylformamide (75 ml) was stirred under argon at room temperature for 4 hours. The resulting mixture was concentrated in vacuo, diluted with ether, washed three times with water and extracted five times with 1N hydrochloric acid. The combined extracts were made basic using NaHCO3 (solid) and extracted three times with ethyl acetate. The combined ethyl acetate extracts were dried over magnesium sulfate, concentrated and the residue was dissolved in ether. To this solution was added a warm solution of p-toluene-sulfonic acid (2.93 g, 15.4 mmole) in ethyl acetate. The resulting orange solution was seeded with product crystals from an earlier run and cooled until crystallization was complete. The resulting crystalline solid was collected and washed with ether to give the title C compound (7.43 g, 13.40 mmole).

D. (S)-[3-(Methylamino)-2-oxo-1-(phenylmethyl)-propyl]carbamic acid, 1,1-dimethylethyl ester, p-toluenesulfonate(1:1)salt

A solution of the compound of part C (7.33 g, 13.2 mmole) and palladium dihydroxide in methanol was stirred under a positive pressure of hydrogen for 3 hours. The resulting solution was filtered and concentrated. The product was crystallized from ether to give the title D compound (5.82 g, 12.53 mmole).

E. (S)-1-[[[3-[[(1,1-Dimethylethoxy)carbonyl]-amino]-2-oxo-4-phenylbutyl]methylamino]-carbonyl]-L-proline, phenylmethyl ester

To a stirring solution of L-proline benzyl ester hydrochloride (6.05 g, 25 mmole) in methylene chloride (100 ml) at -30 C. were added N-methyl morpholine (6.9 ml, 62.5 mmole) and phosgene (40 ml, 48 mmole, 12 percent in benzene). The resulting solution was stirred at -30 for one hour and at room temperature for an additional hour. The mixture was concentrated at reduced pressure and to the residue was added methylene chloride (60 ml), a solution of the compound of part D (7.75 g, 16.68 mmole) in methylene chloride (100 ml) and N-methyl morpholine (5.5 ml, 50 mmole). The resulting mixture was stirred at room temperature overnight and concentrated. The residue was dissolved in ethyl acetate, washed with water, 1N hydrochloric acid, and 10 percent NaHCO3, dried over magnesium sulfate and concentrated to an orange oil. The crude product was chromatographed on silica gel. Fractions containing the desired product were combined and concentrated to give the title E compound as a beige foam (7.17 g, 13.7 mmole).

F (S)-1-[[(3-Amino-2-oxo-4-phenylbutyl)methylamino]carbonyl]-L-proline, phenylmethyl ester, monohydrochloride

A solution of the compound of part E (7.12 g, 13.6 mmole) was stirred in a saturated solution of hydrochloric acid/ethyl acetate for one hour. The resulting precipitate was collected and washed with ethyl acetate to give the title F compound.

G. 1-[[[(S)-3-N2 -(Cyclobutylcarbonyl)-N6 -[(phenylmethoxy)carbonyl]-L-lysyl]amino]-2-oxo-4-phenylbutyl]methylamino]carbonyl]-L-proline phenylmethyl ester, 1.5 hydrochloride

To a solution of the compound of part A (0.54 g, 1.5 mmol) in 20 ml of dimethylformamide -50 C. and under nitrogen was added triethylamine (0.21 ml, 1.5 mmol) and isobutylchloroformate (0.19 ml, 1.5 mmol). After 20 minutes of stirring at -50 C. a solution of the compound of part F (0.69 g, 1.5 mmol) in 10 ml of dimethylformamide was added, followed quickly by the addition of diisopropylethyl amine (0.26 ml, 1.5 mmol). The internal temperature rose to -35 C. After stirring overnight (from -35 C. to room temperature) the reaction mixture was poured into 100 ml of water and extracted three times with ethyl acetate. The combined ethyl acetate extracts were washed twice with saturated sodium hydrogen carbonate, twice with 10 percent potassium hydrogen sulfate, twice with water and dried over magnesium sulfate. The so-treated extracts were thereafter concentrated under reduced pressure to give a yellow oil. Purification by flash chromatography and recrystallization from ethyl acetate/hexane afforded the title G compound as white crystals (0.49 g).

H. 1-[[[(S)-3-[[N2 -(Cyclobutylcarbonyl)-L-lysyl]-amino]-2-oxo-4-phenylbutyl]methylamino]carbonyl]-L-proline, 1.5 hydrochloride

A solution of the compound of part G (0.25 g, 0.32 mmol) in 50 ml of ethanol containing 1N hydrochloric acid (0.64 ml, 0.64 mmol) and 10 percent palladium on carbon was hydrogenated overnight. The reaction mixture was filtered and the filtrate was concentrated. The solid residue was triturated with ether and the product was lyophilized in double distilled water two times affording the title compound as a fluffy white solid (0.14 g).

EXAMPLE 2 1-[[[(S)-3-[[N` -(Cyclobutylcarbonyl)-L-lysyl]-amino]-2-hydroxy-4-phenylbutyl]methylamino]carbonyl]-L-proline, 1.5 hydrochloride A. 1-[[[(S)-3-[[N2 -(Cyclobutylcarbonyl)-N6 -[(phenylmethoxy)carbonyl]-L-lysyl]-amino]-2-hydroxy-4-phenylbutyl]methylamino]carbonyl]L-proline phenylmethyl ester, 1.5 hydrochloride

A sample of the compound from part G of Example 1 was dissolved in ethanol (15 ml). While stirring in an ice bath, sodium borohydride (150 mg, 3.95 mmol) was added. The solution was stirred at room temperature for 90 minutes. It was then evaporated, taken into ethyl acetate and washed with 10 percent aqueous potassium hydrogen sulfate solution. The ethyl acetate solution (after evaporation) was chromatographed over silica gel to obtain 1.1 grams of the title A compound.

B 1-[[[(S)-3-[[N2 -(Cyclobutylcarbo 1)-L-lysyl-]-amino]-2-hydroxy-4-phenylbutyl]-methylamino]carbonyl]-L-proline, 1.5 hydrochloride

The compound from part A of this Example was thereafter treated using the procedures of part H in Example 1 to obtain the title compound.

EXAMPLES 3-30

Using the methods and procedures described above and in Examples 1 and 2, the following additional compounds of the present invention can be made. ##STR70## ##TBL1##

Non-Patent Citations
Reference
1Almquist et al., "Synthesis and Biological Activity . . . 5(S)-Benzamido-4-oxo-6-phenylhexanoyl-L-proline", J. Med. Chem., 1985, 28, pp. 1062-1066, 1067-1071.
2Almquist et al., "Synthesis and Biological Activity . . . Angiotensin Converting Enzyme", J. Med. Chem., (1980), 23, pp. 1392-1398.
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US5463104 *Aug 24, 1993Oct 31, 1995G. D. Searle & Co.Succinoylamino hydroxyethylamino sulfonamides useful as retroviral protease inhibitors
US5475013 *May 20, 1992Dec 12, 1995Monsanto CompanyRetroviral protease inhibitors
US5475027 *Nov 8, 1993Dec 12, 1995G.D. Searle & Co.Retroviral protease inhibitors
US5475138 *Jul 7, 1994Dec 12, 1995Pharm-Eco Laboratories IncorporatedMethod preparing amino acid-derived diaminopropanols
US5482947 *Nov 15, 1993Jan 9, 1996Talley; John J.Retroviral protease inhibitors
US5508294 *May 31, 1995Apr 16, 1996G.D. Searle & Co.Sulfonylalkanoylamino hydroxyethlamino sulfonamides useful as retroviral protease inhibitors
US5510349 *Jun 7, 1995Apr 23, 1996G.D. Searle & Co.Retroviral protease inhibitors
US5510378 *May 25, 1995Apr 23, 1996G.D. Searle & Co.Retroviral protease inhibitors
US5510388 *May 31, 1995Apr 23, 1996G. D. Searle & Co.Sulfonylalkanoylamino hydroxyethylamino sulfonamides useful as retroviral protease inhibitors
US5510487 *May 25, 1995Apr 23, 1996G.D. Searle & Co.Retroviral protease inhibitors
US5521219 *Aug 24, 1993May 28, 1996G. D. Searle & Co.Sulfonylalkanoylamino hydroxyethylamino sulfonamides useful as retroviral protease inhibitors
US5578606 *Oct 30, 1992Nov 26, 1996G. D. Searle & Co.α- and β-amino acid hydroxyethylamino sulfonyl urea derivatives useful as retroviral protease inhibitors
US5583132 *Oct 29, 1993Dec 10, 1996Vazquez; Michael L.Sulfonylalkanoylamino hydroxyethylamino sulfamic acids useful as retroviral protease inhibitors
US5583238 *May 24, 1993Dec 10, 1996G. D. Searle & Co.Method for making intermediates useful in synthesis of retroviral protease inhibitors
US5602119 *Oct 29, 1993Feb 11, 1997Vazquez; Michael L.Succinoylamino hydroxyethylamino sulfamic acid derivatives useful as retroviral protease inhibitors
US5602175 *May 25, 1995Feb 11, 1997G.D. Searle & Co.Retroviral protease inhibitors
US5610190 *Jun 7, 1995Mar 11, 1997G. D. Searle & Co.Retroviral protease inhibitors
US5614522 *Jul 24, 1995Mar 25, 1997G.D. Searle & Co.Retroviral protease inhibitors
US5618966 *May 16, 1995Apr 8, 1997Pharm-Eco Laboratories, IncorporatedMethod forming protease inhibitor synthetic intermediates
US5620977 *Jun 7, 1995Apr 15, 1997G.D. Searle & Co.Retroviral protease inhibitors
US5622949 *Jun 7, 1995Apr 22, 1997G. D. Searle & Co.Retroviral protease inhibitors
US5631405 *Jun 7, 1995May 20, 1997Pharm-Eco Laboratories, IncorporatedMethod of forming amino acid-derived diaminopropanols useful as chemical intermediates for protease-inhibitors
US5639769 *Jan 17, 1996Jun 17, 1997G.D. Searle And Co.Sulfonylalkanoylamino hydroxyethylamino sulfonamides useful as retroviral protease inhibitors
US5643924 *May 31, 1995Jul 1, 1997Monsanto Company Of St. LouisRetroviral protease inhibitors
US5648364 *Mar 21, 1995Jul 15, 1997Monsanto CompanyRetroviral protease inhibitors
US5648511 *May 25, 1995Jul 15, 1997G.D. Searle & Co.Method for making intermediates useful in the synthesis of retroviral protease inhibitors
US5698569 *Jun 7, 1995Dec 16, 1997G. D. Searle & Co.Retroviral protease inhibitors
US5703076 *May 25, 1995Dec 30, 1997G. D. Searle & Co.Retroviral protease inhibitors
US5705500 *Jun 7, 1995Jan 6, 1998G.D. Searle & Co.Sulfonylalkanoylamino hydroxyethylamino sulfonamide retroviral protease inhibitors
US5708004 *May 25, 1995Jan 13, 1998Monsanto CompanyRetroviral protease inhibitors
US5714605 *Oct 10, 1995Feb 3, 1998Monsanto CompanySuccinoylamino hydroxyethylamino sulfonamides useful as retroviral protease inhibitors
US5744481 *Apr 25, 1997Apr 28, 1998G.D. Searle & Co.β-amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors
US5750648 *Jun 3, 1994May 12, 1998G.D. Searle & Co.Retroviral protease inhibitors and combinations thereof
US5753660 *Nov 13, 1996May 19, 1998G. D. Searle & Co.Substituted sulfonylalkanoylamino hydroxyethylamino sulfonamide retroviral protease inhibitors
US5756498 *Jan 11, 1996May 26, 1998G.D. Searle & Co.Sulfonylalkanoylamino hydroxyethylamino sulfonyl urea derivatives useful as retroviral protease inhibitors
US5756533 *Jun 7, 1995May 26, 1998G.D. Searle & Co.Amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors
US5760064 *Jun 6, 1997Jun 2, 1998G.D. SearleSulfonylalkanoylamino hydroxyethylamino sulfanamides useful as retroviral protease inhibitors
US5760076 *Oct 10, 1995Jun 2, 1998G.D Searle & Co.Succinoylamino hydroxyethylamino sulfonamides useful as retroviral protease inhibitors
US5776971 *Jun 7, 1995Jul 7, 1998G.D. Searle & Co.Heterocyclecarbonyl amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors
US5786483 *Jun 7, 1995Jul 28, 1998G. D. Searle & Co.α-and β-amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors
US5830888 *Mar 20, 1995Nov 3, 1998Monsanto CompanyMacrocyclic retroviral protease inhibitors
US5830897 *Jun 7, 1995Nov 3, 1998G. D. Searle & Co.α- and β-amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors
US5872298 *Apr 9, 1997Feb 16, 1999G. D. Searle & Co.Method of preparing intermediates for retroviral protease inhibitors
US5872299 *May 8, 1997Feb 16, 1999G. D. Searle & Co.Method of preparing intermediates for retroviral protease inhibitors
US5948790 *Apr 8, 1997Sep 7, 1999Mosanto CompanyRetroviral protease inhibitors
US5965588 *Mar 26, 1998Oct 12, 1999G.D. Searle & Co.Sulfonylalkanoylamino hydroxyethylamimo sulfonamides useful as retroviral protease inhibitors
US5965601 *Mar 3, 1998Oct 12, 1999G. D. Searle & Co.Amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors
US5968942 *Aug 23, 1994Oct 19, 1999G. D. Searle & Co.α- and β-amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors
US5972989 *Feb 24, 1998Oct 26, 1999G.D. Searle & Co.Heterocyclecarbonyl amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors
US5985870 *Mar 7, 1996Nov 16, 1999G.D. Searle & Co.Sulfonylalkanoylamino hydroxyethylamino sulfonamide retroviral protease inhibitors
US6022872 *Sep 6, 1996Feb 8, 2000G. D. Searle & Co.α- and β-amino acid hydroxyethylamino sulfonyl urea derivatives useful as retroviral protease inhibitors
US6022994 *Mar 12, 1998Feb 8, 2000G. D. Searle &. Co.Succinoylamino hydroxyethylamino sulfonamides useful as retroviral protease inhibitors
US6022996 *Sep 13, 1996Feb 8, 2000G. D. Searle & Co.Method for making intermediates useful in synthesis of retroviral protease inhibitors
US6046190 *Aug 23, 1994Apr 4, 2000G.D. Searle & Co.Hydroxyethylamino sulphonamides useful as retroviral protease inhibitors
US6063795 *May 10, 1999May 16, 2000G.D. Searle & CompanyHeterocyclecarbonyl amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors
US6063963 *Jul 5, 1995May 16, 2000Pharm-Eco Laboratories, Inc.Amino acid-derived diaminopropanols
US6133444 *Jun 7, 1995Oct 17, 2000Perseptive Biosystems, Inc.Synthons for the synthesis and deprotection of peptide nucleic acids under mild conditions
US6143747 *Jan 18, 1996Nov 7, 2000G. D. Searle & Co.Bis-sulfonamide hydroxyethylamino retroviral protease inhibitors
US6147117 *Jul 13, 1999Nov 14, 2000G. D. Searle & Co.Sulfonylalkanoylamino hydroxyethylamino sulfonamides useful as retroviral protease inhibitors
US6150556 *Jun 7, 1995Nov 21, 2000G. D. Dearle & Co.Bis-amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors
US6156768 *Oct 29, 1993Dec 5, 2000G. D. Searle & Co.Alpha- and beta-amino acid hydroxyethylamino sulfamic acid derivatives useful as retroviral protease inhibitors
US6169085Oct 4, 1999Jan 2, 2001G. D. Searle & CompanySulfonylalkanoylamino hydroxyethylamino sulfonamide retroviral protease inhibitors
US6172082Jun 7, 1995Jan 9, 2001G. D. Searle & Co.α- and β-amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors
US6172101Mar 7, 1996Jan 9, 2001G. D. Searle & Co.Heterocyclecarbonyl amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors
US6180646Aug 26, 1998Jan 30, 2001Monsanto CompanyRetroviral protease inhibitors
US6201150Feb 17, 1998Mar 13, 2001G.D. Searle & Co.Method of preparing retroviral protease inhibitor intermediates
US6211176Jul 1, 1999Apr 3, 2001G. D. Searle & Co.α- and β-amino acid hydroxyethylamino sulfonyl urea derivatives useful as retroviral protease inhibitors
US6214861Feb 9, 2000Apr 10, 2001G.D. Searle & Co.Heterocyclecarbonyl amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors
US6248775Apr 8, 1999Jun 19, 2001G. D. Searle & Co.α- and β-amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors
US6310080Dec 1, 1999Oct 30, 2001G. D. Searle & Co.Amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors
US6313345Oct 18, 1999Nov 6, 2001G. D. Searle & Co.Succinoylamino hydroxyethylamino sulfonamides useful as retroviral protease inhibitors
US6316496Feb 1, 2000Nov 13, 2001G. D. Searle & Co.Bis-amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors
US6337398Oct 13, 1995Jan 8, 2002G.D. Searle & Co.Succinoylamino hydroxyethylamino sulfonyl urea derivatives useful as retroviral protease inhibitors
US6380188Sep 29, 2000Apr 30, 2002G. D. Searle & Co.Sulfonylalkanoylamino hydroxyethylamino sulfonamide retroviral protease inhibitors
US6384036Aug 11, 2000May 7, 2002G.D. Searle & Co.Bis-sulfonamide hydroxyethylamino retroviral protease inhibitors
US6388094Nov 1, 1999May 14, 2002G.D. Searle & Co.Method for making intermediates useful in synthesis of retroviral protease inhibitors
US6388132Oct 24, 2000May 14, 2002G. D. Searle & Co.Bis-amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors
US6403585Dec 8, 2000Jun 11, 2002G. D. Searle & Co.α-and β-amino acid hydroxyethylamino sulfonyl urea derivatives useful as retroviral protease inhibitors
US6407134Feb 5, 2001Jun 18, 2002G. D. Searle & Co.Heterocyclecarbonyl amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors
US6417387Mar 5, 2001Jul 9, 2002G.D. Searle & Co.α-and β-amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors
US6444678Aug 4, 2000Sep 3, 2002G. D. Searle & Co.α- and β-amino acid hydroxyethylamino sulfamic acid derivatives useful as retroviral protease inhibitors
US6455581May 25, 1995Sep 24, 2002G.D. Searle & Co.α-and β-amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors
US6458785Apr 18, 2001Oct 1, 2002G. D. SearleAmino acid hydroxyethylamino sulfonamide retroviral protease inhibitors
US6469207Jun 20, 2001Oct 22, 2002G. D. Searle & Co.Succinoylamino hydroxyethylamino sulfonamides useful as retroviral protease inhibitors
US6500832Mar 14, 2000Dec 31, 2002G. D. Searle & Co.α- and β-amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors
US6506759Oct 31, 2000Jan 14, 2003Monsanto CompanyRetroviral protease inhibitors
US6515024Dec 11, 2001Feb 4, 2003G. D. Searle & Co.Succinoylamino hydroxyethylamino sulfonyl urea derivatives useful as retroviral protease inhibitors
US6515162Dec 21, 2000Feb 4, 2003G.D. Searle & Co.Method of preparing retroviral protease inhibitor intermediates
US6534493Oct 24, 2000Mar 18, 2003G.D. Searleα- and β-amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors
US6538006Jul 7, 1999Mar 25, 2003Pharmacia CorporationRetroviral protease inhibitors
US6569882Feb 19, 2002May 27, 2003G. D. Searle & Co.Bis-sulfonamide hydroxyethyl-amino retroviral protease inhibitors
US6570027Apr 3, 2002May 27, 2003G. D. Searle & Co.Method of preparing intermediates useful in synthesis of retroviral protease inhibitors
US6646010May 30, 2002Nov 11, 2003G. D. Searle & Co.α- and β-amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors
US6667307Feb 26, 2002Dec 23, 2003G.D. Searle & Co.Sulfonylalkanoylamino hydroxyethylamino sulfonamide retroviral protease inhibitors
US6673822Apr 12, 2002Jan 6, 2004G.D. Searle & Co.Heterocyclecarbonyl amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors
US6683210Mar 15, 2002Jan 27, 2004G. D. Searle & Co.Bis-amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors
US6683648May 6, 2002Jan 27, 2004G. D. Searle & Co.α- and β-amino acid hydroxyethylamino sulfonyl urea derivatives useful as retroviral protease inhibitors
US6727282Sep 9, 2002Apr 27, 2004G.D. Searle & Co.Succinoylamino hydroxyethylamino sulfonamides useful as retroviral protease inhibitors
US6730669Jul 23, 2002May 4, 2004G. D. Searle & Co.Amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors
US6743929Sep 6, 2000Jun 1, 2004G. D. Searle & Co.Sulfonylalkanoylamino hydroxyethylamino sulfonamides useful as retroviral protease inhibitors
US6762187Sep 18, 2002Jul 13, 2004Monsanto CompanyRetroviral protease inhibitors
US6846954Jul 22, 2002Jan 25, 2005G. D. Searle & Co.α- and β-amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors
US6849760Dec 23, 2002Feb 1, 2005G. D. Searle & Co.Method of preparing retroviral protease inhibitor intermediates
US6861539Aug 12, 2003Mar 1, 2005G. D. Searle & Co.Bis-amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors
US6875790Feb 20, 2003Apr 5, 2005G. D. Searle & Co.Cyclic sulfone containing retroviral protease inhibitors
US6924286Aug 4, 2003Aug 2, 2005G. D. Searle & Co.α- and β-amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors
US6951886Dec 10, 2002Oct 4, 2005G. D. Searle & Co.Succinoylamino hydroxyethylamino sulfonyl urea derivatives useful as retroviral protease inhibitors
US6974876Feb 10, 2003Dec 13, 2005G.D. Searle & Co.Method for preparing intermediates useful in synthesis of retroviral protease inhibitors
US7026333Jul 26, 2000Apr 11, 2006G. D. Searle & Co.Retroviral protease inhibitors
US7026485Mar 5, 2004Apr 11, 2006G.D. Searle & Co.Retroviral protease inhibitors
US7030161Oct 21, 2003Apr 18, 2006G.D. Searle & Co.α-and β-amino acid hydroxyethylamino sulfonyl urea derivatives useful as retroviral protease inhibitors
US7037941Jun 25, 2002May 2, 2006G. D. Searle & Co.Alpha-and Beta-amino acid hydroxyethylamino sulfamic acid derivatives useful as retroviral protease inhibitors
US7038084Feb 24, 2004May 2, 2006G.D. Searle & Co.Succinoylamino hydroxyethylamino sulfonamides useful as retroviral protease inhibitors
US7045518Oct 3, 2003May 16, 2006G.D. Searle & Co.Sulfonylalkanoylamino hydroxyethylamino sulfonamide retroviral protease inhibitors
US7060851Oct 12, 2004Jun 13, 2006G.D. Searle & Co.Method of preparing retroviral protease inhibitor intermediates
US7091219Apr 17, 2003Aug 15, 2006G. D. Searle & Co.Bis-sulfonamide hydroxyethyl-amino retroviral protease inhibitors
US7098202Jan 20, 2004Aug 29, 2006G. D. Searle & Co.Amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors
US7112683Sep 2, 2004Sep 26, 2006G.D. Searle & Co.Cyclic sulfone containing retroviral protease inhibitors
US7141594Nov 19, 2003Nov 28, 2006G. D. Searle & Co.Heterocyclecarbonyl amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors
US7141609Apr 21, 2005Nov 28, 2006G.D. Searle & Co.α- and β-amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors
US7161033Jan 18, 2005Jan 9, 2007G. D. Searle & Co.Bis-amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors
US7189864Oct 13, 2004Mar 13, 2007G.D. Searle & Co.Method of preparing intermediates useful in synthesis of retroviral protease inhibitors
US7199158Jul 18, 2005Apr 3, 2007G.D. Searle & Co.Succinoylamino hydroxyethylamino sulfonyl urea derivatives useful as retroviral protease inhibitors
US7202258Jun 28, 2005Apr 10, 2007G.D. Searle & Co.α- and β-amino acid hydroxyethylamino sulfamic acid derivatives useful as retroviral protease inhibitors
US7232817Sep 27, 2005Jun 19, 2007G.D. Searle & Co.α- and β-amino acid hydroxyethlamino sulfonyl urea derivatives useful as retroviral protease inhibitors
US7297793Feb 8, 2006Nov 20, 2007G.D. Searle, LlcBis-sulfonamide hydroxyethylamino retroviral protease inhibitors
US7312333Jan 13, 2006Dec 25, 2007Pharmacia CorporationRetroviral protease inhibitors
US7320983Sep 25, 2006Jan 22, 2008G.D. Searle Llcα- and β-amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors
US7339078Aug 10, 2006Mar 4, 2008G.D. Searle LlcBis-amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors
US7531538May 15, 2006May 12, 2009G.D. Searle Llcα- and β-Amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors
US7829564Dec 7, 2007Nov 9, 2010G.D. Searle Llcα- and β-amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors
USRE42889Apr 23, 2007Nov 1, 2011G.D. Searle Llcα- and β- amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors
USRE43596Apr 23, 2007Aug 21, 2012G.D. Searle Llcα- and β-amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors
USRE43802Sep 21, 2011Nov 13, 2012G.D. Searle Llcα- and β-amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors
WO1992008688A1 *Nov 18, 1991May 29, 1992Monsanto CoRetroviral protease inhibitors
WO1993023368A1 *May 20, 1993Nov 25, 1993Searle & CoUrea-containing hydroxyethylamine compounds as retroviral protease inhibitors
Classifications
U.S. Classification548/533
International ClassificationC07D207/16, C07C323/60, C07D409/12, C07D209/18, C07D495/10, C07D209/44, C07D233/54, C07D401/12, C07D209/42
Cooperative ClassificationC07D495/10, C07C323/60, C07D209/42, C07D233/64, C07D209/18, C07D401/12, C07D409/12, C07D209/44, C07D207/16
European ClassificationC07D209/44, C07C323/60, C07D207/16, C07D209/18, C07D209/42, C07D233/64, C07D409/12, C07D401/12, C07D495/10