Cyclohexapeptidyl hydroxypropionitrile compounds

Abstract: Certain propionitrile compounds which have a cyclohexapeptidyl nucleus and which are found to have antibiotic activity with physical properties suitable for use in therapeutic compositions are described. A novel process for their preparation is also described.

Description: BACKGROUND ART EP-A-0447186 (Merck & Co., Inc.) describes compounds from which those of the present inventuion can be made having an aminocarbonyl group in place of the cyano group. Adeferati et al, J. Am. Chem. Soc., 1991 , 113, 3542-3545 describes the synthesis of an echinocandin-type antibiotic. DESCRIPTION OF THE INVENTION The present invention is directed to certain cyclohexapeptidyl propionitrile compounds having the formula In the foregoing and succeeding formulas, R 1 is H or OH R 2 is H or OH R 3 is H, OH or OR where R is C 1 -C 4 alkyl or benzyl R 4 is H or OH R 5 is H, OH or CH 3 R 6 is H or CH 3 , and R I is C 9 -C 21 alkyl, C 9 -C 21 alkenyl, or C 1 -C 10 alkoxyphenyl or C 1 -C 10 alkoxynaphthyl. Where the expression "alkyl", "alkenyl" or "alkoxy" is employed, it is intended to include branched as well as straight chain radicals. Representative nuclei for the nitrile, Compound I, and the sequence ID for these compounds may be seen in the following table. Since the amino acid nuclei would be the same irrespective of substituent in the lipophilic side chain, the sequence identification number is assigned for the nuclear variation. NITRILE COMPOUND NUCLEI R 1 R 2 R 3 R 4 R 5 R 6 SEQ. ID I-1 OH OH OH OH H CH 3 1 I-2 OH OH OH OH CH 3 CH 3 2 I-3 H OH OH OH CH 3 H 3 I-4 OH H OH OH CH 3 CH 3 4 I-5 H H OH H CH 3 CH 3 5 I-6 H H H H CH 3 CH 3 6 I-7 OH OH H H CH 3 CH 3 7 I-8 OH OH H H H CH 3 8 I-9 OH OH OH OH OH CH 3 9 I-10 H OH OH OH H H 10 I-11 H OH OCH 3 OH CH 3 H 11 I-12 H OH H OH H CH 3 12 I-13 OH OH H OH H CH 3 13 I-14 H OH OH OH H CH 3 27 I-15 OH OH OCH 3 OH H CH 3 28 The compounds are soluble in lower alcohols and polar aprotic solvents such as dimethylformamide (DMF) and pyridine, mixture of alkanol and water. polyethylene glycol and water, acetonitrile and water and the like. They are insoluble in solvents such as ether and acetonitrile. The compounds of the present invention are useful as intermediates for extremely active antifungal agents which have properties suitable for direct use and as intermediates for agents useful in the treatment and/or inhibition of Pneumocytis carinii pneumonia to which immune compromised patients are especially susceptible. The compounds of the present invention may be prepared from a natural product or a derivative of a natural product. The nitrile may be represented by compounds of formula (I) (Seq. ID Nos. 1-13, 27 and 28) and the starting materials may be represented by compounds of formula (E) (Seq. ID Nos. 14-26, 29 and 30) as seen in the following diagrams: In certain cases, when a natural product with the corresponding nucleus is not known, the compound may be obtained by first preparing a closely related nitrile and thereafter modifying. Thus a compound with an I-14 nucleus may be obtained after first preparing a compound of I-1 nucleus and thereafter reducing R 1 from OH to H. The nitriles (Compound I) are useful intermediates in the preparation of the amine compounds of the following formulas which are claimed in copending application: EP-A-0 535 959, filed October 1, 1991. and The starting materials for the nitriles are natural products or derivatives of natural products and are obtained from various sources and may be obtained as subsequently described. The sequence identification numbers for the starting materials, Compound E (Seq. ID Nos. 14-26, 29 and 30), which correspond to the nitriles are seen below. STARTING MATERIAL R 1 R 2 R 3 R 4 R 5 R 6 Seq. ID E-1 OH OH OH OH H CH 3 14 E-2 OH OH OH OH CH 3 CH 3 15 E-3 H OH OH OH CH 3 H 16 E-4 OH H OH OH CH 3 CH 3 17 E-5 H H OH H CH 3 CH 3 18 E-6 H H H H CH 3 CH 3 19 E-7 OH OH H H CH 3 CH 3 20 E-8 OH OH H H H CH 3 21 E-9 OH OH OH OH OH CH 3 22 E-10 H OH OH OH H H 23 E-11 H OH OCH 3 OH CH 3 H 24 E-12 H OH H OH H CH 3 25 E-13 OH OH H OH H CH 3 26 E-14 H OH OH OH H CH 3 29 E-15 OH OH OCH 3 OH H CH 3 30 The preparation of Compound I (Seq. ID Nos. 1-13, 27 and 28) may be carried out by the dehydration of the carboxamide group to the nitrile. When this method is employed the reaction is preferably carried out under nitrogen with cyanuric chloride in a solvent. It may be carried out in the presence of molecular sieves but if carried out in the absence of sieves, reaction time is critical, and usually order of addition becomes important. In the absence of sieves, or without careful control of reaction time, degradation may occur even when the R 3 hydroxyl is protected with an ether group. Suitable reagents which may be employed in place of cyanuric chloride are anhydrides such as acetic anhydride, trifluoroacetic anhydride and phosphorus pentoxide; acid chlorides such as oxalyl chloride, phosphorus oxychloride, thionyl chloride, p-toluenesulfonyl chloride and chlorosulfonyl isocyanate; phosphonium reagents such as phosphorus pentachloride, triphenylphosphine/carbon tetrachloride, triphenylphosphonium ditriflate and triphenylphosphonium dichloride; carbodiimides such as dicyclohexylcarbodiimide; other dehydrating agents such as aluminum chloride, titanium tetrachloride, ethyl(carboxysulfamoyl)triethylammonium hydroxide and inner salt. Suitable solvents include dimethylformamide or weakly basic solvents such as pyridine, collidine and the like. Molecular sieves may be in the size range 3A to 5A. The relative amounts of Compound E (Seq. ID Nos. 14-26, 29 and 30) and reagents vary, but in general the dehydrating agent is used in excess. From about 1.5 to 15 equivalents of the dehydrating agent are employed. The molecular sieves are used in amounts of 1 to 10 equivalents. In carrying out the reaction using sieves, a suspension of molecular sieves in a rigorously dried solvent is first prepared, and while stirring under an atmosphere of nitrogen, there is added, cyanuric chloride or other dehydrating agent and thoroughly mixed. To the resulting mixture while stirring under an atmosphere of nitrogen is added the starting material, Compound E and the stirring continued for about 12 to 24 hours or until HPLC analysis of the reaction mixture indicates substantial completion of the reaction with the formation of the nitrile. The sieves are removed by filtration, preferably on a sintered glass funnel, and the filtrate concentrated and purified by preparative HPLC. The mobile phase used in the purification are varying ratios of a water/acetonitrile composition and an acetonitrile/water composition. These compositions are referred to in the examples as A and B. Composition A is 95/5 water/acetonitrile containing 0.1% trifluoroacetic acid (TFA) or acetic acid. Composition B is 95/5 acetonitrile/water containing 0.1% TFA or acetic acid. The exact mobile phase used for HPLC assays and the mobile phase used in preparative HPLCs may differ not only from each other but also from compound to compound but can be determined by the skilled artisan without difficulty. In carrying out the reaction in the absence of sieves, solid cyanuric chloride is added in a single portion to a solution of Compound E in an aprotic solvent and stirred rapidly for a short time and the reaction mixture then quenched by adding aqueous sodium acetate directly to the reaction mixture. The volatiles are then removed in vacuo to obtain a solid residue which may be purified as above described. When R 1 is H, R 2 , R 3 and R 4 are OH, R 5 is H or CH 3 and R 6 is CH 3 , the nitrile compound may be made using a nitrile compound, in which R 1 is OH with the remaining Rs being the same, and reducing it by methods known to the skilled in the art. Conveniently, this may be carried out by adding trifluoracetic acid to the nitrile and sodium triacetoxyborobydride contained together and thereafter mixing until a clear solution is obtained and thereafter recovering the product as a precipitate by pouring into water. The precipitate product may then be purified by preparative HPLC by placing on the column in a methanol/water mixture and eluting with water/acetonitrile. When R 3 is O-alkyl, the nitrile may be made using another nitrile compound in which R 3 is OH. This may be accomplished by dissolving the nitrile compound in alkanol and adding an acid such as p-toluenesulfonic acid and stirring until the reaction is complete. The compound may be obtained by precipitation and purification as described above. The following examples illustrate the invention but are not to be construed as limiting. EXAMPLE I Preparation of Nitrile Compound 550 milligrams (2.98 mmol; 1.5 molar eq) of cyanuric chloride was added to a suspension of 4A molecular sieves pre-prepared by stirring together 10.2 grams of 4A molecular sieves under nitrogen for 0.5 hour with 45 milliliters of DMF (predried over a combination of 13X and 3A molecular sieves), and the stirring continued for 5 minutes. To the resulting suspension was added 2.08 grams (1.95 mmol) of Compound E-1 (Seq. ID No. 14) (R 1 , R 2 , R 3 and R 4 are OH; R 5 is H; R 6 is CH 3 ; R I is 9,11-dimethyltridecyl). The resulting mixture still under nitrogen was then stirred for 18 hours. At the end of this period an HPLC analysis was carried out employing a "ZORBAX" (Dupont, 4.9 mm X 25 cm) C8 column and eluting isocratically with 60/40 A:B (containing 0.1% TFA) at ambient temperature with detection by ultraviolet absorption at 210 nm which showed about a 2:1 ratio of product to starting material. The molecular sieves were filtered onto a sintered glass funnel and washed consecutively with 5 milliliters of DMF and 5 milliliters of methanol. The filtrate was concentrated in vacuo to a final volume of 20 milliters and filtered through a 0.45 µ Whatman polypropylene syringe filter. The filtrate was diluted with mobile phase 65/35 A:B to a volume of 40 milliliters and pump injected at 10 milliliters per minute onto a Waters 45 mm ID radial compression column packed with 15 µ, 100 Angstrom Δ-Pak C18 stationary phase. The column was eluted initially at 20 mL/min and the elution continued until the front running impurities had been eluted. The composition of the eluting agent was then stepped to 60/40 A:B and the flow increased to 40 mL/min. Fractions containing the desired product were pooled and concentrated in vacuo to remove most of the acetonitrile. The residue was lyophilized to obtain 800 milligrams (40 percent yield) of the nitrite (Seq. ID No. 1). The compound had the following spectral characteristics. 1 H-NMR (400 MHz, CD 3 OD): δ 7.12 (d, 2H), 6.73 (d, 2H), 5.31 (d, 1H), 1.20 (d, 3H), 0.88 (t, 3H), 0.87 (d, 6H) Mass spectra (FAB): 1054 (M+Li) EXAMPLE II Compound Ia of Example I may be prepared in the absence of sieves. In such an operation, 1.0 gram of Compound E-1 was placed in 12.0 milliliters of dry DMF at 17°C and stirred rapidly. Solid cyanuric.chloride (0.26 g, 1.4 mmol) then was added in a single portion and the mixture was stirred for exactly 5.5 minutes. The reaction mixture was then quenched with 4.2 mL aqueous 1M sodium acetate. The volatiles were removed in vacuo to obtain a solid. HPLC analysis 45/55 A:B (0.1% TFA) on "ZORBAX" C8 indicated 82 percent of the product was the desired nitrile. The nitrile may be purified as in Example I or by pouring a concentrated methanolic solution of the residue into dry acetonitrile, collecting the precipitate, and repeating the precipitation, this time from water, then collecting the solid and dissolving in methanol followed by removing the volatiles to obtain a granular solid. EXAMPLE III Preparation of Nitrile Compound In an operation carried out in a manner similar to that described in Example I, 290 milligrams (1.57 mmol) of cyanuric chloride was added to a solution of 2.0 grams (1.94 mmol) of Compound E-12 (Seq. ID No. 25) (R 1 and R 3 =H; R 2 and R 4 =OH; R 5 =H; R 6 =CH 3 ; R I is 9,10-dimethyltridecyl) in 8.0 milliters of DMF and the reaction mixture stirred under nitrogen for 24 hours. At this time, an additional 290 milligrams (1.57 mmol) was added and the reaction continued for one hour whereupon the reaction was judged complete by HPLC "ZORBAX" column isocratic elution with 45/55 A/B (containing 0.1% TFA) at 40°C, detection at λ=210 nm. The reaction mixture was diluted with mobile phase (50/50 A:B) and filtered through a 0.45 µ Whatman polypropylene syringe filter and injected onto a Waters 45 mm I.D. radial compression column packed with 15µ, 100A Δ-Pack C18 stationary phase. The desired fractions were combined and lyophilized to obtain 670 milligrams (34 percent) of nitrile, (Seq. ID No. 12) having a HPLC retention time of 8.0 min on a "ZORBAX" column when eluted isocratically with 45/55 A:B at 1.5 mL/min at 40°C; detection at λ=210 nm. 1 H-NMR (400 MHz, CD 3 OD): δ 7.00 (d, 2H), 6.70 (d, 2H), 5.02 (d, 1H), 4.98 (d, 1H), 1.20 (d, 3H), 0.89 (t, 3H), 0.86 (d, 6H) Mass spectra (FAB): 1020 (M+Li) EXAMPLE IV 250 milligrams (0.242 mmole) of the lipopeptide Compound E-12 (R 1 and R 3 are H, R 2 and R 4 are OH; R 5 is H; R 6 is CH 3 ; R I is 9,11-dimethyltridecyl; Seq. ID No. 25) was dissolved in 3 milliliters of dry pyridine and cooled to 0°C. Trifluoroacetic anhydride (0.36mL, 2.5mmol) was added in five portions. The starting lipopeptide was consumed at this point as determined by analytical HPLC (50/50 H 2 O:CH 3 CN), 2ml/min, "ZORBAX" C8 column, λ=210, 277nm). The reaction was then quenched by the addition of 1 mL of water. The volatiles were removed in vacuo to obtain a residue. The residue was purified by preparative HPLC (50/50 H 2 O/CH 3 CN, 15mL/min, 21.2 x 250 "ZORBAX" C8, collecting 22.5 mL fractions λ=210,277nm), combining the appropriate fractions and lyophilizing to obtain 56 milligrams (23 percent) of a white powder. The compound was characterized by 13 C NMR, 1 H NMR, IR (υ=2258cm -1 , weak), 2D-NMR(COSY), UV and mass spectroscopy (M+Li=1020 amu) to be compound Ib with R I as 9,10-dimethyltridecyl (Seq. ID No. 12). EXAMPLE V To a solution of 44 milligrams (42 µmol) of Compound Ia (Seq. ID No. 1) (prepared as described in Example I) in 2.0 milliliters of methanol is added 20 milligrams (2 eq) of camphorsulfonic acid and the resulting mixture is stirred at room temperature for three hours. The reaction mixture is injected directly onto "ZORBAX" (25mm x 25cm) C8 column and eluted with 50/50 A:B at 8.0mL/min. The pure fractions as determined by HPLC are pooled and lyophilized to obtain Compound Ic. (Seq. ID No. 28). EXAMPLE VI To a solution of 110 milligrams (0.104 mmol) of a lipopeptide compound (R 1 , R 2 , R 3 and R 4 are OH, R 5 is H, R 6 is CH 3 and R I is C 6 H 4 OC 8 H 17 Seq. ID. No. 1) in sieve-dried DMF under an atmosphere of nitrogen was added 59 milligrams (0.322 mmol) of cyanuric acid in one portion. The reaction was allowed to proceed for 5.5 minutes and then quenched by the addition of 1.35 milliliters of 2M sodium acetate solution. HPLC analysis showed a product to starting material ratio of 15.5:1. The reaction mixture was diluted with 2.0 milliliters of 50 percent aqueous acetonitrile and injected onto a radial compression C18 Delta-Pak column (15 µ, 100A; 25 mm x 50 cm). Elution was started at 12.0 mL/min. with 75:25 water/acetonitrile (0.1% TFA) until all the DMF and other front running materials had been eluted. The gradient was then stepped up to 50:50 over the course of 30 minutes and pure fractions of the product were collected, combined, and lyophilized to obtain 60 milligrams (55.5% yield) of product of >99.5% purity as determined by HPLC ("ZORBAX" C18; isocratic elution with 6:4 water/acetonitrile (0.1% TFA) 1.5 mL/min.; 40°C; λ210 nm; retention time = 9.74 min.). The product had the following spectral characteristics: 1 H-NMR (400 MHz; CD 3 OD) δ 7.82 (d,2 H), 7.12 (d, 2 H) 6.94 (d, 2 H), 6.75 (d, 2 H), 5.37 (d, 1 H) 2.86 (dd, 1 H), 2.76 (dd, 1 H), 2.44 (m, 1 H), 2.29 (m, 1 H), 1.21 (d, 3 H), 0.9 (t, 3 H). Mass Spectra (FAB) 1048 (M+Li) EXAMPLE VII The nitrile formula (Ia) prepared as described in Example I was employed as starting material for the preparation of a different nuclear configuration of formula (Ie) Eleven milliliters of trifluoroacetic acid was added to 0.570 gram (0.544 mmol) of nitrile (Ia) and 1.10 grams (5.19 mmol) of sodium triacetoxyborohydride and the mixture stirred for 120 seconds to obtain a clear solution. The solution was poured into 150 milliliters of distilled water to obtain a precipitate which was recovered. The solid was purified by dissolving in a small amount of methanol, and adding just enough water to the point of precipitation and purified by preparative HPLC ("ZORBAX" C18 and eluting with 53%A/47%B where A is 95% water/5% acetonitrile and B is 5% water/95% acetonitrile) and thereafter lyophilizing the appropriate fractions to obtain 0.220 gram of the desired compound. The product had the following spectral properties: 1 H-NMR (400 MHz; CD 3 OD) δ 7.01 (d, 1H, J=10 Hz), 6.69 (d, 1H, 10 Hz), 5.33 (d, 1H, J=3 Hz), 5.06 (d, 1H, J=5 Hz) and 5.00 (d, 1H, J=4 Hz). Mass Spectra: (FAB) 1038 (M+Li) EXAMPLE VIII Compound E-1 is cultivated with Actinoplanaceae to obtain a cyclopeptide nucleus compound which is acylated with an active ester to obtain a compound in which the side chain is varied. Thus modified compounds, in a manner similar to that described above, is dehydrated to obtain the following compounds: Nitrile Compound R 1 R 2 R 3 R 4 R 5 R 6 R I SEQ ID If OH OH OH OH H CH 3 C 13 H 27 1 Ig OH OH OH OH H CH 3 C 6 H 4 OC 8 H 17 1 Ih OH OH OH OH H CH 3 (CH 2 ) 7 CH=CH(CH 2 ) 7 CH 3 1 Ii OH OH OH OH H CH 3 C 10 H 6 OC 8 H 17 1 Ij OH OH OH OH H CH 3 C 13 H 27 (n) 1 EXAMPLE IX In similar operations the following compounds may be prepared. Nitrile Compound R 1 R 2 R 3 R 4 R 5 R 6 R I SEQ ID Ik H OH H OH H CH 3 C 17 H 25 12 Il H OH H OH H CH 3 (CH 2 ) 7 CH=CH(CH 2 ) 7 CH 3 12 Im H OH H OH H CH 3 C 6 H 4 OC 8 H 17 12 In H OH H OH H CH 3 C 16 H 33 12 Io H OH H OH H CH 3 C 10 H 6 OC 8 H 17 12 EXAMPLE X 1000 compressed tablets each containing 500 mg of Compound Ia are prepared from the following formulation: Compound Grams Compound Ia (Seq. ID No. 1) 500 Starch 750 Dibasic calcium phosphate, hydrous 5000 Calcium stearate 2.5 The finely powdered ingredients are mixed well and granulated with 10 percent starch paste. The granulation is dried and compressed into tablets. EXAMPLE XI 1000 hard gelatin capsules, each containing 500 mg of Compound Ib are prepared from the following formulation: Compound Grams Compound Ib 500 Starch 250 Lactose 750 Talc 250 Calcium stearate 10 A uniform mixture of the ingredients is prepared by blending and used to fill two-piece hard gelatin capsules. EXAMPLE XII An aerosol composition may be prepared having the following formulation: Per Canister Compound Ia 24 mg Lecithin NF Liquid Concentrated 1.2 mg Trichlorofluoromethane, NF 4.026 g Dichlorodifluoromethane, NF 12.15 g EXAMPLE XIII 250 milliliters of an injectible solution may be prepared by conventional procedures having the following formulation: Dextrose 12.5 g 26% aqueous polyethylene glycol 300 250 ml Compound Ib 400 mg The ingredients are blended and thereafter sterilized for use. Preparation of Starting Materials : The starting materials for the compounds are natural products or derivatives of natural products. The following compounds are natural products produced by cultivating an appropriate organism in nutrient medium. E-1 may be produced by cultivating Zalerion arboricola ATCC 20868 in a nutrient medium enriched in mannitol as the primary source of carbon as described in U.S. Patent No. 5,021,341, June 4, 1991. E-2 may be produced by cultivating Zalerion arboricola ATCC 20868 in nutrient medium as described in U.S. 4,931,352, June 5, 1990 or in nutrient medium enriched in glycerol as described in U.S. 4,968,608, November 6, 1990. E-2 nucleus with a different R may be produced by cultivating Acrophialophora limonispora in nutrient medium as described in U.S. 4,173,629. E-3, E-10 and E-11 may be produced by cultivating Cryptosporiopsis ATCC 20594 in nutrient medium as described by Pache et al in 13th ICC (1983), PS 4.8/3, Part 115, Abstract No. 10 and PCT WO 82/00587. E-4, E-5 and E-6 may be produced by cultivating Zalerion arboricola ATCC 20868 in nutrient medium. E-7 may be produced by cultivating Zalerion arboricola ATCC 20958 in nutrient medium as described in U.S. 5,021,403. E-8 may be produced by cultivating Zalerion arboricola ATCC 20958 in nutrient medium. E-9 may be produced by cultivating Zalerion arboricola ATCC 74030 in nutrient medium. Starting materials which are cyclohexapeptides in which the nucleus of the foregoing has been modified to produce novel hexapeptides in which R 3 or both R 3 and R 1 are hydrogen instead of hydroxyl may be obtained by intimately mixing a compound in which R 3 is hydroxyl and R 1 may be hydroxyl with a reducing agent such as sodium cyanoborohydride in the presence of a strong acid such as trifluoroacetic acid and the mixture stirred until the reaction is complete. The volatiles are then removed under reduced pressure and the residue purified by reverse phase chromatography employing water/acetonitrile to obtain a purified product. When R 1 is OH and it is desired to reduce only R 3 , essentially the same procedure is used except that the reactant lipopeptide is first dissolved in glacial acetic acid and the reaction carried out in a similar manner. A compound in which R 1 and R 3 are H, and R 2 and R 4 are OH, R 5 is H and R 6 is CH 3 may be identified as E-12 and a compound in which R 3 is H and R 1 , R 2 and R 4 are OH, R 5 is H and R 6 is CH 3 may be identified as E-13. Starting materials in which R I is a different group from that of the natural product may be obtained by deacylating the lipophilic group of the natural product by subjecting the natural product in a nutrient medium to a deacylating enzyme until substantial deacylation occurs, said enzyme having first been obtained by cultivating a microorganism of the family Pseudomondacease or Actinoplanaceae , as also described in Experentia 34, 1670 (1978) or U.S. 4,293,482, and thereafter recovering the deacylated cyclopeptide, and acylating the deacylated cyclopeptide by mixing together with an appropriate active ester R I COX to obtain Compound E with the desired acyl group as also described in U.S. 4,287,120 and 4,293,489. When R 1 is H, R 2 , R 3 and R 4 are OH, R 5 is H or CH 3 and R 6 is CH 3 , the nitrile intermediate may be made using another nitrile compound, in which R 1 is OH with the remaining R 5 being the same, and reducing R 1 by methods known to the skilled in the art. Conveniently this may be carried out by adding trifluoroacetic acid to the nitrile and triacetoxyborohydride and mixing together until a clear solution is obtained and thereafter recovering the product as a precipitate by pouring into water. The precipitate product may then be purified by preparative HPLC by placing on the column in a methanol/water mixture eluting with water/acetonitrile. SEQUENCE LISTING (2) INFORMATION FOR SEQ ID NO: 1: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 6 (B) TYPE: AMINO ACID (C) STRANDEDNESS: NA (D) TOPOLOGY: CIRCULAR (ii) MOLECULE TYPE: (A) DESCRIPTION: PEPTIDE (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 1 (2) INFORMATION FOR SEQ ID NO: 2: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 6 (B) TYPE: AMINO ACID (C) STRANDEDNESS: NA (D) TOPOLOGY: CIRCULAR (ii) MOLECULE TYPE: (A) DESCRIPTION: PEPTIDE (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 2 (2) INFORMATION FOR SEQ ID NO: 3: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 6 (B) TYPE: AMINO ACID (C) STRANDEDNESS: NA (D) TOPOLOGY: CIRCULAR (ii) MOLECULE TYPE: (A) DESCRIPTION: PEPTIDE (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 3 (2) INFORMATION FOR SEQ ID NO: 4: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 6 (B) TYPE: AMINO ACID (C) STRANDEDNESS: NA (D) TOPOLOGY: CIRCULAR (ii) MOLECULE TYPE: (A) DESCRIPTION: PEPTIDE (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 4 (2) INFORMATION FOR SEQ ID NO: 5: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 6 (B) TYPE: AMINO ACID (C) STRANDEONESS: NA (D) TOPOLOGY: CIRCULAR (ii) MOLECULE TYPE: (A) DESCRIPTION: PEPTIDE (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 5 (2) INFORMATION FOR SEQ ID NO: 6: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 6 (B) TYPE: AMINO ACID (C) STRANDEDNESS: NA (D) TOPOLOGY: CIRCULAR (ii) MOLECULE TYPE: (A) DESCRIPTION: PEPTIDE (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 6 (2) INFORMATION FOR SEQ ID NO: 7: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 6 (B) TYPE: AMINO ACID (C) STRANDEDNESS: NA (D) TOPOLOGY: CIRCULAR (ii) MOLECULE TYPE: (A) DESCRIPTION: PEPTIDE (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 7 (2) INFORMATION FOR SEQ ID NO: 8: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 6 (B) TYPE: AMINO ACID (C) STRANDEDNESS: NA (D) TOPOLOGY: CIRCULAR (ii) MOLECULE TYPE: (A) DESCRIPTION: PEPTIDE (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 8 (2) INFORMATION FOR SEQ ID NO: 9: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 6 (B) TYPE: AMINO ACID (C) STRANDEONESS: NA (D) TOPOLOGY: CIRCULAR (ii) MOLECULE TYPE: (A) DESCRIPTION: PEPTIDE (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 9 (2) INFORMATION FOR SEQ ID NO: 10: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 6 (B) TYPE: AMINO ACID (C) STRANDEDNESS: NA (D) TOPOLOGY: CIRCULAR (ii) MOLECULE TYPE: (A) DESCRIPTION: PEPTIDE (xi) SEQUENCE DESCRIPTION: SEQ IO NO: 10 (2) INFORMATION FOR SEQ ID NO: 11: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 6 (B) TYPE: AMINO ACID (C) STRANDEDNESS: NA (D) TOPOLOGY: CIRCULAR (ii) MOLECULE TYPE: (A) DESCRIPTION: PEPTIDE (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 11 (2) INFORMATION FOR SEQ ID NO: 12: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 6 (8) TYPE: AHINO ACID (C) STRANDEDNESS: NA (D) TOPOLOGY: CIRCULAR (ii) MOLECULE TYPE: (A) DESCRIPTION: PEPTIDE (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 12 (2) INFORMATION FOR SEQ ID NO: 13: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 6 (B) TYPE: AMINO ACID (C) STRANDEDNESS: NA (D) TOPOLOGY: CIRCULAR (ii) MOLECULE TYPE: (A) DESCRIPTION: PEPTIDE (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 13 (2) INFORMATION FOR SEQ ID NO: 14: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 6 (B) TYPE: AMINO ACID (C) STRANDEDNESS: NA (D) TOPOLOGY: CIRCULAR (ii) MOLECULE TYPE: (A) DESCRIPTION: PEPTIDE (xi) SEQUENCE DESCRIPTION; 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Claims: A compound having the formula: wherein R 1 is H or OH R 2 is H or OH R 3 is H, OH or OR where R is C 1 -C 4 alkyl or benzyl R 4 is H or OH R 5 is H, OH or CH 3 R 6 is H or CH 3 , and R I is C 9 -C 21 alkyl, C 9 -C 21 alkenyl, C 1 -C 10 alkoxyphenyl, or C 1 -C 10 alkoxynaphthyl. A compound according to Claim 1 having a formula selected from the group consisting of:

Inventors: BALKOVEC JAMES M, ZAMBIAS ROBERT A, BALKOVEC, JAMES M., ZAMBIAS, ROBERT A.
Applicants: MERCK & CO INC, MERCK & CO., INC.
Application year: 1992
Main classification: C07K7
IPC codes: A61P31, C07K7, A61K38