Camptothecin derivatives, preparations thereof and antitumor agents

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to new water-soluble camptothecin derivatives, a process of the preparation thereof and antitumor agents containing the same as an active ingredient.
2. Description of the Prior Art
The present inventors have made an exploratory research and provided a number of new camptothecin (hereinafter referred to CPT) derivatives with excellent antitumor activities, and found that totally synthetic CPT derivatives carrying a lower alkyl group in 7-position on the B-ring and also hetero substituent and/or alkyl group in 9-, 10- and 11-position on the A-ring among others showed strong antitumor activity (see JP, A, H1-186892).
The present inventors have also made extensive researches to make the derivatives water-soluble by various means in order to solve a problem in case of administration. Especially, CPT derivatives synthesized by subjecting 7-ethylCPT to open the E-lactone ring by the diamines followed by acylation of the hydroxymethyl group showed excellent water solubility without decrease of antitumor activity contrasting to the known E-ring opened water soluble CPT derivatives (see JP, A, H1-131179 or U.S. Pat. No. 4,914,205).
In addtion to further research to obtain other new CPT derivatives with more excellent antitumor activity and with useful water solubility in case of administration, there is also a great demand in the art for creating new CPT derivatives which solve both toxicity and usage problems.
BRIEF SUMMARY OF THE INVENTION
Accordingly, an object of this invention is to provide new CPT derivatives possessing excellent characteristics in an antitumor activity. It is another object to provide new CPT derivatives which solve water solubility problem. In order to achieve those objects, we provided a process for the preparation of new water-soluble CPT derivatives prepared from CPT derivatives carrying a lower alkyl group in 7-position on the B-ring and also hetero substituent and/or alkyl group in 9-, 10- and 11-position on the A-ring by subjecting them to open the E-lactone ring by the diamines followed by acylation of the hydroxymethyl group. As a result of our extensive safety and galenical researches made for these new water-soluble CPT derivatives, it has been realized to achieve the above mentioned objects, and we succeeded in providing excellent new CPT derivatives as an antitumor agent in the invention.

DETAILED DESCRIPTION OF THE INVENTION
In accordance with the present invention, there are provided new CPT derivatives represented by the general formula: ##STR3## wherein R.sup.1 represents a hydrogen atom or a C.sub.1 -C.sub.6 alkyl group, R.sup.2 represents a hydrogen or a C.sub.1 -C.sub.6 alkoxy group, R.sup.3 represents a hydrogen or halogen atom or a C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, hydroxyl, C.sub.2 -C.sub.6 acyloxy or methoxyethoxymethoxy group, R.sup.4 represents a hydrogen or halogen atom, and R.sup.5 represents a C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 unsaturated alkyl, alkylthioalkyl, alkoxyalkyl, pyridyl or substituted phenyl group, with the proviso that all of the R.sup.2, R.sup.3 and R.sup.4 substituents should not be a hydrogen atom, and a process for preparing new camptothecin derivatives. In further accordance with the present invention, there are provided antitumor agents containing new CPT derivatives of general formula (1) as an active ingredient.
The new CPT derivatives of the invention are prepared from CPT derivatives carrying a hydrogen atom or a lower alkyl group in 7-position and also hetero and/or alkyl group in 9-, 10- and 11-position by N,N-dimethylethylenediamine without solvent followed by acylation of 17-hydroxymethyl group with appropriate acylating agents. The starting CPT derivatives carrying a hydrogen atom or a lower alkyl group in 7-position and also hetero substituent and/or alkyl group in 9-, 10- and 11-position are the known CPT derivatives (9-methoxyCPT, 10-hydroxyCPT, 10-methoxyCPT, 11-hydroxyCPT, 11-methoxyCPT etc.) prepared from natural substances or are obtained semisynthetically or synthetically by the known procedures (see JP, A, S58-39684 U.S. Pat. Nos. 4,473,692 and 4,545,880; JP, A, S58-134095 or U.S. Pat. Nos. 4,473,692 and 4,545,880; JP, A, S59-51287 or U.S. Pat. No. 4,604,463; JP, A, S59-51289 or U.S. Pat. No. 4,604,463; JP, A, H1-279891 or U.S. Pat. Nos. 4,939,255 and 5,061,795; JP, A, H1-186892 U.S. Pat. No. 5,061,800; JP, A, H4-503505; JP, A, H5-502017; WO-91/04260; WO-92/11263; U.S. Pat. No., 5,122,606 and others).
Although a reaction condition disclosed by in JP, A, H1-131179 U.S. Pat. No. 4,914,205 by us for the E-ring opening by N,N-dimethylethylenediamine followed by acylation of 17-hydroxyl group with appropriate acylating agents can be applied, it has been found that aimed compounds were not necessarily prepared in satisfactory yields according to this procedure. We have examined reaction conditions of this procedure and found that in the first step of the E-lactone ring opening reaction by N,N-dimethylethylenediamine, using an excess amount of N,N-dimethylethylenediamine alone without solvent gave the E-ring opened intermediate followed by acylation of 17-hydroxyl group with appropriate acylating agents to afford the aimed compounds in very good yields.
As the acylating agent used for the acylation there is no specific agent, but corresponding acid anhydrides, acid halogenides, for example, acid chlorides, acid bromides and other equivalent acylating agents can be used. A reaction mixture of a corresponding carboxylic acid treated with a condensation agent, for example, dicyclohexylcarbodiimide can be also used for the said acylation.
Illustrative of the corresponding carboxylic acids used as the said acylating agents are, for example, saturated aliphatic acids with 2-20 carbon atoms, unsaturated aliphatic acids with 3-20 carbon atoms, aliphatic acids with a cycloalkyl group, or aliphatic acids with, for example, a halogen atom or alkylthio, amino, acylamino, hydroxyl, alkoxy, or alkoxycarbonyl group, aromatic acids with 6-20 carbon atoms or aromatic acids with, for example, a halogen atom or hydroxyl, alkoxy or lower alkyl group, heteroaromatic acids or amino acids. Examples of the acylating agents include acetyl chloride, benzoyl chloride, propionyl chloride, butyryl chloride, methoxybenzoyl chloride, fluorobenzoyl chloride, bromobenzoyl chloride, chlorobenzoyl chloride, nitrobenzoyl chloride, trifluoromethylbenzoyl chloride, naphthoyl chloride, cyclopropanecarbonyl chloride, thenoyl chloride, crotonyl chloride, cinnamoyl chloride, phenylacetyl chloride, phenylbenzoyl chloride, cyclohexanecarbonyl chloride, stearoyl chloride, oleoyl chloride, methoxycarbonylbezoyl chloride, ethyl succinyl chloride, linoleyl chloride, chlorobutyryl chloride, ethylbenzoyl chloride, methylthiopropionyl chloride, pivaloyl chloride, nicotinoyl chloride, isonicotinoyl chloride and picolinoyl chloride.
In the said acylation N,N-dimethylaminopyridine or the like can be present in the reaction as a catalyst.
In adding, to keep carefully an anhydrous condition not only in the ring-opening process but in the acylation process and further, for example, in the pulverization, the purification and the crystalization process can increase a yield of an aimed compound.
The new CPT derivatives of this invention show excellent water solubility by being converted to acid addition salts thereof with proper acids such as hydrochloric acid. The compounds of this invention show excellent results in safety and in antitumor activity and therefore can be provided as new antitumor agents.
The present invention will now be illustrated in more detail by way of examples.
SYNTHETIC EXAMPLES
General Synthetic Methods
Example 1
Preparation of ring-opened compounds (B1-B13)
As a starting material CPT derivatives (A1-A12, for each substituent refer Table 1) with each substituent in 7-position and in 9-, 10- and 11-position on the A-ring were prepared according to the above mentioned literature. 9-Methoxy CPT(A13) isolated from natural substances was employed in this example. And for the compounds carrying hydroxyl group on the A-ring, the compound (A10') which was obtained by a usual O-methoxyethoxymethylation was used.
To 3.0 g, for example, of the starting CPT derivative (A1-A13) was added excess anhydrous N,N-dimethylethylenediamine (5-100 eq. for example 15 ml). The reaction mixture was stirred under nitrogen at 50.degree. C. for 1.5 hr. After reacted the reaction mixture was evaporated to dryness under reduced pressure. The residue was dissolved in dry methylene chloride (for example 15 ml), and the solution was poured into large amount of dry n-hexane (for example 500 ml). The precipitated crystals were filtered, washed with dry n-hexane and dried to give the hydroxyamide (B1-B13, E-lactone-ring opened compounds) in an almost quantitative yield.
The yields and each spectral data are shown in the following Table 2.
Example 2
Acylation of the 17-hydroxyl group
To a solution of the above obtained hydroxyamide (for example 1.0 g) in dry methylene chloride (for example 20 ml) was added dropwise an acylating agent (1.2 eq.)in presence of dimethylaminopyridine (DMPA, for example 100 mg) under ice cooling. The reaction mixture was stirred at room temperature overnight and washed with 7% aqueous sodium hydrogen bicarbonate and saturated aqueous sodium chloride solution. The methylene chloride layer was dried over anhydrous sodium sulfate, followed by removal of insoluble materials, and evaporated to dryness under reduced pressure. The residue was subjected to silica gel column chromatography (10% MeOH--CHC1.sub.3) and crystallized from chloroform-n-hexane to give the 17-O-acyl-21-N, N-dimethylaminoethylamide derivative (C1-C48) related to the invention.
As for an O-methoxyethoxymethyl derivative a solution of the compound in 10% trifluoroacetic acid-methylene chloride was stirred overnight. After stirring triethylamine (eq. mol) was added dropwise under ice cooling to the reaction mixture. The reaction mixture was evaporated to dryness under reduced pressure. The residue was dissolved in methylene chloride, washed with 7% aqueous sodium hydrogen bicarbonate and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, followed by removal of insoluble materials, and evaporated to dryness under reduced pressure. The residue was subjected to silica gel column chromatography (10% MeOH--CHC1.sub.3) and crystallized from acetone-CHC1.sub.3 to give the 17-O-acyl-21-N,N-dimethylaminoethylamide derivative (C28, C30, C32, C34, C36, C38) related to the invention.
The yields of the synthesized derivatives and their spectral data are shown in Table 1 and Table 3.
The water solubility data of the obtained new camptothecin derivatives related to the invention are shown in Table 4.
�Antitumor Effect!
For the obtained new camptothecin derivatives of the invention, their results of antitumor activity, toxicology test, usage-dose, and galenical preparation are described below.
�Antitumor Activity!
It is well accepted that antitumor effect for a rodent leads to a reliable result for antitumor effect in a warm-blooded animal. The present inventors investigated antitumor effect for mice as a model.
�Antitumor activity for L1210!
5.times.10.sup.5 cells of mouse leukemia L1210 were transplanted intraperitoneally to a group of six female CDF1 mice (7 weeks old, body weight 17-19 g). The test compound was administered intraperitoneally on day 1, 5 and 9 and its life prolonging effect was observed.
In a case of the administration of a test compound as an acid addition salt the test compound was dissolved in water. The total administration amount was 1.56 mg/kg-400 mg/kg. The antitumor activity was expressed by the value (T/C%) wherein T denotes the mean survival days in the drug administered group and C denotes those in the non administered group. In case of equal to or more than 125% the drug is considered to be effective. A therapeutic index was calculated by examining the least effective dose and the maximum tolerance dose.
�Experimental Result!
The antitumor experimental results of the compounds described in the previous example are shown in Table 5. As shown in Table 5, the new camptothecin derivatives in the present invention showed about 6 fold more favorable therapeutic index than camptothecin itself. At an optimum dose there was the case that 5 mice among 6 mice in the group survived. The results also show their effectiveness at lower doses, remarkable increase of antitumor activity and enlargement of a therapeutic margin.
�Toxicity Experiment!
Acute toxicity test was conducted by intraperitoneal administration using a group of twenty ICR male mice (4 weeks old, body weight around 20 g). The results are shown in Table 6.
LD.sub.50 value was calculated by the Richfield-Willcokson method from a lethal ratio observing the fate of mice during 1 week after administration of a test compound.
From the above experimental results, it is understood that the new camptothecin derivatives have better antitumor activity and can be used as less toxic drugs than their mother compound, camptothecin, for a treatment of cancer.
The antitumor agents of the present invention can be administered by a injection such as intravenous, intradermal and intramuscular injection, and by oral administration. Especially preferable examples are to administer the compounds as their acid-addition salts appropriate as medicaments by intravenous or oral administration.
In an intravenous administration, the dose of each compound above mentioned depends upon the aim of a therapeutic treatment, and is in range 5-400 mg/body per day, preferably 20-200 mg/body for adults. In an oral administration a range 50-2000 mg/body per day, preferably 100-1000 mg/body for adults.
As a preparation method of the antitumor agents of the present invention, a usual method for each preparation can be selected according to a formulation. As a formulation suitable for absorption through stomach intestine, the antitumor agents of the invention may be prepared in, for example, tablet, powder, granule, capsule or soft capsule, and examples of the oral liquid preparation include water or oil suspension, solution, syrup and elixir etc. A preparation for injection may be stored in an ample or a large container. In these formulation an excipient such an antiseptic or dissolvent can be used.
A formulation of a liquid preparation may be suspension, solution and emulsion with oily or aqueous vehicle, and may include an excipient such as emulsifier. Corresponding to a preparation of the antitumor agents of the invention, a content of the active drug is 0.1% or more, preferably 1-50%.
The preparation examples of the antitumor agents of the invention are further illustrated in, though not limited by, the following examples.
Preparation 1 Injection
After dissolving the compound C.sub.7 (R.sup.1 .dbd.C.sub.2 H.sub.5, R.sup.2 .dbd.H, R.sup.3 .dbd.CH.sub.3, R.sup.4 .dbd.H, R.sup.5 .dbd.C.sub.2 H.sub.4 SCH.sub.3) in 0.1N HCl containing equivalent molar HCl , the solution was filtered, and lyophilized to give 50 mg of the HCl salt of the compound C7. The salt was sealed into an ample in a germfree condition and stored under cooling in the dark.
Preparation 2 Tablet
______________________________________Compound C.sub.7 50 mgLactose 89 mgHydroxypropylcellulose 2.7 mgCrystalline cellulose 15 mgTalc 1.6 mgMagnesium stearate 1.7 mg______________________________________
The above ingredients were mixed and formed directly into tablets (160 mg/tablet) using a tablet machine.
TABLE 1__________________________________________________________________________(Yields of each compounds) ##STR4## Yield (%)Compd. No. A R.sup.1 R.sup.2 R.sup.3 R.sup.4 R.sup.5 A.fwdarw.B B.fwdarw.C__________________________________________________________________________C.sub.1 A.sub.11 Me H OEt H CH.sub.2 CH.sub.2 SMe 98 38C.sub.2 A.sub.12 " " H Br " 99 26C.sub.3 A.sub.1 Et " Cl H Et 94 51C.sub.4 A.sub.1 " " " " Pr " 50C.sub.5 A.sub.1 " " " " CH.sub.2 CH.sub.2 SMe " 47C.sub.6 A.sub.2 " " Br " " 98 47C.sub.7 A.sub.3 " " Me " " 98 43C.sub.8 A.sub.4 " " H F Et 95 71C.sub.9 A.sub.4 " " " F Pr " 75C.sub.10 A.sub.4 " " " " CH.sub.2 CH.sub.2 SMe " 72C.sub.11 A.sub.4 " " " " C.sub.6 H.sub.4OMe " 59C.sub.12 A.sub.5 " " " Cl CH.sub.2 CH.sub.2 SMe 92 30C.sub.13 A.sub.6 " " F F Et 98 56C.sub.14 A.sub.6 " " " " Pr " 58C.sub.15 A.sub.6 " " " " CH.sub.2 CH.sub.2 SMe " 42C.sub.16 A.sub.6 Et H F F C.sub.6 H.sub.4OMe 98 37C.sub.17 A.sub.7 " " Cl Cl Et 92 59C.sub.18 A.sub.7 " " " " Pr " 60C.sub.19 A.sub.7 " " " " CH.sub.2 CH.sub.2 SMe " 56C.sub.20 A.sub.8 " " OMe F Et 97 70C.sub.21 A.sub.8 " " " " Pr " 67C.sub.22 A.sub.8 " " " " CH.sub.2 CH.sub.2 SMe " 65C.sub.23 A.sub.9 " " Me " Et 94 84C.sub.24 A.sub.9 " " " " Pr " 82C.sub.25 A.sub.9 " " " " CH.sub.2 CH.sub.2 SMe " 80C.sub.26 A.sub.9 Et H Me F C.sub.6 H.sub.4OMe 94 78C.sub.27 C.sub.28 A.sub.10 " " " " OMEM OH H " Et " 96 ##STR5##C.sub.29 C.sub.30 A.sub.10 " " " " OMEM OH " " Pr " " ##STR6##C.sub.31 C.sub.32 A.sub.10 " " " " OMEM OH " " CH.sub.2 CH.sub.2 SMe " " ##STR7##C.sub.33 C.sub.34 A.sub.10 " " " " OMEM OH " " CHCHCH.sub.3 " " ##STR8##C.sub.35 C.sub.36 A.sub.10 " " " " OMEM OH " " C.sub.6 H.sub.4F.sub.(p) " " ##STR9##C.sub.37 C.sub.38 A.sub.10 Et " H " OMEM OH H " C.sub.6 H.sub.4F.sub.(m) " 96 ##STR10##C.sub.39 A.sub.3 " " Me "4-pyridyl 98 89C.sub.40 A.sub.1 " " Cl " " 94 75C.sub.41 A.sub.4 " " H F " 95 93C.sub.42 A.sub.9 " " Me " " 94 85C.sub.43 A.sub.8 " " OMe " " 97 95C.sub.44 A.sub.13 H OMe H H2-pyridyl 96 80.8C.sub.45 A.sub.10 Et H OH H Me -- --C.sub.46 A.sub.10 " " " " iso-Pr -- --C.sub.47 A.sub.10 " " " " C.sub.2 H.sub.4 OEt -- --C.sub.48 A.sub.10 " " OAc " C.sub.6 H.sub.4F.sub.(p) 83 --__________________________________________________________________________ ##STR11## ##STR12## ##STR13##
TABLE 2__________________________________________________________________________(Spector Data of Hydroxy Amide Compounds)__________________________________________________________________________B.sub.1 (7-Et-10-Cl--)Yellow powder (from n-Hexane-chloroform)C.sub.26 H.sub.31 N.sub.4 O.sub.4 Cl, MS �M+H!.sup.+ =499,IR.sub..nu..sup.MAX /.sub.KBr (cm.sup.-1): 1650, 1590, 1510..sup.1 H-NMR(.delta.ppm) in CDCl.sub.3 : 1.10(3H, t, J=7Hz), 1.34(3H, t,J=8Hz), 2.20-2.32(1H,m), 2.27(6H, s), 2.39-2.61(3H, m), 2.90-3.05(2H, m), 3.20-3.33(1H, m),3.60-3.75(1H, m), 4.78(1H, d, J=13Hz), 5.00(1H, d, J=19Hz), 5.06(1H, d,J=19Hz),5.10(1H, d, J=13Hz), 7.44(1H, br-t, J=5Hz), 7.50(1H, s), 7.62(1H, dd,J=2, 9Hz), 7.82(1H, d, J=2Hz), 7.95(1H, d, J=9Hz).B.sub.2 (7-Et-10-Br--)Pale yellow powder(from n-Hexane-chloroform)C.sub.26 H.sub.31 N.sub.4 O.sub.4 Br, MS �M+H!.sup.+ =543,IR.sub..nu..sup.MAX /.sub.KBr (cm.sup.-1): 1645, 1585, 1510..sup.1 H-NMR(.delta.ppm) in CDCl.sub.3 : 1.10(3H, t, J=7Hz), 1.35(3H, t,J=8Hz), 2.20-2.33(1H,m), 2.29(6H, s), 2.35-2.63(3H, m), 2.99(2H, q, J=8Hz), 3.20-3.35(1H, m),3.60-3.75(1H, m), 4.78(1H, d, J=13Hz), 5.02(1H, d, J=19Hz), 5.07(1H, d,J=19Hz),5.10(1H, d, J=13Hz), 7.43(1H, br-t, J=6Hz), 7.50(1H, s), 7.75(1H, dd,J=2, 9Hz), 7.88(1H, d, J=9Hz), 8.02(1H, d, J=2Hz).B.sub.3 (7-Et-10-Me--)Colorless powder (from n-Hexane-chloroform)C.sub.27 H.sub.34 N.sub.4 O.sub.4, MS �M+H!.sup.+ =479,IR.sub..nu..sup.MAX /.sub.KBr (cm.sup.-1): 1645, 1580, 1560, 1510..sup.1 H-NMR(.delta.ppm) in CDCl.sub.3 : 1.10(3H, t, J=7Hz), 1.32(3H, t,J=8Hz), 2.20-2.33(1H,m), 2.27(6H, s), 2.38-2.60(3H, m), 2.57(3H, s), 2.92-3.05(2H, m),3.20-3.33(1H,m), 3.61-3.75(1H, m), 4.80(1H, d, J=14Hz), 5.02(1H, d, J=19Hz), 5.08(1H, d, J=19Hz), 5.12(1H, d, J=14Hz), 7.34(1H, br-t, J=6Hz), 7.51(1H, s),7.54(1H, dd, J=2, 9Hz), 7.64(1H, br-s), 7.99(1H, d, J=9Hz).B.sub.4 (7-Et-11-F--)Pale yellow powder(from n-Hexane-chloroform)C.sub.26 H.sub.31 N.sub.4 O.sub.4 F, MS �M+H!.sup.+ =483,IR.sub..nu..sup.MAX /.sub.KBr (cm.sup.-1): 1645, 1590, 1510..sup.1 H-NMR(.delta.ppm) if CDCl.sub.3 : 1.10(3H, t, J=7Hz), 1.35(3H, t,J=8Hz), 2.20-2.33(1H,m), 2.28(6H, s), 2.38-2.62(3H, m), 2.97-3.14(2H, m), 3.20-3.33(1H, m),3.63-3.76(1H, m), 4.78(1H, d, J=13Hz), 5.03(1H, d, J=19Hz), 5.08(1H, d,J=19Hz),5.12(1H, d, J=13Hz), 7.32(1H, ddd, J=3, 8, 10Hz), 7.39(1H, br-t, J=6Hz),7.51(1H, s), 7.67(1H, dd, J=3, 10Hz), 7.93(1H, dd, J=6, 9Hz).B.sub.5 (7-Et-11-Cl--)Pale yellow powder(from n-Hexane-chloroform)C.sub.26 H.sub.31 N.sub.4 O.sub.4 Cl, MS �M+H!.sup.+ =499,IR.sub..nu..sup.MAX /.sub.KBr (cm.sup.-1): 1645, 1600, 1590..sup.1 H-NMR(.delta.ppm) in CDCl.sub.3 : 1.10(3H, t, J=7hz), 1.36(3H, t,J=8Hz), 2.20-2.33(1H,m), 2.28(6H, s), 2.39-2.62(3H, m), 2.97-3.12(2H, m), 3.21-3.33(1H, m),3.62-3.78(1H, m), 4.76(1H, d, J=14Hz), 5.00(1H, d, J=19Hz), 5.05(1H, d,J=19Hz),5.10(1H, d, J=14Hz), 7.39-7.52(3H, m), 7.84(1H, d, J=9Hz), 7.97(1H, d,J=2Hz).B.sub.6 (7-Et-10, 11-F.sub.2 --)Yellow powder (from n-Hexane-chloroform)C.sub.26 H.sub.30 N.sub.4 O.sub.4 F.sub.2, MS �M+H!.sup.+ =501,IR.sub..nu..sup.MAX /.sub.KBr (cm.sup.-1): 1645, 1590, 1515..sup.1 H-NMR(.delta.ppm) in CDCl.sub.3 : 1.10(3H, t, J=7hz), 1.36(3H, t,J=8Hz), 2.18-2.64(4H,m), 2.29(6H, s), 3.06(2H, q, J=8Hz), 3.22-3.37(1H, m), 3.60-3.78(1H, m),4.76(1H, d, J=14Hz), 5.06(1H, d, J=19Hz), 5.11(1H, d, J=19Hz), 5.13(1H,d, J=14Hz),7.36-7.44(1H, br), 7.51(1H, s), 7.69(1H, dd, J=8, 11Hz), 7.81(1H, dd,J=8, 11Hz).B.sub.7 (7-Et-10, 11-Cl.sub.2 --)Yellow powder (from n-Hexane-chloroform)C.sub.26 H.sub.30 N.sub.4 O.sub.4 Cl.sub.2, MS �M+H!.sup.+ =533,IR.sub..nu..sup.MAX /.sub.KBr (cm.sup.-1): 1650, 1595, 1520..sup.1 H-NMR(.delta.ppm) in CDCl.sub.3 : 1.09(3H, t, J=7Hz), 1.38(3H, t,J=8Hz), 2.18-2.34(1H,m), 2.29(6H, s), 2.38-2.64(3H, m), 2.94-3.11(2H, m), 3.23-3.38(1H, m),3.60-3.75(1H, m), 4.71(1H, d, J=14Hz), 4.97(1H, d, J=19Hz), 5.03(1H, d,J=19Hz),5.06(1H, d, J=14Hz), 7.43(1H, s), 7.51(1H, br-t, J=5Hz), 7.94(1H, s),8.02(1H, s).B.sub.8 (7-Et-10-OMe-11-F--)Yellow powder(from n-Hexane-chloroform)C.sub.27 H.sub.33 N.sub.4 O.sub.5 F, MS �M+H!.sup.+ =513,IR.sub..nu..sup.MAX /.sub.KBr (cm.sup.-1): 1650, 1590, 1510..sup.1 H-NMR(.delta.ppm) in CDCl.sub.3 : 1.11(3H, t, J=7Hz), 1.31(3H, t,J=8Hz), 2.20-2.37(1H,m), 2.27(6H, s), 2.41-2.60(3H, m), 2.85-3.04(2H, m), 3.21-3.33(1H, m),3.60-3.73(1H, m), 4.00(3H, s), 4.73(1H, d, J=13Hz), 4.86(1H, d, J=19Hz),4.94(1H,d, J=19Hz), 5.05(1H, d, J=13Hz), 6.93(1H, d, J=9Hz), 7.38(1H, s),7.51(1H,br-t, J=6Hz), 7.55(1H, d, J=12Hz).B.sub.9 (7-Et-10-Me-11-F--)Pale yellow powder(from n-Hexane-chloroform)C.sub.27 H.sub.33 N.sub.4 O.sub.4 F, MS �M+H!.sup.+ =497,IR.sub..nu..sup.MAX /.sub.KBr (cm.sup.-1): 1645, 1585, 1505..sup.1 H-NMR(.delta.ppm) in CDCl.sub.3 : 1.10(3H, t, J=7hz), 1.35(3H, t,J=8Hz), 2.21-2.35(1H,m), 2.28(6H, s), 2.40-2.62(3H, m), 2.48(3H, s), 2.94-3.12(2H, m),3.23-3.37(1H,m), 3.59-3.74(1H, m), 4.76(1H, d, J=13Hz), 4.95(1H, d, J=19Hz), 5.01(1H,d, J=19Hz), 5.09(1H, d, J=13Hz), 7.46(1H, s), 7.47(1H, br-t, J=6Hz),7.52(1H,d, J=11Hz), 7.65(1H, d, J=8Hz).B.sub.10 (7-Et-10-OMEM--)Yellow powder (from n-Hexane-chloroform)C.sub.30 H.sub.40 N.sub.4 O.sub.7, MS �M+H!.sup.+ =569,IR.sub..nu..sup.MAX /.sub.KBr (cm.sup.-1): 1650, 1625, 1585, 1510.sup.1 H-NMR(.delta.ppm) in CDCl.sub.3 : 1.10(3H, t, J=7hz), 1.30(3H, t,J=8Hz), 2.20-2.33(1H,m), 2.26(6H, s), 2.39-2.61(3H, m), 2.87-3.03(2H, m), 3.24-3.33(1H, m),3.39(3H, s), 3.52-3.73(3H, m), 3.83-3.94(2H, m), 4.80(1H, d, J=13Hz),4.98(1H,d, J=19Hz), 5.04(1H, d, J=19Hz), 5.09(1H, d, J=13Hz), 5.40(1H, d, J=7hz),5.43,(1H, d, J=7hz), 7.38-7.44(2H, m), 7.46(1H, s), 7.48(1H, br-t, J=6Hz),7.97(1H,d, J=9Hz).B.sub.11 (7-Me-10-OEt--)Pale yellow powder(from n-Hexane-chloroform)C.sub.27 H.sub.34 N.sub.4 O.sub.5, MS �M+H!.sup.+ =495,IR.sub..nu..sup.MAX /.sub.KBr (cm.sup.-1): 1645, 1620, 1590, 1510..sup.1 H-NMR(.delta.ppm) in CDCl.sub.3 : 1.11(3H, t, J=7hz), 1.54(3H, t,J=7hz), 2.23-2.33(1H,m), 2.28(6H, s), 2.39(3H, s), 2.43-2.59(3H, m), 3.21-3.37(1H, m), 3.55-3.72(1H, m), 3.97-4.17(2H, m), 4.80(1H, d, J=13Hz), 4.81(1H, d, J=18Hz),4.89(1H,d, J=18Hz), 5.01(1H, d, J=13Hz), 6.72(1H, d, J=3Hz), 7.30(1H, dd, J=3,9Hz),7.40(1H, s), 7.49(1H, br-t, J=6Hz), 7.90(1H, d, J=9Hz).B.sub.12 (7-Me-10-Br--)Pale yellow powder(from n-Hexane-chloroform)C.sub.25 H.sub.29 N.sub.4 O.sub.4 Br, MS �M+H!.sup.+ =529,IR.sub..nu..sup.MAX /.sub.KBr (cm.sup.-1): 1645, 1595, 1515..sup.1 H-NMR(.delta.ppm) in CDCl.sub.3 : 1.11(3H, t, J=7Hz),2.18-2.33(1H, m), 2.29(6H, s),2.40-2.65(3H, m), 2.60(3H, s), 3.20-3.35(1H, m), 3.60-3.75(1H, m),4.77(1H, d,J=13Hz), 4.87(1H, d, J=19Hz), 4.93(1H, d, J=19Hz), 5.06(1H, d, J=13Hz),7.40-7.48(2H, m), 7.51(1H, dd, J=2, 9Hz), 7.61(1H, d, J=9Hz), 8.14(1H, d,J=2Hz).B.sub.13 (9-OMe--)Pale yellow powder(from n-Hexane-chloroform)C.sub.25 H.sub.30 N.sub.4 O.sub.5, MS �M+H!.sup.+ =467,IR.sub..nu..sup.MAX /.sub.KBr (cm.sup.-1): 3360, 1650, 1615, 1585, 1515..sup.1 H-NMR(.delta.ppm) in CDCl.sub.3 : 1.08(3H, t, J=7Hz),2.18-2.34(1H, m), 2.23(6H, s),2.38-2.57(3H, m), 3.16-3.29(1H, m), 3.58-3.72(1H, m), 3.96(3H, s),4.79(1H, d,J=13Hz), 5.02(1H, d, J=19Hz), 5.08(1H, d, J=13Hz), 5.09(1H, d, J=19Hz),6.77(1H,d, J=8Hz), 7.38(1H, br-t, J=5Hz), 7.50(1H, s), 7.57(1H, dd, J=8, 8Hz),7.63(1H, d, J=8Hz), 8.50(1H, s).__________________________________________________________________________
TABLE 3__________________________________________________________________________(Spectral Data of 17-O-Acyl-21-amide Compounds)__________________________________________________________________________C.sub.1mp 101-106.degree. C., Pale yellow needles (from n-Hexane-chloroform)C.sub.31 H.sub.40 N.sub.4 O.sub.6 S.H.sub.2 O, MS �M + H!.sup.+ = 597,Anal., (C, H, N): Found (calcd.) 60.67, 6.58, 8.96 (60.57, 6.89, 9.11),IR.nu..sup.MAX /.sub.KBr (cm.sup.-1): 1725, 1650, 1620, 1590, 1510.sup.1 H-NM (.delta.ppm) in CDCl.sub.3 : 1.09(3H, t, J=7Hz), 1.54(3H, t,J=7Hz), 2.09(3H,s), 2.22-2.38(1H, m), 2.28(6H, s), 2.41-2.68(5H, m), 2.57(3H, s),2.72-2.80(2H,m), 3.24-3.34(1H, m), 3.42-3.53(1H, m), 4.13(2H, q, J=7Hz),4.82-5.37(1H,br), 4.96(1H, d, J=19Hz), 5.07(1H, d, J=19Hz), 5.49(1H, d, J=12Hz),5.53(1H,d, J=12Hz), 6.88(1H, br-s), 7.35(1H, dd, J=3, 9Hz), 7.38(1H, br-t,J=6Hz),7.49(1H; s), 7.98(1H, d, J=9Hz).C.sub.2mp 108-118.degree. C., Yellow powder (from n-Hexane-chloroform)C.sub.29 H.sub.35 N.sub.4 O.sub.5 BrS.1/2O, MS �M + H!.sup.+ = 631,Anal. (C, H, N): Found (calcd.) 54.08, 5.76, 8.48 (54.37, 5.66, 8.75)IR.nu..sup.MAX /.sub.KBr (cm.sup.-1): 1725, 1650, 1600, 1515..sup.1 H-NMR (.delta.ppm) in CDCl.sub.3 : 1.17 (3H, t, J=7Hz), 2.09(3H,s), 2.22-2.38(1H, m),2.29(6H, s), 2.43-2.82(7H, m), 2.65(3H, s), 3.24-3.35(1H, m),3.44-3.57(1H, m),4.91(1H, d, J=19Hz), 5.01(1H, d, J=19Hz), 5.49(2H, s), 7.48(1H, dd, J=2,9Hz;1H, s), 7.53(1H, br-t, J=6Hz), 7.59(1H, d, J=9Hz), 8.14(1H, d, J=2Hz).C.sub.3mp 130-133.degree. C., Yellow powder (from n-Hexane-chloroform),�.alpha.!.sup.25 /.sub.D = +27.5(CH.sub.3 OH, c = 0.2), C.sub.29 H.sub.35N.sub.4 O.sub.5 Cl.1/2H.sub.2 O, MS �M + H!.sup.+ = 555,Anal. (C, H, N): Found (calcd.) 61.74, 6.43, 9.66 (61.75, 6.43, 9.93),IR.nu..sup.MAX /.sub.KBr (cm.sup.-1): 1730, 1650, 1600, 1515..sup.1 H-NHR (.delta.ppm) in CDCl.sub.3 : 1.11(3H, t, J=7Hz), 1.12(3H, t,J=7Hz), 1.34(3H, t,J=8Hz), 2.20-2.59(6H, m), 2.26(6H, s), 2.92-3.10(2H, m), 3.21-3.35(1H,m), 3.38-3.51(1H, m), 4.99(1H, d, J=19Hz), 5.10( 1H, d, J=19Hz), 5.26-5.60(1H,br),5.47(1H, d, J=12Hz), 5.50(1H, d, J=12Hz), 7.43(1H, br-t, J=5Hz), 7.49(1H,s),7.62(1H, dd, J=2, 9Hz), 7.73(1H, d, J=2Hz); 7.92(1H, d, J=9Hz).C.sub.4mp 136-138.degree. C., Yellow powder (from n-Hexane-chloroform),�.alpha.!.sup.25 /.sub.D = +26.5(CH.sub.3 OH, c = 0.2), C.sub.30 H.sub.37N.sub.4 O.sub.5 Cl.1/2H.sub.2 O, MS �M + H!.sup.+ = 569,Anal. (C, H, N): Found (calcd.) 62.69, 6.58, 9.73 (62.33, 6.63, 9.69),IR.nu..sup.MAX /.sub.KBr (cm.sup.-1): 1725, 1650, 1595, 1515..sup.1 H-NMR (.delta.ppm) in CDCl.sub.3 : 0.92(3H, t, J=7Hz), 1.12(3H, t,J=7Hz), 1.33(3H, t,J=8Hz), 1.64(2H, sextet, J=7Hz), 2.16-2.35(3H, m), 2.25(6H, s),2.38-2.59(3H,m), 2.90-3.07(2H, m), 3.21-3.32(1H, m), 3.39-3.50(1H, m), 4.96(1H, d,J=19Hz),5.07(1H, d, J=19Hz), 5.31-5.60(1H, br), 5.45(1H, d, J=12Hz), 5.50(1H, d,J=12Hz), 7.46(1H, br-t, J=5Hz), 7.47(1H, s), 7.60(1H, dd, J=2, 9Hz),7.68(1H, d,J=2Hz), 7.89(1H, d, J=9Hz).C.sub.5mp 139-144.degree. C., Yellow powder (from n-Hexane-chloroform),�.alpha.!.sup.25 /.sub.D = +20.5(CH.sub.3 OH, c = 0.2), C.sub.30 H.sub.37N.sub.4 O.sub.5 ClS.1/2H.sub.2 O, MS �M + H!.sup.+ = 601,Anal. (C, H, N): Found (calcd.) 59.28, 6.31, 9.01 (59.05, 6.28, 9.18),IR.nu..sup.MAX /.sub.KBr (cm.sup.-1): 1725, 1650, 1600, 1515..sup.1 H-NMR (.delta.ppm) in CDCl.sub.3 : 1.10(3H, t, J=7Hz), 1.34(3H, t,J=8Hz), 2.09(3H,s), 2.23-2.35(1H, m), 2.31(6H, s), 2.44-2.68(5H, m), 2.70-2.80(2H, m),2.93-3.09(2H, m), 3.24-3.35(1H, m), 3.43-3.57(1H, m), 5.00(1H, d, J=19Hz),5.09(1H,d, J=19Hz), 5.51(2H, s), 7.51(1H, s), 7.52(1H, br-t, J=5Hz), 7.62(1H, dd,J=2,9Hz), 7.74(1H, d, J=2Hz), 7.93(1H, d, J=9Hz).C.sub.6mp 149-151.degree. C., Pale yellow needles (from n-Hexane-chloroform),�.alpha.!.sup.25 /.sub.D = +18.5(CH.sub.3 OH, c = 0.2), C.sub.30 H.sub.37N.sub.4 O.sub.5 BrS, MS �M + H!.sup.+ = 645,Anal. (C, H, N): Found (calcd.) 55.95, 5.70, 8.50 (55.81, 5.78, 8.68),IR.nu..sup.MAX /.sub.KBr (cm.sup.-1): 1725, 1650, 1610, 1515..sup.1 H-NMR (.delta.ppm) in CDCl.sub.3 : 1.09(3H, t, J=7Hz), 1.36(3H, t,J=8Hz), 2.10(3H,s), 2.22-2.35(1H, m), 2.25(6H, s), 2.38-2.55(3H, m), 2.57-2.68(2H, m),2.71-2.81(2H, m), 2.97-3.10(2H, m), 3.24-3.34(1H, m), 3.38-3.50(1H, m),4.98-5.34(1H,br), 5.05(1H, d, J=19Hz), 5.13(1H, d, J=19Hz), 5.49(1H, d, J=12Hz);5.57(1H,d, J=12Hz), 7.40(1H, br-t, J=6Hz), 7.53(1H, s), 7.77(1H, dd, J=2, 9Hz),7.90(1H, d, J=9Hz), 8.00(1H, d, J=2Hz).C.sub.7mp 130-134.degree. C., Yellow powder (from n-Hexane-chloroform),�.alpha.!.sup.25 /.sub.D = +21.5(CH.sub.3 OH, c = 0.2), C.sub.31 H.sub.40N.sub.4 O.sub.5 S, MS �M + H!.sup.+ = 581,Anal. (C, H, N): Found (calcd.) 63.88, 7.02, 9.43 (64.11, 6.94, 9.65),IR.nu..sup.MAX /.sub.KBr (cm.sup.-1): 1725, 1650, 1600, 1515..sup.1 H-NMR (.delta.ppm) in CDCl.sub.3 : 1.09(3H, t, J=7Hz), 1.32(3H, t,J=8Hz), 2.09(3H,s), 2.20-2.36(1H, m), 2.26(6H, s), 2.41-2.55(3H, m), 2.54(3H, s),2.57-2.67(2H,m), 2.71-2.81(2H, m), 2.93-3.09(2H, m), 3.25-3.35(1H, m), 3.41-3.52(1H,m), 4.99(1H, d, J=19Hz), 5.97(1H, d, J=19Hz), 5.50(1H, d, J=12Hz),5.54(1H,d, J=12Hz), 7.44(1H, br-t, J=6Hz), 7.51(1H, dd, J=2, 8Hz), 7.52(1H, s),7.55(1H, br-s), 7.94(1H, d, J=8Hz).C.sub.8mp 164-166.degree. C., Pale yellow powder (from n-Hexane-chloroform),�.alpha.!.sup.25 /.sub.D = +24.0(CH.sub.3 OH, c = 0.2), C.sub.29 H.sub.35N.sub.4 O.sub.5 F.2H.sub.2 O, MS �M + H!.sup.+ = 539,Anal. (C, H, N): Found (calcd.) 60.24, 6.80, 9.84 (60.61, 6.84, 9.75),IR.nu..sup.MAX /.sub.KBr (cm.sup.-1): 1725, 1650, 1595, 1510..sup.1 H-NMR (.delta.ppm) in CDCl.sub.3 : 1.08(3H, t, J=7Hz), 1.13(3H, t,J=7Hz), 1.36(3H,t, J=8Hz), 2.24-2.63(6H, m), 2.30(6H, s), 3.02-3.20(2H, m), 3.25-3.55(2H,m),5.07(1H, d, J=19Hz), 5.14(1H, d, J=19Hz), 5.21-5.41(1H, br), 5.51(2H,br-s),7.31(1H, ddd, J=2, 9, 10Hz), 7.41(1H, br-t, J=5Hz), 7.55(1H, s), 7.69(1H,dd,J=2, 10Hz), 7.93(1H, dd, J=6, 9Hz).C.sub.9mp 134-137.degree. C., Pale yellow powder (from n-Hexane-chloroform),�.alpha.!.sup.25 /.sub.D = +22.0(CH.sub.3 OH, c = 0.2), C.sub.30 H.sub.37N.sub.4 O.sub.5 F.3/2H.sub.2 O, MS �M + H!.sup.+ = 553,Anal. (C, H, N): Found (calcd.) 62.06, 6.85, 9.70 (62.16, 6.96, 9.67),IR.nu..sup.MAX /.sub.KBr (cm.sup.-1): 1725, 1650, 1595, 1510..sup.1 H-NMR (.delta.ppm) in CDCl.sub.3 : 0.93(3H, t, J=7Hz), 1.09(3H, t,J=7Hz), 1.36(3H, t,J=8Hz), 1.65(2H, sextet, J=7Hz), 2.20-2.36(3H, m), 2.25(6H, s),2.39-2.53(3H,m), 3.02-3.17(2H, m), 3.25-3.35(1H, m), 3.38-3.49(1H, m), 5.05(1H, d,J=19Hz),5.12(1H, d, J=19Hz), 5.22-5.40(1H, br), 5.47(1H, d, J=12Hz), 5.53((1H, d,J=12Hz), 7.30(1H, ddd, J=3, 9, 10Hz), 7.38(1H, br-t, J=5Hz), 7.53(1H, s),7.67(1H,dd, J=3, 10Hz), 7.91(1H, dd, J=6, 9Hz).C.sub.10mp 135-138.degree. C., Pale yellow powder (from n-Hexane-chloroform),�.alpha.!.sup.25 /.sub.D = +16.5(CH.sub.3 OH, c = 0.2), C.sub.30 H.sub.37N.sub.4 O.sub.5 FS.3/2H.sub.2 O, MS �M + H!.sup.+ = 585Anal. (C, H, N): Found (calcd.) 58.74, 6.48, 9.21 (58.90, 6.59, 9.16),IR.nu..sup.MAX /.sub.KBr (cm.sup.-1): 1730, 1650, 1595, 1510..sup.1 H-NMR (.delta.ppm) in CDCl.sub.3 : 1.09(3H, t, J=7Hz), 1.36(3H, t,J=8Hz), 2.10(3H,s), 2.20-2.36(1H, m), 2.25(6H, s), 2.40-2.54(3H, m), 2.58-2.68(2H, m),2.72-2.82(2H, m), 3.04-3.18(2H, m), 3.25-3.36(1H, m), 3.39-3.50(1H, m),4.99-5.31(1H,br), 5.06(1H, d, J=19Hz), 5.14(1H, d, J=19Hz), 5.49(1H, d, J=12Hz),5.58(1H,d, J=12Hz), 7.31(1H, ddd, J=3, 9, 10Hz), 7.39(1H, br-t, J=5Hz), 7.55(1H,s), 7.68(1H, dd, J=3, 10Hz), 7.93(1H, dd, J=6, 9Hz).C.sub.11mp 180-182.degree. C., Pale yellow powder (from n-Hexane-chloroform),�.alpha.!.sup.25 /.sub.D = -59.5(CH.sub.3 OH, c = 0.2), C.sub.34 H.sub.37N.sub.4 O.sub.6 F.H.sub.2 O, MS �M + H!.sup.+ = 617Anal. (C, H, N): Found (calcd.) 64.34, 6.40, 8.98 (64.34, 6.19, 8.83),IR.nu..sup.MAX /.sub.KBr (cm.sup.-1): 1700, 1650, 1600, 1510.sup.1 H-NMR (.delta.ppm) in CDCl.sub.3 : 1.12(3H, t, J=7Hz), 1.34(3H, t,J=8Hz), 2.18(6H, s), 2.29-2.44(3H, m), 2.47-2.59(1H, m), 2.99-3.22(3H, m), 3.30-3.42(1H, m),5.03(1H, d,J=19Hz), 5.12(1H, d, J=19Hz), 5.58-5.93(1H, br), 5.73(1H, d, J=12Hz),5.81(1H,d, J=12Hz), 6.82(2H, d, J=9Hz), 7.22-7.28(1H, m), 7.51(1H, br-t, J=5Hz),7.57(1H,1H, s), 7.63(1H, dd, J=3, 10Hz), 7.85(1H, dd, J=6, 9Hz), 7.96(2H, d,J=9Hz).C.sub.12mp 131-133.degree. C., Pale yellow powder (from n-Hexane-chloroform),�.alpha.!.sup.25 /.sub.D = +25.5(CH.sub.3 OH, c = 0.2), C.sub.30 H.sub.37N.sub.4 O.sub.5 ClS.H.sub.2 O, MS �M + H!.sup.+ = 601,Anal. (C, H, N): Found (calcd.) 57.80, 6.05, 8.91 (58.20, 6.35, 9.05)IR.nu..sup.MAX /.sub.KBr (cm.sup.-1): 1730, 1650, 1605, 1515..sup.1 H-NMR (.delta.ppm) in CDCl.sub.3 : 1.09(3H, t, J=7Hz), 1.37(3H, t,J=8Hz), 2.10(3H,s), 2.22-2.36(1H, m), 2.26(6H, s), 2.40-2.54(3H, m), 2.56-2.68(2H, m),2.70-2.81(2R, m), 3.02-3.18(2H, m), 3.25-3.35(1H, m), 3.40-3.52(1H, m),4.97-5.35(1H,br), 5.05(1H, d, J=19Hz), 5.13(1H, d, J=19Hz), 5.49(1H, d, J=11Hz),5.57(1H,d, J=11Hz), 7.42(1H, br-t, J=6Hz), 7.46(1H, dd, J=2, 9Hz), 7.54(1H, s),7.85(1H, d, J=9Hz), 8.02(1H, d, J=2Hz).C.sub.13mp 168-170.degree. C., Yellow powder (from n-Hexane-chloroform),�.alpha.!.sup.25 /.sub.D = +24.0(CH.sub.3 OH, c = 0.2), C.sub.29 H.sub.34N.sub.4 O.sub.5 F.sub.2.H.sub.2 O, MS �M + H!.sup.+ = 557,Anal. (C, H, N): Found (calcd.) 60.91, 6.22, 9.75 (60.62, 6.31, 9.75),IR.nu..sup.MAX /.sub.KBr (cm.sup.-1): 1725, 1655, 1600, 1515..sup.1 H-NMR (.delta.ppm) in CDCl.sub.3 : 1.07(3H, t, J=7Hz), 1.13(3H, t,J=7Hz), 2.36(3H, t,J=8Hz), 2.18-2.52(6H, m), 2.24(6H, s), 3.07(2H, q, J=8Hz), 3.25-3.36(1H,m),3.38-3.49(1H, m), 5.06-5.38(1H, br), 5.10(1H, d, J=19Hz), 5.16(1H, d,J=19Hz),5.48(1H, d, J=12Hz), 5.56(1H, d, J=12Hz), 7.36(1H, br-t, J=5Hz), 7.55(1H,s),7.69(1H, d, J=8, 11Hz), 7.86(1H, d, J=8, 11Hz).C.sub.14mp 160-162.degree. C., Yellow powder (from n-Hexane-chloroform),�.alpha.!.sup.25 /.sub.D = +21.5(CH.sub.3 OH, c = 0.2), C.sub.30 H.sub.36N.sub.4 O.sub.5 F.sub.2.1/2H.sub.2 O, MS �M + H!.sup.+ = 571,Anal. (C, H, N): Found (calcd.) 61.73, 6.53, 9.75 (62.16, 6.43, 9.67),IR.nu..sup.MAX /.sub.KBr (cm.sup.-1): 1720, 1655, 1600, 1520..sup.1 H-NMR (.delta.ppm) in CDCl.sub.3 : 0.93(3H, t, J=7Hz), 1.07(3H, t,J=7Hz), 1.36(3H, t, J=8Hz),1.65(2H, sextet, J=7Hz), 2.16-2.36(3H, m), 2.24(6H, s), 2.38-2.52(3H, m),3.07(2H,q, J=8Hz), 3.25-3.36(1H, m), 3.37-3.48(1H, m), 5.05-5.34(1H, br),5.10(1H, d,J=19Hz), 5.16(1H, d, J=19Hz), 5.47(1H, d, J=12Hz), 5.57(1H, d, J=12Hz),7.35(1H,br-t, J=5Hz), 7.55(1H, s), 7.70(1H, dd, J=8, 11Hz), 7.86(1H, dd, J=8,11Hz).C.sub.15mp 119-125.degree. C., Yellow needles (from n-Hexane-chloroform),�.alpha.!.sup.25 /.sub.D = +22.0(CH.sub.3 OH, c = 0.2), C.sub.30 H.sub.36N.sub.4 O.sub.5 F.sub.2 S.H.sub.2 O, MS �M + H!.sup.+ = 603,Anal. (C, H, N): Found (calcd.) 57.83, 6.03, 9.08 (58.05, 6.17, 9.03),IR.nu..sup.MAX /.sub.KBr (cm.sup.-1): 1725, 1650, 1600, 1515..sup.1 H-NMR (.delta.ppm) in CDCl.sub.3 : 1.08(3H, t, J=7Hz), 1.36(3H, t,J=8Hz), 2.10(3H, s), 2.20-2.34(2H, m), 2.25(6H, s), 2.40-2.54(3H, m), 2.58-2.70(2H, m),2.71-2.83(2H, m),3.07(2H, q, J=8Hz), 3.26-3.37(1H, m), 3.40-3.52(1H, m), 5.08(1H, d,J=19Hz),5.15(1H, d, J=19Hz), 5.49(1H, d, J=12Hz), 5.60(1H, d, J=12Hz), 7.43(1H,br-t,J=5Hz), 7.55(1H, s), 7.67(1H, dd, J=8, 11Hz), 7.83(1H, dd, J=8, 11Hz).C.sub.16mp 175-178.degree. C., Colorless needles (from n-hexane-chloroform)�.alpha.!.sup.25 /.sub.D = -57.0(CH.sub.3 OH, c = 0.2), C.sub.34 H.sub.37N.sub.4 O.sub.6 F.sub.2.1/2H.sub.2 O, MS �M + H!.sup.+ = 635,Anal. (C, H, N): Found (calcd.) 63.74, 5.79, 8.93 (63.44, 5.79, 8.70),IR.nu..sup.MAX /.sub.KBr (cm.sup.-1): 1695, 1650, 1600, 1510..sup.1 H-NMR (.delta.ppm) in CDCl.sub.3 : 1.10(3H, t, J=7Hz), 1.35(3H, t,J=8Hz), 2.19(6H,s), 2.26-2.55(4H, m), 3.05(2H, q, J=8Hz), 3.14-3.25(1H, m), 3.30-3.42(1H,m),5.08(1H, d, J=19Hz), 5.15(1H, d, J=19Hz), 5.55-5.90(1H, br), 5.70(1H, d,J=12Hz), 5.84(1H, d, J=12Hz), 6.84(2H, d, J=9Hz), 7.48(1H, br-t, J=5Hz),7.55(1H,s), 7.65(1H, dd, J=8, 11Hz), 7.82(1H, dd, J=8, 11Hz), 7.97(2H, d,J=9Hz).C.sub.17mp 153-156.degree. C., Yellow powder (from n-hexane-chloroform)�.alpha.!.sup.25 /.sub.D = +34.5(CH.sub.3 OH, c = 0.2), C.sub.29 H.sub.34N.sub.4 O.sub.5 Cl.sub.2.1/2H.sub.2 O, MS �M + H!.sup.+ = 589,Anal. (C, H, N): Found (calcd.) 58.12, 5.74, 9.35 (58.20, 5.89, 9.36),IR.nu..sup.MAX /.sub.KBr (cm.sup.-1): 1725, 1650, 1600, 1515..sup.1 H-NMR (.delta.ppm) in CDCl.sub.3 : 1.11(3H, t, J=7Hz), 1.12(3H, t,J=7Hz), 1.38(3H, t, J=8Hz), 2.19-2.38(3H, m), 2.27(6H, s), 2.40-2.58(3H, m), 2.96-3.14(2H, m),3.21-3.32(1H, m), 3.40-3.51(1H, m), 4.99(1H, d, J=19Hz), 5.08(1H, d, J=19Hz),5.45(1H,d, J=12Hz), 5.49(1H, d, J=12Hz), 7.46(1H, s), 7.49(1H, br-t, J=5Hz),7.89(1H, s), 8.05(1H, s).C.sub.18mp 142-147.degree. C., Yellow powder (from n-hexane-chloroform)�.alpha.!.sup.25 /.sub.D = +31.5(CH.sub.3 OH, c = 0.2),C.sub.30 H.sub.36 N.sub.4 O.sub.5 Cl.sub.2.1/2H.sub.2 O, MS �M + H!.sup.+ = 603,Anal. (C, H, N): Found (calcd.) 58.97, 5.95, 9.06 (58.82, 6.09, 9.15),IR.nu..sup.MAX /.sub.KBr (cm.sup.-1): 1725, 1650, 1600, 1515.sup.1 H-NMR (.delta.ppm) in CDCl.sub.3 : 0.92(3H, t, J=7Hz), 1.11(3H, t,J=7Hz), 1.38(3H,t, J=8Hz), 1.64(2H, sextet, J=7Hz), 2.18-2.35(3H, m), 2.26(6H, s), 2.39-2.56(3H, m), 2.98-3.14(2H, m), 3.21-3.32(1H, m), 3.38-3.52(1H, m),5.00(1H,d, J=19Hz), 5.09(1H, d, J=19Hz), 5.48(2H, s), 7.45(1H, br-t, J=5Hz),7.47(1H, s), 7.92(1H, s), 8.07(1H, s).C.sub.19mp 139-142.degree. C., Yellow needles (from n-hexane-chloroform)�.alpha.!.sup.25 /.sub.D = +27.5(CH.sub.3 OH, c = 0.2), C.sub.30 H.sub.36N.sub.4 O.sub.5 Cl.sub.2 S.1/2H.sub.2 O, MS �M + H!.sup.+ = 635,Anal. (C, H, N): Found (calcd.) 55.94, 5.69, 8.79 (55.90, 5.79, 8.69),IR.nu..sup.MAX /.sub.KBr (cm.sup.-1): 1725, 1650, 1600, 1515..sup.1 H-NMR (.delta.ppm) in CDCl.sub.3 : 1.09(3H, t, J=7Hz), 1.38(3H, t,J=8Hz), 2.09(3H,s), 2.21-2.37(1H, m), 2.29(6H, s), 2.43-2.67(5H, m), 2.70-2.81(2H, m),2.99-3.16(2H, m), 3.24-3.35(1H, m), 3.42-3.55(1H, m), 5.03(1H, d, J=19Hz),5.11(1H,d, J=19Hz), 5.49(1H, d, J=12Hz), 5.54(1H, d, J=12Hz), 7.49(1H, br-t,J=6Hz),7.50(1H, s), 7.96(1H, s), 8.11(1H, s).C.sub.20mp 112-117.degree. C., Pale yellow powder (from n-hexane-chloroform)�.alpha.!.sup.25 /.sub.D = +28.5(CH.sub.3 OH, c = 0.2), C.sub.30 H.sub.37N.sub.4 O.sub.6 F.3/2H.sub.2 O, MS �M + H!.sup.+ = 569,Anal. (C, H, N): Found (calcd.) 60.15, 6.78, 9.40 (60.49, 6.77, 9.41),IR.nu..sup.MAX /.sub.KBr (cm.sup.-1): 1725, 1650, 1595, 1515..sup.1 H-NMR (.delta.ppm) in CDCl.sub.3 : 1.12(3H, t, J=7Hz), 1.13(3H, t,J=7Hz), 1.31(3H,t, J=8Hz), 2.21-2.63(6H, m), 2.28(6H, s), 2.88-3.08(2H, m), 3.18-3.30(1H,m),3.40-3.52(1H, m), 4.00(3H, s), 4.89(1H, d, J=19Hz), 5.02(1H, d, J=19Hz),5.41(1H,d, J=12Hz), 5.50(1H, d, J=12Hz), 6.89(1H, d, J=9Hz), 7.40(1H, s),7.46(1H,br-t, J=6Hz), 7.57(1H, d, J=12Hz).C.sub.21mp 109-113.degree. C., Pale yellow powder (from n-hexane-chloroform)�.alpha.!.sup.25 /.sub.D = +29.5(CH.sub.3 OH, c = 0.2), C.sub.31 H.sub.39N.sub.4 O.sub.6 F.2H.sub.2 O, MS �M + H!.sup.+ = 583,Anal. (C, H, N): Found (calcd.) 60.09, 6.99, 9.29 (60.18, 7.01, 9.06),IR.nu..sup.MAX /.sub.KBr (cm.sup.-1): 1725, 1650, 1595, 1510..sup.1 H-NMR (.delta.ppm) in CDCl.sub.3 : 0.92(3H, t, J=7Hz), 1.13(3H, t,J=7Hz), 1.31(3H,t, J=8Hz), 1.63(2H, sextet, J=7Hz), 2.18-2.37(3H, m), 2.28(6H, s),2.39-2.63(3H,m), 2.87-3.07(2H, m), 3.17-3.30(1H, m), 3.41-3.53(1H, m), 4.00(3H, s),4.89(1H, d, J=19Hz), 5.02(1H, d, J=19Hz), 5.34-5.57(1H, br), 5.40(1H, d,J=12Hz), 5.49(1H, d, J=12Hz), 6.89(1H, d, J=9Hz), 7.40(1H, s), 7.46(1H,br-t, J=6Hz), 7.57(1H, d, J=12Hz).C.sub.22mp 125-129.degree. C., Pale yellow powder (from n-hexane-chloroform)�.alpha.!.sup.25 /.sub.D = +22.0(CH.sub.3 OH, c = 0.2), C.sub.31 H.sub.39N.sub.4 O.sub.6 FS.3/2H.sub.2 O, MS �M + H!.sup.+ = 615,Anal. (C, H, N): Found (calcd.) 59.82, 6.40, 9.02 (59.89, 6.60, 8.73),IR.nu..sup.MAX /.sub.KBr (cm.sup.-1): 1725, 1650, 1600, 1510..sup.1 H-NMR (.delta.ppm) in CDCl.sub.3 : 1.11(3H, t, J=7Hz), 1.33(3H, t,J=8Hz), 2.09(3H,s), 2.22-2.36(1H, m), 2.26(6H, s), 2.39-2.69(5H, m), 2.71-2.80(2H, m),2.94-3.10(2H, m), 3.21-3.34(1H, m), 3.39-3.15(1H, m), 4.04(3H, s),4.93-5.38(1H,br), 4.97(1H, d, J=19Hz), 5.07(1H, d, J=19Hz), 5.50(2H, s), 7.01(1H, d,J=9Hz), 7.38(1H, br-t, J=6Hz), 7.44(1H, s), 7.64(1H, d, J=12Hz).C.sub.23mp 164-165.degree. C., Pale yellow powder (from n-hexane-chloroform)�.alpha.!.sup.25 /.sub.D = +24.5(CH.sub.3 OH, c = 0.2), C.sub.30 H.sub.37N.sub.4 O.sub.6 F.3/2H.sub.2 O, MS �M + H!.sup.+ = 553,Anal. (C, H, N): Found (calcd.) 61.88, 6.85, 9.71 (62.16, 6.96, 9.67),IR.nu..sup.MAX /.sub.KBr (cm.sup.-1): 1725, 1650, 1595, 1510..sup.1 H-NMR (.delta.ppm) in CDCl.sub.3 : 1.09(3H, t, J=7Hz), 1.13(3H, t,J=7Hz), 1.36(3H, t,J=8Hz), 2.19-2.57(6H, m), 2.25(6H, s), 2.48(3H, s), 2.99-3.16(2H, m),3.23-3.34(1H, m), 3.38-3.49(1H, m), 5.02(1H, d, J=19Hz), 5.10(1H, d, J=19Hz),5.49(2H,s), 7.38(1H, br-t, J=5Hz), 7.49(1H, s), 7.58(1H, d, J=11Hz), 7.67(1H, d,J=8Hz).C.sub.24mp 148-154.degree. C., Pale yellow needles (from n-hexane-chloroform)�.alpha.!.sup.25 /.sub.D = +24.0(CH.sub.3 OH, c = 0.2), C.sub.31 H.sub.39N.sub.4 O.sub.6 F.1/2H.sub.2 O, MS �M + H!.sup.+ = 567,Anal. (C, H, N): Found (calcd.) 64.28, 7.07, 9.65 (64.68, 7.00, 9.73),IR.nu..sup.MAX /.sub.KBr (cm.sup.-1): 1725, 1650, 1600, 1510..sup.1 H-NMR (.delta.ppm) in CDCl.sub.3 : 0.93(3H, t, J=7Hz), 1.09(3H, t,J=7Hz), 1.36(3H,t, J=8Hz), 1.64(2H, sextet, J=7Hz), 2.19-2.35(3H, m), 2.24(6H, s),2.38-2.54(3H,m), 2.48(3H, s), 2.99-3.16(2H, m), 3.23-3.34(1H, m), 3.38-3.50(1H, m),5.02(1H, d, J=19Hz), 5.10(1H, d, J=19Hz), 5.21-5.42(1H, br), 5.47(1H, d,J=12Hz), 5.51(1H, d, J=12Hz), 7.38(1H, br-t, J=5Hz), 7.49(1H, s), 7.58(1H,d,J=11Hz), 7.68(1H, d, J=8Hz).C.sub.25mp 107-121.degree. C., Yellow needles (from n-hexane-chloroform)�.alpha.!.sup.25 /.sub.D = +54.0(CH.sub.3 OH, c = 0.2), C.sub.31 H.sub.39N.sub.4 O.sub.5 FS.2H.sub.2 O, MS �M + H!.sup.+ = 599,Anal. (C, H, N): Found (calcd.) 60.75, 6.67, 9.15 (60.55, 6.83, 8.83),IR.nu..sup.MAX /.sub.KBr (cm.sup.-1): 1725, 1650, 1595, 1510..sup.1 H-NMR (.delta.ppm) in CDCl.sub.3 : 1.10(3H, t, J=7Hz), 1.36(3H, t,J=8Hz), 2.09(3H,s), 2.22-2.35(1H, m), 2.28(6H, s), 2.40-2.66(5H, m), 2.46(3H, s),2.72-2.81(2H,m), 2.97-3.14(2H, m), 3.24-3.34(1H, m), 3.42-3.54(1H, m), 4.98(1H, d, J=19Hz), 5.07(1H, d, J=19Hz), 5.51(2H, s), 7.47(1H, s), 7.48(1H, br-t,J=5Hz),7.54(1H, d, J=11Hz), 7.63(1H, d, J=8Hz).C.sub.26mp 189-192.degree. C., Pale yellow powder (from n-hexane-chloroform)�.alpha.!.sup.25 /.sub.D = -59.0(CH.sub.3 OH, c = 0.2), C.sub.35 H.sub.39N.sub.4 O.sub.6 F.H.sub.2 O, MS �M + H!.sup.+ = 631,Anal. (C, H, N): Found (calcd.) 64.43, 6.57, 8.73 (64.80, 6.37, 8.64),IR.nu..sup.MAX /.sub.KBr (cm.sup.-1): 1700, 1650, 1605, 1510..sup.1 H-NMR (.delta.ppm) in CDCl.sub.3 : 1.12(3H, t, J=7Hz), 1.34(3H, 6,J=8Hz), 2.17(6H,s), 2.28-2.42(3H, m), 2.45(3H, s), 2.48-2.60(1H, m), 2.96-3.18(3H, m),3.28-3.39(1H, m), 4.98(1H, d, J=19Hz), 5.09(1H, d, J=19Hz), 5.52-5.98(1H, br),5.74(1H, d, J=12Hz), 5.78(1H, d, J=12Hz), 6.82(2H, d, J=9Hz), 7.48-7.55(3H,m),7.60(1H, d, J=8Hz), 7.95(1H, d, J=9Hz).C.sub.27mp 82-87.degree. C., Yellow prisms (from n-hexane-chloroform)�.alpha.!.sup.25 /.sub.D = +24.0(CH.sub.3 OH, c = 0.2), C.sub.33 H.sub.44N.sub.4 O.sub.8.H.sub.2 O, MS �M + H!.sup.+ = 625,Anal. (C, H, N): Found (calcd.) 61.85, 7.12, 8.81 (61.67, 7.21, 8.72),IR.nu..sup.MAX /.sub.KBr (cm.sup.-1): 1730, 1650, 1620, 1510..sup.1 H-NMR (.delta.ppm) in CDCl.sub.3 : 1.08(3H, t, J=7Hz), 1.12(3H, t,J=7Hz), 1.30(3H,t, J=8Hz), 2.25-2.41(3H, m), 2.35(6H, s), 2.43-2.66(3H, m), 2.91-3.07(2H,m),3.27-3.37(1H, m), 3.39(3H, s), 3.46-3.63(3H, m), 3.83-3.93(2H, m),4.99(1H, d,J=19Hz), 5.08(1H, d, J=19Hz), 5.27-5.62(1H, br), 5.38(1H, d, J=7Hz),5.41(1H,d, J=7Hz), 5.46(1H, d, J=12Hz), 5.50(1H, d, J=12Hz), 7.34(1H, d, J=3Hz),7.39(1H,dd, J=3, 9Hz), 7.44-7.55(2H, s, br-t), 7.96(1H, d, J=9Hz)C.sub.28mp 214-215.degree. C., Pale yellow powder (from n-hexane-chloroform)�.alpha.!.sup.25 /.sub.D = +34.0(CH.sub.3 OH, c = 0.2), C.sub.29 H.sub.36N.sub.4 O.sub.6, MS �M + H!.sup.+ = 537,Anal. (C, H, N): Found (calcd.) 64.67, 6.69, 10.22 (64.91, 6.76, 10.44),IR.nu..sup.MAX /.sub.KBr (cm.sup.-1): 1720, 1645, 1620, 1585..sup.1 H-NMR (.delta.ppm) in DMSO-d.sub.6 : 0.87(3H, t, J=7Hz), 1.05(3H,t, J=8Hz), 1.31(3H,t, J=8Hz), 2.08-2.24(2H, m), 2.27(2H, q, J=8Hz), 2.74(6H, s),2.99-3.15(4H,m), 3.22-3.54(2H, m), 5.25(2H, s), 5.31(1H, d, J=11Hz), 5.37(1H, d,J=11Hz),6.28(1H, s), 7.38-7.47(3H, m), 8.02(1H, d, J=10Hz), 8.30(1H, br-t,J=6Hz),9.43-9.88(1H, br), 10.36(1H, s).C.sub.29mp 78-82.degree. C., Yellow needles (from n-hexane-chloroform)�.alpha.!.sup.25 /.sub.D = +22.5(CH.sub.3 OH, c = 0.2), C.sub.34 H.sub.46N.sub.4 O.sub.8.3/2H.sub.2 O, MS �M + H!.sup.+ = 639,Anal. (C, H, N): Found (calcd.) 61.61, 7.03, 8.38 (61.34, 7.42, 8.42),IR.nu..sup.MAX /.sub.KBr (cm.sup.-1): 1725, 1620, 1585, 1510..sup.1 H-NMR (.delta.ppm) in CDCl.sub.3 : 0.93(3H, t, J=7Hz), 1.08(3H, t,J=7Hz), 1.30(3H, t, J=8Hz),1.64(2H, sext, J=7Hz), 2.23-2.38(3H, m), 2.34(6H, s), 2.43-2.64(3H, m),2.89-3.08(2H, m), 3.25-3.36(1H, m), 3.39(3H, s), 3.45-3.63(3H, m),3.83-3.93(2H, m),4.98(1H, d, J=19Hz), 5.08(1H, d, J=19Hz), 5.30-5.58(1H, br), 5.37(1H, d,J=7Hz), 5.41(1H, d, J=7Hz), 5.46(1H, d, J=12Hz), 5.49(1H, d, J=12Hz),7.34(1H, d,J=3Hz), 7.39(1H, dd, J=3, 9Hz), 7.44-7.52(2H, s, br-t), 7.95(1H, d,J=9Hz).C.sub.30mp 218-219.degree. C., Colorless powder (from n-hexane-chloroform)�.alpha.!.sup.25 /.sub.D = +32.5(CH.sub.3 OH, c = 0.2), C.sub.30 H.sub.38N.sub.4 O.sub.6, MS �M + H!.sup.+ = 551,Anal. (C, H, N): Found (calcd.) 65.34, 6.99, 10.04 (65.44, 6.96, 10.17),IR.nu..sup.MAX /.sub.KBr (cm.sup.-1): 1715, 1645, 1620, 1585..sup.1 H-NMR (.delta.ppm) in DMSO-d.sub.6 : 0.87(3H, t, J=7Hz), 0.90(3H,t, J=7Hz), 1.30(3H,t, J=8Hz), 1.55(2H, sextet, J=7Hz), 2.12(6H, s), 2.25-2.32(6H, m),3.02-3.25(4H,m), 5.26(2H, s), 5.29(1H, d, J=11Hz), 5.37(1H, d, J=11Hz), 6.28(1H, s),7.37(1H, s), 7.38-7.45(2H, m), 7.78(1H, br-t, J=6Hz), 8.04(1H, d,J=10Hz),10.29(1H, br-s).C.sub.31mp 84-90.degree. C., Pale yellow powder (from n-hexane-chloroform)�.alpha.!.sup.25 /.sub.D = +18.0(CH.sub.3 OH, c = 0.2), C.sub.34 H.sub.46N.sub.4 O.sub.8 S.H.sub.2 O, MS �M + H!.sup.+ = 671,Anal. (C, H, N): Found (calcd.) 59.33, 6.77, 7.96 (59.28, 7.02, 8.13),IR.nu..sup.MAX /.sub.KBr (cm.sup.-1): 1725, 1620, 1585, 1510..sup.1 H-NMR (.delta.ppm) in CDCl.sub.3 : 1.07(3H, t, J=7Hz), 1.31(3H, t,J=8Hz), 2.09(3H,s), 2.24-2.41(1H, m), 2.36(6H, s), 2.42-2.68(5H, m), 2.71-2.80(2H, m),2.93-3.07(2H, m), 3.27-3.41(1H, m), 3.39(3H, s), 3.49-3.61(3H, m),3.83-3.92(2H,m), 5.00(1H, d, J=19Hz), 5.10(1H, d, J=19Hz), 5.22-5.60(1H, br), 5.38(1H,d,J=7Hz), 5.42(1H, d, J=7Hz), 5.52(2H, s), 7.37(1H, d, J=3Hz), 7.41(1H, dd,J=3,9Hz), 7.44-7.54(2H, br-m), 7.97(1H, d, J=9Hz).C.sub.32mp 172-175.degree. C., Pale yellow powder (from n-hexane-chloroform)�.alpha.!.sup.25 /.sub.D = +25.0(CH.sub.3 OH, c = 0.2), C.sub.30 H.sub.38N.sub.4 O.sub.6 S, MS �M + H!.sup.+ = 583,Anal. (C, H, N): Found (calcd.) 61.62, 6.52, 9.44 (61.84, 6.57, 9.61),IR.nu..sup.MAX /.sub.KBr (cm.sup.-1): 1725, 1645, 1620, 1585..sup.1 H-NMR (.delta.ppm) in DMSO-d.sub.6 : 0.87(3H, t, J=7Hz), 1.30(3H,t, J=8Hz), 2.02-2.32(4H, m), 2.07(3H, s), 2.13(6H, s), 2.52-2.59(2H, m), 2.64-2.72(2H, m),3.00-3.26(4H, m), 5.26(2H, s), 5.34(1H, d, J=11Hz), 5.42(1H, d, J=11Hz),6.22(1H, s),7.34-7.48(3H, m), 7.79(1H, br-t, J=6Hz), 8.04(1H, d, J=10Hz), 10.30(1H,br).C.sub.33mp 78-86.degree. C., Yellow needles (from n-Hexane-chloroform)C.sub.34 H.sub.44 N.sub.4 O.sub.8.1/2H.sub.2 O, MS �M + H!.sup.+ = 637,Anal. (C, H, N): Found (calcd.) 63.02, 7.02, 8.67 (63.24, 7.02, 8.68),IR.nu..sup.MAX /.sub.KBr (cm.sup.-1): 1710, 1620, 1585, 1510..sup.1 H-NMR (.delta.ppm) in CDCl.sub.3 : 1.08(3H, t, J=7Hz), 1.31(3H, t,J=8Hz), 1.83(3H,dd, J=2, 7Hz), 2.25(6H, s), 2.26-2.37(1H, m), 2.39-2.53(3H, m),2.94-3.08(2H,m), 3.21-3.47(1H, m), 3.39(3H, s), 3.54-3.61(2H, m), 3.84-3.91(2H, m),5.04(1H,d, J=19Hz), 5.12(1H, d, J=19Hz), 5.39(1H, d, J=7Hz), 5.42(1H, d, J=7Hz),5.53(1H, d, J=12Hz), 5.61(1H, d, J=12Hz), 5.80-5.88(1H, m), 6.98(1H, dq,J=7,14Hz), 7.32-7.55(4H, m), 8.00(1H, d, J=9Hz).C.sub.34Yellow powder (from n-Hexane-chloroform)C.sub.30 H.sub.36 N.sub.4 O.sub.6, MS �M + H!.sup.+ = 549,IR.nu..sup.MAX /.sub.KBr (cm.sup.-1): 1705, 1675, 1645, 1590, 1510..sup.1 H-NMR (.delta.ppm) in DMSO-d.sub.6 : 0.88(3H, t, J=7Hz), 1.31(3H,t, J=8Hz), 1.84(3H,dd, J=2, 7Hz), 2.08-2.26(2H, m), 2.74(6H, s), 2.98-3.04(4H, m),3.29-3.52(2H,m), 5.26(2H, s), 5.35(1H, d, J=11Hz), 5.42(1H, d, J=11Hz), 5.80-5.90(1H,m),6.30(1H, s), 6.87(1H, dq, J=7, 16Hz), 7.38-7.48(3H, m), 8.20(1H, d,J=3Hz),9.46-9.63(1H, br), 10.35(1H, s).C.sub.35mp 102-105.degree. C., Yellow prisms (from n-Hexane-chloroform)C.sub.37 H.sub.43 N.sub.4 O.sub.8 F, MS �M + H!.sup.+ = 691,IR.nu..sup.MAX /.sub.KBr (cm.sup.-1): 1710, 1650, 1620, 1600, 1505..sup.1 H-NMR (.delta.ppm) in CDCl.sub.3 : 1.14(3H, t, J=7Hz), 1.27(3H, t,J=8Hz), 2.16(6H,s), 2.22-2.42(3H, m), 2.49-2.62(1H, m), 2.82-3.18(3H, m), 3.18-3.42(1H,m),3.39(3H, s), 3.50-3.64(2H, m), 3.80-3.93(2H, m), 4.94(1H, d, J=19Hz),5.08(1H,d, J=19Hz), 5.35(1H, d, J=7Hz), 5.40(1H, d, J=7Hz), 5.55-5.77(1H, br),5.78(2H,s), 7.01(2H, dd, J=9, 9Hz), 7.22(1H, d, J=3Hz), 7.27(1H, s), 7.35(1H,dd,J=3, 9Hz), 7.48(1H, br-t, J=6Hz), 7.50(1H, s), 7.90(1H, d, J=9Hz),8.02(2H,dd, J=6, 9Hz).C.sub.36mp 231-232.degree. C., Colorless powder (from n-Hexane-chloroform)�.alpha.!.sup.25 /.sub.D = -6.5(CH.sub.3 OH, c = 0.2), C.sub.33 H.sub.35N.sub.4 O.sub.6 F, MS �M + H!.sup.+ = 603,IR.nu..sup.MAX /.sub.KBr (cm.sup.-1): 1710, 1645, 1620, 1585, 1520..sup.1 H-NMR (.delta.ppm) in DMSO-d.sub.6 : 0.91(3H, t, J=7Hz), 1.30(3H,t, J=8Hz), 2.11-2.30(2H, m), 2.53(6H, s), 2.62-2.90(2H, m), 2.99-3.40(4H, m), 5.29(2H,s),5.57(1H, d, J=11Hz), 5.62(1H, d, J=11Hz), 6.36(1H, s), 7.33(1H, dd, J=9,9Hz),7.38-7.48(3H, m), 7.97(2H, dd, J=6, 9Hz), 8.04(1H, d, J=9Hz),8.94-10.27(1H,br), 10.34(1H, s).C.sub.37mp 105-109.degree. C., Yellow prisms (from n-Hexane-chloroform)�.alpha.!.sup.25 /.sub.D = +62.0(CHCl.sub.3, c = 0.2), C.sub.37 H.sub.43N.sub.4 O.sub.8 F, MS �M + H!.sup.+ = 691,Anal. (C, H, N): Found (calcd.) 63.02, 7.02, 8.67 (63.24, 7.02, 8.68),IR.nu..sup.MAX /.sub.KBr (cm.sup.-1): 1710, 1620, 1585, 1510..sup.1 H-NMR (.delta.ppm) in CDCl.sub.3 : 1.14(3H, t, J=7Hz), 1.27(3H, t,J=8Hz), 2.16(6H,s), 2.23-2.43(3H, m), 2.50-2.66(1H, m), 2.83-3.05(1H, m), 3.06-3.19(1H,m),3.27-3.44(1H, m), 3.39(3H, s), 3.50-3.63(2H, m), 3.80-3.92(2H, m),4.95(1H, d,19Hz), 5.08(1H, d, J=19Hz), 5.35(1H, d, J=7Hz), 5.40(1H, d, J=7Hz),5.50-5.82(1H,br), 5.77(1H, d, J=12Hz), 5.81(1H, d, J=12Hz), 7.13-7.25(2H, m),7.27-7.39(2H, m), 7.48(1H, br-t, J=6Hz), 7.50(1H, s), 7.66-7.73(1H, m), 7.80(1H,d, J=8Hz), 7.90(1H, d, J=9Hz).C.sub.38mp 223-224.degree. C., Colorless powder (from n-Hexane-chloroform)C.sub.33 H.sub.35 N.sub.4 O.sub.6 F, MS �M + H!.sup.+ = 603,IR.nu..sup.MAX /.sub.KBr (cm.sup.-1): 1710, 1645, 1620, 1590, 1520..sup.1 H-NMR (.delta.ppm) in DMSO-d.sub.6 : 0.91(3H, t, J=7Hz), 1.30(3H,t, J=8Hz), 2.08-2.34(2H, m), 2.54(6H, s), 2.54-2.75(2H, m), 2.95-3.43(4H, m), 5.29(2H,s),5.58(1H, d, J=11Hz), 5.65(1H, d, J=11Hz), 6.35(1H, s), 7.34-7.68(6H, m),7.76(1H,d, J=7Hz), 8.05(1H, d, J=9Hz), 8.08-8.22(1H, br), 9.22-9,66(1H, br),10.32(1H, s)C.sub.39mp 162-164.degree. C., Yellow powder (from n-Hexane-chloroform)C.sub.33 H.sub.37 N.sub.5 O.sub.5.H.sub.2 O, MS �M + H!.sup.+ = 584,Anal. (C, H, N): Found (calcd.) 65.44, 6.53, 11.54 (65.87, 6.53, 11.64),IR.nu..sup.MAX /.sub.KBr (cm.sup.-1): 1720, 1645, 1595, 1515.sup.1 H-NMR (.delta.ppm) in CDCl.sub.3 : 1.13(3H, t, J=7Hz), 1.31(3H, t,J=8Hz), 2.16(6H,s), 2.27-2.42(3H, m), 2.51(3H, s), 2.52-2.63(1H, m), 2.90-3.14(3H, m),3.30-3.41(1H, m), 4.89(1H, d, 19Hz), 5.10(1H, d, J=19Hz), 5.62-5.84(1H, br),5.81(1H,d, J=12Hz), 5.86(1H, d, J=12Hz), 7.44-7.53(3H, m), 7.55(1H, s), 7.81(2H,dd, J=1, 5Hz), 7.89(1H, d, J=9Hz), 8.67(2H, dd, J=1, 5Hz).C.sub.40mp 165-167.degree. C., Yellow powder (from n-Hexane-chloroform)C.sub.32 H.sub.34 N.sub.5 O.sub.5 Cl.1/2H.sub.2 O, MS �M + H!.sup.+ =604,Anal. (C, H, N): Found (calcd.) 62.54, 5.78, 11.35 (62.69, 5.75, 11.42),IR.nu..sup.MAX /.sub.KBr (cm.sup.-1): 1720, 1650, 1595, 1515.sup.1 H-NMR (.delta.ppm) in CDCl.sub.3 : 1.14(3H, t, J=7Hz), 1.34(3H, t,J=8Hz), 2.16(6H,s), 2.27-2.41(3H, m), 2.52-2.64(1H, m), 2.93-3.13(3H, m), 3.30-3.30(1H,m),5.01(1H, d, J=19Hz), 5.12(1H, d, J=19Hz), 5.51-5.57(1H, br), 5.80(1H, d,J=12Hz), 5.86(1H, d, J=12Hz), 7.49(1H, t, J=5Hz), 7.53(1H, s), 7.62(1H, dd,J=2,9Hz), 7.70(1H, d, J=2Hz), 7.81(2H, dd, J=1, 5Hz), 7.90(1H, d, J=9Hz),8.68(2H,dd, J=1, 5Hz).C.sub.41mp .about.171.degree. C., Pale yellow powder (from n-Hexane-chloroform)C.sub.30 H.sub.34 N.sub.4 O.sub.4 F, MS �M + H!.sup.+ = 588,IR.nu..sup.MAX /.sub.KBr (cm.sup.-1): 1720, 1650, 1595, 1510..sup.1 H-NMR (.delta.ppm) in CDCl.sub.3 : 1.15(3H, t, J=7Hz), 1.35(3H, t,J=8Hz), 2.16(6H,s), 2.27-2.42(3H, m), 2.52-2.66(1H, m), 2.98-3.18(3H, m), 3.29-3.40(1H,m),5.02(1H, d, 19Hz), 5.12(1H, d, J=19Hz), 5.72-5.91(1H, br, D.sub.2 Oex.),5.81(1H, d,J=12Hz), 5.87(1H, d, J=12Hz), 7.23(1H, ddd, J=3, 8, 10Hz), 7.52(1H, t,J=5Hz,D.sub.2 Oex.), 7.55(1H, s), 7.57(1H, dd, J=3, 10Hz), 7.80(2H, dd, J=2,4Hz), 7.82(1H,dd, J=6, 9Hz), 8.67(2H, dd, J=2, 4Hz)C.sub.42mp .about.169.degree. C., Pale yellow powder (from n-Hexane-chloroform)C.sub.31 H.sub.36 N.sub.4 O.sub.4 F, MS �M + H!.sup.+ = 602,IR.nu..sup.MAX /.sub.KBr (cm.sup.-1): 1720, 1650, 1600, 1505..sup.1 H-NMR (.delta.ppm) in CDCl.sub.3 : 1.13(3H, t, J=7Hz), 1.36(3H, t,J=8Hz), 2.17(6H,s), 2.28-2.60(4H, m), 2.47(3H, m), 2.98-3.17(3H, m), 3.29-3.40(1H, m),5.02(1H,d, J=19Hz), 5.13(1H, d, J=19Hz), 5.30-5.50(1H, br), 5.81(1H, d, J=12Hz),5.84(1H, d, J=12Hz), 7.39(1H, br-t, J=5Hz, D.sub.2 Oex.), 7.52(1H, s),7.54(1H, d,J=12Hz), 7.64(1H, d, J=8Hz), 7.81(2H, dd, J=2, 5Hz), 8.68(2H, dd, J=2,5Hz).C.sub.43mp 159-164.degree. C., Yellow needles (from n-Hexane-chloroform)C.sub.31 H.sub.36 N.sub.4 O.sub.5 F, MS �M + H!.sup.+ = 618,IR.nu..sup.MAX /.sub.KBr (cm.sup.-1): 1720, 1650, 1595, 1510..sup.1 H-NMR (.delta.ppm) in CDCl.sub.3 : 1.17(3H, t, J=7Hz), 1.30(3H, t,J=8Hz), 2.17(6H,s), 2.26-2.42(3H, m), 2.54-2.68(1H, m), 2.87-3.08(3H, m), 3.28-3.41(1H,m),4.00(3H, s), 4.90(1H, d, J=19Hz), 5.04(1H, d, J=19Hz), 5.48-5.82(1H, br,D.sub.2 Oex.), 5.76(1H, d, J=12Hz), 5.86(1H, d, J=12Hz), 6.85(1H, d,J=9Hz), 7.45(1H,s,), 7.52(1H, t, J=6Hz, D.sub.2 Oex.), 7.55(1H, d, J=12Hz), 7.81(2H, dd,J=2,5Hz), 8.67(2H, dd, J=2, 5Hz).C.sub.44mp 147-150.degree. C., Yellow powder (from n-Hexane-chloroform)C.sub.31 H.sub.33 N.sub.5 O.sub.6.H.sub.2 O, MS �M + H!.sup.+ = 572,Anal. (C, H, N): Found (calcd.) 62.85, 6.03, 11.78 (63.15, 5.98, 11.88),IR.nu..sup.MAX /.sub.KBr (cm.sup.-1): 3390, 1710, 1650, 1615, 1590, 1520.sup.1 H-NMR (.delta.ppm) in CDCl.sub.3 : 1.08(3H, t, J=7Hz), 2.15(6H,s), 2.29-2.55(4H, m),3.22-3.41(2H, m), 4.02(3H, s), 5.14(1H, d, J=19Hz), 5.20(1H, d, J=19Hz),5.34(1H, br-s), 5.77(1H, d, J=12Hz), 5.94(1H, d, J=12Hz), 6.87(1H, d, J=8Hz),7.39-7.47(2H, m), 7.60-7.68(2H, m), 7.73(1H, d, J=9Hz), 7.80(1H, ddd, J=2, 8,8Hz),8.13(1H, d, J=8Hz), 8.65-8.70(2H, m).C.sub.45Colorless powder (from n-Hexane-chloroform)C.sub.28 H.sub.34 N.sub.4 O.sub.6, MS �M + H!.sup.+ = 523,C.sub.46Yellow powder (from n-Hexane-chloroform)C.sub.30 H.sub.38 N.sub.4 O.sub.6, MS �M + H!.sup.+ = 551,C.sub.47Yellow powder (from n-Hexane-chloroform)C.sub.31 H.sub.40 N.sub.4 O.sub.7, MS �M + H!.sup.+ = 581,C.sub.48mp 179-182.degree. C., Colorless powder (from n-Hexane-chloroform)C.sub.35 H.sub.37 N.sub.4 O.sub.7 F, MS �M + H!.sup.+ = 645,__________________________________________________________________________
TABLE 4______________________________________(Water solubility)Compd. No. solubility (mg/ml) Compd. No. solubility (mg/ml)______________________________________C.sub.1 >64 C.sub.21 >63C.sub.2 >67 C.sub.22 >65C.sub.3 29 C.sub.23 20C.sub.4 41 C.sub.24 42C.sub.5 21 C.sub.25 >63C.sub.6 25 C.sub.26 9C.sub.7 21 C.sub.28 >56C.sub.8 20 C.sub.30 >58C.sub.9 >59 C.sub.32 >62C.sub.10 >62 C.sub.34 >59C.sub.11 8 C.sub.36 17C.sub.12 >64 C.sub.38 6C.sub.13 >59C.sub.14 >60C.sub.15 >64C.sub.16 6C.sub.17 >64C.sub.18 35C.sub.19 24C.sub.20 >60______________________________________
TABLE 5______________________________________(Antitumor activity of camptothecin derivatives) Optimum dose andCom- antitumor activity Therapeutic Indexpound Total 40-day (Maximum torelable dose/No. dose (mg/kg) T/C % survivors Minimum effective dose)______________________________________C.sub.1 6.25 252 0/6 4 (6.25/1.56)C.sub.2 25 214 0/6 8 (25/3.13)C.sub.3 6.25 275 1/6 >4 (6.25/<1.56)C.sub.4 6.25 280 1/6 >4 (6.25/<1.56)C.sub.5 6.25 295 3/6 >4 (6.25/<1.56)C.sub.6 6.25 183 1/6 >4 (6.25/<1.56)C.sub.7 100 368 5/6 32 (100/3.13)C.sub.8 12.5 364 4/6 8 (12.5/1.56)C.sub.9 12.5 293 2/6 8 (12.5/1.56)C.sub.10 12.5 240 1/6 8 (12.5/1.56)C.sub.11 50 243 0/6 8 (50/6.25)C.sub.12 25 281 1/6 16 (25/6.25)C.sub.13 1.56 214 0/6 --C.sub.14 1.56 257 1/6 --C.sub.15 1.56 260 0/6 --C.sub.16 12.5 259 0/6 2 (12.5/6.25)C.sub.17 6.25 286 2/6 4 (6.25/1.56)C.sub.18 3.13 225 0/6 >2 (3.13/<1.56)C.sub.19 3.13 198 0/6 >2 (3.13/<1.56)C.sub.20 3.13 312 0/6 >2 (3.13/<1.56)C.sub.21 3.13 265 0/6 >2 (3.13/<1.56)C.sub.22 1.56 228 0/6 --C.sub.23 12.5 317 0/6 >8 (12.5/<1.56)C.sub.24 25 326 1/6 >16 (25/1.56)C.sub.25 12.5 300 1/6 >8 (12.5/<1.56)C.sub.26 50 264 0/6 >4 (50/12.5)C.sub.28 200 180 0/6 16 (200/12.5)C.sub.30 200 235 0/6 32 (200/6.25)C.sub.32 200 198 0/6 32 (200/6.25)C.sub.36 200 214 0/6 16 (200/12.5)C.sub.38 200 226 0/6 16 (200/12.5)C.sub.39 50 376 3/6 16 (50/3.13)C.sub.40 12.5 266 1/6 4 (6.25/1.56)C.sub.41 25 300 2/6 >16 (25/<1.56)C.sub.42 12.5 257 2/6 >8 (12.5/1.56)C.sub.43 6.25 275 2/6 >4 (6.25/1.56)C.sub.45 400 147 0/6 4 (400/100)C.sub.46 400 189 0/6 16 (400/25)C.sub.47 400 156 0/6 4 (200/50)C.sub.48 200 188 0/6 8 (200/25)controlCPT- 60 203 0/6 6 (60/10)Na salt______________________________________
TABLE 6______________________________________(Acute Toxicity of camptotecin derivatives)Compd. No. LD.sub.50 value (mg/kg) Compd. No. LD.sub.50 value (mg/kg)______________________________________C.sub.1 164.5 C.sub.22 68.6C.sub.2 241.1 C.sub.23 184.2C.sub.3 185.6 C.sub.24 203.2C.sub.4 142.4 C.sub.25 154.3C.sub.5 167.5 C.sub.26 113.0C.sub.6 116.3 C.sub.28 340.6C.sub.7 234.5 C.sub.30 361.5C.sub.8 124.5 C.sub.32 307.0C.sub.9 152.1 C.sub.36 477.2C.sub.10 145.8 C.sub.38 420.6C.sub.11 146.1 C.sub.39 320.1C.sub.12 284.5 C.sub.40 213.4C.sub.13 67.6 C.sub.41 220.1C.sub.14 98.3 C.sub.42 310.5C.sub.15 85.2 C.sub.43 164.9C.sub.16 65.6 C.sub.45 376.2C.sub.17 112.0 C.sub.46 478.3C.sub.18 92.3 C.sub.47 471.2C.sub.19 94.8 C.sub.48 418.3C.sub.20 84.5 ControlC.sub.21 124.3 CPT-Na salt 227.0______________________________________

Number	Name	Date	Kind
4914205	Sawada et al.	Apr 1990
5122606	Wani et al.	Jun 1992

Number	Date	Country
0 296 612	Jun 1988	EPX
A S58-39684	Mar 1983	JPX
A 258-134095	Aug 1983	JPX
A S59-51287	Mar 1984	JPX
A S59-51289	Mar 1989	JPX
A H1-131179	May 1989	JPX
A H1-186892	Jul 1989	JPX
A H1-279891	Nov 1989	JPX
A H4-503505	Jun 1992	JPX
A H5-502017	Apr 1993	JPX
WO9003169	Apr 1990	WOX
WO9104260	Apr 1991	WOX
WO9211263	Jul 1992	WOX

Camptothecin derivatives, preparations thereof and antitumor agents

Information

Patent Number

Date Filed

Date Issued

Inventors

Original Assignees

Examiners

Agents

CPC

US Classifications

Field of Search

US

International Classifications

Abstract

Description

Claims

Priority Claims (1)

Parent Case Info

US Referenced Citations (2)

Foreign Referenced Citations (13)

Non-Patent Literature Citations (2)

Continuations (1)

Entry
Yaegashi, et al Chem Pharm Bull vol. 42, No. 12 pp. 2518-2825 (Dec. 1994).
Seigo Sawada et al., "Chemical Modification of an Antitumor Alkloid, 20(S)-Camptothecin: E-Lactone Ring-Modified Water-Soluble Derivatives of 7-Ethylcamptothecin", Chem. Pharm. Bull. 41(2):310-313, 1993.