JPS6310783A - Novel forskolin derivative - Google Patents

Abstract

NEW MATERIAL:A compound (salt) expressed by formula I [R<1> represents H, formula II (q is 1-5), etc.; R<4> represents vinyl, ethyl, etc.; R<2> and R<3> represent formula III (R<5> and R<6> represent H, alkyl, etc.; m is integer of 1-5), H, formula CO(CH2)nX (X represents H or amino; n is integer of 1-5), etc.] EXAMPLE:6-Dimethylaminoacetylforskolin. USE:A remedy for cardiac insufficiency, hypotensor, vasodilator for brain and remedy for immunodeficiency. PREPARATION:For example, a forskolin substituted at its 7-th position, etc. expressed by formula IV is reacted with an organic base such as triethylamine, etc., in a solvent such as N,N-dimethylformamide, etc., to rearrange the substituent at 7-th position to 6-th position and obtain the compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a novel forskolin derivative having positive inotropic action, hypotensive action, and adenylate cyclase activating action.

[Conventional technology]

Forskolin, which has a positive inotropic effect, a blood pressure lowering effect, and an adenylate cyclase activating effect, is already known [JP-A-52-79015゜Drug Research (Dr.
ug Research), 31 1248 (198
1)).

[Problem that the invention seeks to solve]

However, forskolin is poorly soluble in water and has a zero concentration in water at room temperature.
．． Water-soluble derivatives are desired because they dissolve only 0.026% of the time and necessitate formulation efforts.

[Means for solving problems]

Therefore, the present inventors conducted various studies.

General formula (T) (where I and R1 are a hydrogen atom and R4 is a vinyl group, an ethyl group, or a cycloprobyl group, (1) Either R2 or R3 has the partial structural formula C0
A class alkyl group or a lower alkylene group in which R5 and R6 are bonded, and the bond chain contains an oxygen atom and a nitrogen atom (- is an optional lower alkylene group, m is an integer of 1 to 5), and the other is A hydrogen atom or a group represented by the partial structural formula Co(CI(z).X) (where R7 and R11 are hydrogen atoms.

It is a lower alkyl group or a lower alkylene group in which R7 and R8 are bonded and which may contain an oxygen atom or a nitrogen atom in the bonded chain, and is an integer of nkt1 to 5. ) is shown. ) or (2) R” is a hydrogen atom or -COC)I2C14
When C02H, R3 is hydrogen atom 1 formula -COCH3
, -C0C)h CI2C)I2C02H, or -
COCH(OH) CH2or-i (however, when R2 is a hydrogen atom, R3 is a hydrogen atom or a group other than COCH3), and H and R' are partial structural formulas Co C, CH2
) pCO2H, or a group represented by CO(CH2)qN τG (where R'lR" is a hydrogen atom or a lower alkyl group, p is an integer of 0 to 5, and q is an integer of 1 to 5.) rt2 is a hydrogen atom % R3 is an acetyl group % R' is a vinyl group It has been found that it is water-soluble and has positive inotropic effects, antihypertensive effects, and adenylate cyclase activating effects.

The present invention was completed based on the above findings.

In the general formula (1), the lower alkyl group has 1 carbon number, such as a methyl group, ethyl group, propyl group, butyl group, etc.
-4 alkyl groups are mentioned. Examples of the lower alkylene group which may contain an oxygen atom or nitrogen atom in the bond chain include -(CH2)3, +C)I2+4.
+cI (2 forces.

Examples include C・~Cs, such as H = Chi Chu (CH2 or (C Ru) 2-0- (C Ru coating).

The above general formula (one CO+C in R2 or R3 of Il)
k).

Examples include diethylaminoacetyl group, diethylaminopropionyl group, butylaminoacetyl group, dimethylaminepropionyl group, dimethylaminobutyryl group, pyrrolidinobutyryl group, pyrrolidinoacetyl group, piperazinoacetyl group, 1 morpholinoacetyl group, and the like. In addition, the other -Co(-CI(2) is, for example, an acetyl group,
Examples include a propionyl group, a butyryl group, and the same aminoacyl groups as the above-mentioned various aminoacyl groups. Preferred compounds include R3 being a lower alkylcarboxyl group, such as an acetyl group, and R2 being -CO(C)h)n-N<16 and n
Examples include compounds where R5 and R6 are lower alkyl groups.

Next, a method for producing the compound represented by the general formula (11) will be explained.

■, The following formula (
The compound of general formula X) can be produced by any of the following methods.

(1) 7-f acetylforskolin (R1=R2
=R3=H, R'=-CH=Cl), or 7-diacetyl-14,15-dihydroforskolin (R'=R
2=R3=H, R'=CH2CI (3) or 13-
Cyclopropyl-7-deacetyl-14,15-dinorforscholine (R'=R2=R3=H,R'-cyclopropyl group) [wherein R5, R6 and m are the same as above] By condensing a compound represented by or a reactive derivative thereof, a compound where R3=Co(CH2)mN<7 can be obtained.

(2) 7-f7 mole 1-fluorscholine fudeacetyl-14,1s-cyhydrophoscholine mata is I3-cyclopropyl-7-deacetyl-14,1
5-dinorforskolin with the general formula (III) condensing its reactive derivatives,
Then, the general formula (IV) [wherein R5 and R6 are the same as above] can be obtained.

f3) 7-Diacetylforskolin or 7-zoaya, 4. ′-? , '-ji, 1. 7 Oyascolin mata is 13-cyclopropyl-7-teacetyl-14,15-dinorforskolin with the general formula ■CH=CH2+C)L 2-C0OH(V) [in the formula T
hm represents an integer of 2 to 4] The compounds are reacted.

In the condensation of the above (1) to (3), the general formula (Ill,
(III) When the carboxylic acid itself is used as the IM compound, benzene, chloroform, or ether.

Using dicyclohexylcarbodiimide, dicyclohexylcarpodiide + 4-dimethylaminopyridine, carbonyldiimidazole or diphenylphosphoryl azide in a solvent such as ethyl acetate, for example at -20°C to 200°C.
℃, usually from 0.5 to around the boiling point of the solvent under water cooling.
Carrying out the condensation reaction for 72 hours, preferably 2 to 48 hours gives favorable results.

Examples of compounds of the general formula (ll) include dimethylaminoacetic acid and n-butylaminoacetic acid.

Examples include diethylaminoacetic acid, pyrrolidinoacetic acid, piperazinoacetic acid, monophorinoacetic acid, dimethylamine propionic acid, and pyrrolidinobutyric acid.

Examples of the compound of general formula (m) include chloroacetic acid, bromoacetic acid, etc., logenoacetic acid, chloropropionic acid, chlorobutyric acid, chlorovaleric acid.

Examples include methanesulfonyloxyacetic acid, p-1 luenesulfonyloxybutyric acid, and methanesulfonyloxyvaleric acid.

Examples of the compound of general formula M include acrylic acid, methacrylic acid, vinyl acetic acid, and allyl acetic acid.

In the condensation of the above (1) to (3), general formula (II),
(III).

When using the reactive derivative of □, the reaction is carried out using a base such as pyridine or triethylamine in a solvent such as benzene, chloroform, or ether-acetic acid. 2 near the boiling point
~48 hours gives favorable results.

Examples of the reactive derivatives include acid halides, acid anhydrides, mixed acid anhydrides, and Roihi's anhydrides.

In the above method for producing f21 and +31, the reaction with the amine of the general formula σ is carried out in a solvent such as dichloromethane by stirring for about 0.5 to 5 hours under cooling with water.

Examples of the amine of general formula (1v) include dimethylamine, butylamine, and diethylamine.

Examples include pyrrolidine, piperazine, and morpholine.

(417-f acetylforskolin, curtaric anhydride, benzene, chloroform, ether.

Compound No. 26 can be obtained by reaction using a base such as pyridine or triethylamine in a solvent such as ethyl acetate. The reaction takes place under water cooling and around the boiling point of the solvent.
Running for 8 hours gives favorable results.

15) By condensing glyceric acid or its reactive derivatives with 7-diacetylforskolin,
The compound is obtained.

If glyceric acid itself is used in the condensation, habenzene, chloroform, or ether.

Using dicyclohexylcarbodiimide, dicyclohexylcarbodiimide + 4-dimethylaminepyridine, carbonyldiimidazole or diphenylphosphoryl azide in a solvent such as ethyl acetate, a condensation reaction is carried out for 2 to 48 hours, for example, under water cooling near the boiling point of the solvent. Gives favorable results.

When a reactive derivative is used in the condensation, it can be obtained by reaction using a base such as pyridine or triethylamine in a solvent such as benzene, chloroform, ether, or ethyl acetate. Preferably, the reaction is carried out under water cooling for 2 to 48 hours at around the boiling point of the solvent.

Examples of the reactive derivatives include acid nologides, acid anhydrides, mixed acid anhydrides, and Roihi's anhydrides.

2. The following compounds in which R2 is a group other than a hydrogen atom and R1 and R3 are both hydrogen atoms are 7-substituted forskolin or hafu obtained by the method in 1 above (however, excluding H). ft.
It can be obtained by rearranging the substituent at the 7-position of substituted-14,15-dihydroforskolin or 7-substituted-13-cyclopropyl-14,15-dinorforskolin to the 6-position.

The rearrangement reaction is carried out in an organic solvent such as dimethyl sulfoxide, N,N-dimethylformamide, methanol, acetate/, acetonitrile dioxane, or tetrahydrofuran, or in a mixed solvent of each solvent and water, preferably N
.

in N-dimethylformamide or a mixed solvent of acetonitrile and water in an amount of 0.1 to 10 equivalents, preferably 1 to 10 equivalents.
3 equivalents of alkali metal hydrides, hydroxides, carbonates 1, inorganic bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium hydride, or tri-lower alkylamines such as triethylamine, 1,8 −
The reaction is carried out by reacting an organic base such as diazabicyclo(5,4,0]-7-undecene with forskolin substituted at the 7-position.The reaction is carried out at approximately -20°C and at a temperature of approximately 2000G, usually under water cooling and at the boiling point of the solvent. Nearby from 1 minute to 48 hours,
It is preferably carried out at room temperature for 30 minutes to 1 hour.

It can also be obtained by treating the intermediate obtained in the condensation step (2) or (3) of 1 above in the same manner as 2 above, and then reacting it with the amine of formula (IV) above.

3. In general formula (1), R2 is -COCI-I2C
The following compound, which is 1-12C0OH and in which R1 and R3 are both hydrogen atoms, can be obtained as follows. That is, the above 1 (4
), 7-substituted forskolin can be obtained by using succinic anhydride in place of glutaric anhydride, and then transferring the substituent at the 7-position to the 6-position.

The rearrangement reaction is carried out in a polar solvent such as dimethylsulfoxide, N,N-dimethylformamide, methanol, acetone, acetonitrile, etc., or in a mixed solvent of each solvent and water, preferably in a mixture of N,N-dimethylformamide or acetonitrile and water. In the mixed solvent, 0.1 to 10 equivalents, preferably 1 to 3 equivalents of sodium hydroxide, potassium hydroxide, potassium carbonate.

This is carried out by allowing an inorganic base such as sodium hydride or an organic base such as triethylamine or 1,8-diazabicyclo[5°4.0]-7-undecene to act on forskolin substituted at the 7-position. The reaction is carried out under water cooling at around the boiling point of the solvent for 1 minute to 48 hours, preferably at room temperature for 30 minutes to 1 hour.

4. In the general formula m, R1 is a hydrogen atom, and R2゜R
The following compounds in which both 3 are groups other than hydrogen atoms can be obtained by any of the following methods.

(1) 6-substituted-7- obtained by method 20 above
Deacetylforskolin, 6-ffl-7-deacetyl-14,15-dihydroforskolin or 6-ffl-7-deacetyl-14,15-dihydroforskolin
Substituted-13-cyclopropyl-7-deacetyl-14,
15-dinorforskolin or 6-alkanoyl-7-derocetyl-forskolin obtained by the same method as above is represented by the general formula % (%) [wherein Y and m are the same as above] The compound or its reactive derivative as described above in 1(I
) to condense in the same manner.

Examples of the compound of general formula (Vl) include acetic acid, propionic acid, butyric acid, and those exemplified as compounds of general formula I.

(2) In the case of a compound in which the substituent at the 7-position is a nitrogen-containing group, the 6-deoxycetyl phoscolin obtained by the method in 2 above is used instead of the 7-decetylphorscolin used in 1 (2) or (3) above.
Substituted -7-deacetylforskolin 6- and -7-
Deacetyl-14,15-dihydroforskolin or 6-substituted-13-cyclopropyl-14,15-dinorforskolin or It can be obtained by carrying out the same reaction as 1(2) or (3).

(3) In the general formula (11), R1 is a hydrogen atom and R
2 is -COClCH2C0OH, and R3 is CO
CH3,C0CHz CHz C)h C0OH, or -〇 OCR(OH)CH20H, as the first step, synthesize 6-(2-carboxyethylcarbonyl)-7-deacetylforskolin by method 3 above. Then, the desired product can be obtained by reacting with acetic acid or a reactive derivative thereof, or by performing acylation according to the method (4) or (5) of 1 above.

In addition, in the above-mentioned reactions 1 to 4, instead of the starting material such as 7-deacetylforskolin, the 1-position hydroxyl group is replaced with a ryosyl group such as an acetyl group, or an ether group such as a methyl ether group.

By using a compound protected with a silyl ether group such as t-butyldimethylsilyl ether group and removing the protecting group in the final step, the compound of the present invention of the general formula fT) can be obtained.

5. 6- and/or 7-di(-! or mono) in the general formula m, where R4 is an ethyl group or a cyclopropyl group
Substituted-13-cyclopropylmata is 14.15-dihydro-forskolin is obtained by hydrogenating or acetic acid It can be produced by reacting diazomethane using palladium or the like as a catalyst.

6. In general formula (1), % R' is -CO(C)h)
, C0OH or -CO(CH2)q N part 0 (wherein, R2, R3+ R'* R'+ R10+ p
and q are the same as above) A compound represented by (wherein R2, R3 and R4 are the same as above) is added with a carboxylic acid represented by the general formula or a reactive derivative thereof in a solvent. It is obtained by reacting at 20°C to 200°C.

6- represented by the general formula (VJll) which is a raw material compound
Amizalkylcarbonyl-7-deacetylforskolin or 6-amizalkylcarbonyl-7-deacetyl-14,15-dihydroforskolin or I3
-cyclopropyl-6-aminoalkylcarbonyl-7
-Deacetyl-14.15-Dinorforskolin is a 7-amizalkylcarbonyl-7-deacetylphorus compound represented by the general formula (where R', R', R', and m are the same as above). Choline or I3-cyclopropyl-aminoalkylcarbonyl-7-deacetyl-14,15-
React dinorforskolin with a base in an organic solvent.

It can be obtained by rearranging the group -CO(C)I2)N46.

In reactions 1 to 6 above, carboxyl groups and hydroxyl groups on R1, R2, and n3 are ester groups such as methyl ester groups and ethyl ester groups, acyl groups such as acetyl groups, ether groups such as methyl ether groups, and acetonide groups, t A compound protected with a silyl ether group such as -butyldimethylsilyl ether group is used, and the amino groups on R1, R2, and n3 are acyl groups such as acetyl group, silyl ether group such as t-butyldimethylsilyl ether group, etc. The compound of the present invention having the general formula (Tl) can also be obtained by using a compound protected with and removing the protecting group in the final step.

Unless otherwise specified, the compounds of the present invention are preferably carried out in an organic solvent or a mixed bath medium of these and water, unless otherwise specified.
Reaction conditions.

It can be obtained as a free base, a free acid, or a salt depending on the method of processing.

Free bases and free acids can be converted into salts by conventional methods, if desired. As salt.

Inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate, or formate, acetate, fumarate, maleate, etc.)
Citrate, tartrate.

It can be an organic acid salt such as lactate or methanesulfonate.

Free acids include sodium salt, potassium acid, magnesium salt,
Metal salts such as calcium salts can be converted into organic base salts such as quaternary ammonium salts and pyridinium salts.

In addition, among the compounds of the present invention, those having an asymmetric carbon in R2 or R3 theoretically have optical isomers, so 1
The present invention includes these optical isomers. Optical isomers can be separated by known methods such as chromatography and fractional crystallization.

Next, Table 1 shows the compounds of the present invention produced by the above method.

[For production]

Next, the action of the compound of the present invention will be explained.

1.Positive inotropic effect, hypotensive effect Beagles or hybrids, male or female, were set on fire under ventoparbital sodium anesthesia, and a polyethylene tube was inserted from the carotid artery into the left ventricle to measure the left ventricular pressure. Insert a polyethylene tube into the femoral artery. These polyethylene tubes are connected to a pressure transducer and continuously recorded on a recorder via a pressure strain gauge.

Furthermore, the rate of rise in left ventricular pressure (dp/dt) is determined using a differential meter, and is similarly recorded continuously, and is used as an index of inotropy.

The drug effect is expressed as a relative value to the maximum response to each forskolin index. That is, the maximum change in dp/at increase and mean blood pressure (MBP) decrease when forskolin 30 μg/kg is intravenously administered is set as 1, and the test compound is 300 μg/kg or 30 μg/kg, respectively.
The maximum change when administered intravenously is expressed as a relative value.

2. Adenylate cyclase activation effect CGI-Dru, mmon using a membrane fraction obtained from guinea pig myocardial homogenate as an adenylate cyclase preparation
d, D-L-5everson, L-Duncan
, J-Biol, Chem, 246.4166
(1971)].

The measurement was performed using the method of Salomon et al. (Y-Salomon,
C-Londos, M., Rodbell, Ana
Labeled cAMP produced by adenylate cyclase using labeled ATP as a substrate is measured according to the method (Biochem-1, Biochem-1, 58, 541 (1974)). The reaction solution is
5mM MgCh.

20mM creatine phosphate, 100U/ml creatine phosphokinase, ImM cAMP, Irn
MC”C (TJD ATP (approx. 7 Cpm/ pmo
l ) and forskolin or test compound (l μM)
25 mM Tris, HCI (pH 7,5
) and start the reaction by adding the enzyme preparation to a final volume of 100 μm. Enzyme bonds are 150 membrane proteins.
~200μg/100μm. After reacting at 37°C for 10 minutes, add a reaction stop solution (2% sodium dodecyl sulfate (SDS), 40mM ATP, 1.4mM c
After stopping the reaction by boiling 00 μl of AMP, pI-17,5), 50 μl of (3H) cAMP (approximately 20,000 c
pm). After this Dowex 501! Separate cAMP using a T fat column and neutral alumina column and measure radioactivity. The adenyl cyclase activation effect of the test compound (1 μM) is expressed as a percentage of the activation effect of forskolin (I μM). represent.

[n=4 (Fall 10.17 is n=6 38.39゜4
1 is n = 2), mean territorial standard error].

Next, Table 2 shows the results of the above 1°2 test for representative compounds of the present invention.

3. Solubility As a result of measuring the solubility of the compounds of the present invention in water, all of the compounds showed a solubility χ of 0.1% or more. Since the solubility of forskolin in water is 0.0026%, the compound of the present invention has a solubility of forskolin of 38@ or more.

〔effect〕

As described above, the compound of the present invention has excellent positive inotropic action, antihypertensive action, adenylate cyclase activating action, and water solubility superior to that of forskolin. Therefore, the compound of the present invention is expected to be used as a therapeutic agent for acute or chronic heart failure, an antihypertensive agent, and a cerebral vasodilator. It is also expected to be used as a therapeutic agent for diseases caused by cAMP accessory cylinder abnormalities, such as glaucoma, asthma, immunodeficiency, tumors, and digestive system diseases.

The dosage in this case varies depending on the symptoms of thoughts being administered, age, and administration method, but is usually 0.01 to 30 ■/kg.
/ day.

In the present invention, preferred compounds include 6-dimethylaminoacetyl phorscolin (compound 1'!x I
O) 6-(3-dimethylaminopropionyl)forskolin (compound position 17) 6-(4-dimethylaminobutyryl)forskolin (
Compound 20) 7-zoacetyl-7-(2,3-dihydroxypropionyl)forskolin (Compound 6-(4-aminobutyryl)Forskolin (Compound-38) 6-(4-pyrrolidinoacetyl)Forskolin (Compound 38) 39) 6-(4-dimethylaminobutyryl) -14゜15-
Examples include dihydro-forskolin (compound %45). Among them, compounds that are particularly well known for their medicinal properties are compounds such as +7.20.38.

The compound of the present invention can be mixed with a suitable pharmaceutical carrier to form tablets, granules, fine granules, powders, and capsules.

Preparations such as injections, eye drops, patches, ointments, etc.
It can be administered orally or parenterally. In particular, since it has better water solubility than forskolin, it can be made into an aqueous solution formulation suitable for drip infusion or intravenous administration, and is therefore expected to have a therapeutic effect when administered parenterally.

The compounds of the present invention will be described in more detail below with reference to Examples.

Example 1 7-Diacetyl-tudimethylaminoacetylforskolin (compound m1) 7-Diacetylforskolin (500μ), viridiy
(250 mg) and dichloromethane (1 omi) under water cooling, a dichloromethane solution of H (1 ml) of chlorocetyl chloride (250 ml) was added, and the mixture was stirred at room temperature for 1 hour. Then, under water cooling, pyridine (751T1g),
Acetyl chloride (75Ing) in dichloromethane MW (
Seal the container and incubate for an additional 3 hours at room temperature. After the reaction is completed, one reaction solution is condensed under reduced pressure to remove dichloromethane and unreacted reagents. 7-Diacetyl-dichloroacetylforskolin is obtained as an oil and the next reaction is carried out without purification.

First, this oil was dissolved in dichloromethane (10 ml), dimethylamine (3 ml) was added under water cooling, and the mixture was stirred for 1 hour. After the reaction is completed, one reaction solution is concentrated under reduced pressure, the resulting residue is filled with water, and extracted with ethyl acetate. The organic layer is washed with water, dried over magnesium sulfate, and then the desiccant is filtered off. The PM is concentrated under reduced pressure, and the residue 1 (78011[) is purified by silica gel chromatography. Elution with ethyl acetate yields 7-diacetyl-thu-dimethylaminoacetylforskolin (46 sq+, yield 76% from 7-diacetylforskolin).

ml) 162-166°C (hexane-ethyl acetate) IR
(Nujol) ν: 3450, 3200.1735
゜1705 cm″″′ MS m/z (relative intensity): 4s3 (M, s),
357 (6) 102 (71), 59 (52), 58
(100) Hydrochloride is obtained by dissolving this crystal in dioxane and adding 1 equimole of hydrogen chloride dissolved in dioxane α.

mp 284-287℃ (EtOH) III (Nujol) v: 1740.1710cm
-' Using the following amine instead of dimethylamine, 7-
Reaction with theacetyl-twochloroacetylforskolin likewise gives compounds nos. 2-6.

Yield from near-deacetylforskolin.

IR and MS data are shown in Table 3.

Example 2 7-zoacetyl-7-(3-dimethylaminopropionyl)forskolin (compound m7) forskolin (1
5g), t-butyldimethylchlorosilane (z, 2sg
), imidazole (5.25 g), and N,N-dimethylformamide (45 ml) was stirred at 70°C for 21 hours.

After the reaction is complete, the reaction solution is poured into water and extracted with ethyl acetate. After washing the organic layer with water, it is dried with magnesium sulfate, and the desiccant is removed in an oven. Pg was concentrated under reduced pressure to obtain crude 1-(t-butyldimethylsilyl)-forskolin (21.62 g
).

This oil (21.62 g) was mixed with methanol (250 ml).
) and then diluted with IN NaOH (40 ml) under ice-cooling.
). The mixture was stirred overnight at room temperature, and after one reaction was completed, the reaction solution was concentrated under reduced pressure. Add water to the resulting residue and extract with ethyl acetate. After washing the organic layer with water, it is dried with magnesium sulfate, and the desiccant is removed in an oven. The filtrate was concentrated under reduced pressure and the residue (20 g) was purified by silica gel chromatography. Bathe with hexane-tyl acetate (5:1) to obtain -(t-butyldimethylsilyl)-7-diacetylforskolin (17.42 g, 99% forskolin) as an oil.

IR(neat)v: 3500.3300.171
0cm-'MS m/z (relative intensity): 482 (
M, 0.8), 466 (100), 407 (8), 31
1 (20), 191 (36), 75 (100) This oil (1.5 g), pyridine (320 ■).

3-chloropropionyl chloride (513 ml) was added dropwise to a mixture of dichloromethane (10 mt). After stirring overnight at room temperature and completing one reaction, water was added and extracted with ethyl acetate. After washing the organic layer with water and drying, the desiccant is distributed from door to door. Concentrate the PR to obtain crude 1-(t-butyldimethylsilyl)-7-(3-chloropropionyl)-7-diacetylforskolin (2,09 g) as an oil.

A dichloromethane solution (10 ml) of this oil (Ig)
), add excess dimethylamine under water cooling.

After the reaction was completed for 2 hours at room temperature, the reaction solution was concentrated and the crude 1-(t-butyldimethylsilyl)-
7-zoacetyl-7-(3-dimethylaminopropionyl)forskolin (877■) is obtained.

'H-NMR (CDC13) δ: 5.4 4
(I H, d, J = 4.6 Hz.

4.62 (IH, br s), 4.60 (IH, b
r s ), 2.86 (6H, s), 1.70 (3
H,s), 1.45(31-1,s).

1.33 (3H, s), 1.26 (3H, s), 1.0
5 (3H.

s), 0.87 (9H, s), 0.14 (3I (, s)
, 0.02 (3H, s).

Kono oil (865 mg, l methanol gn (10 m
Trifluoroacetic acid (4) was added to the mixture under water cooling, and the mixture was stirred at room temperature for 43 hours. After the completion of the reaction, concentrate 1 reaction Mv,
The resulting residue is diluted with dilute hydrochloric acid and washed with ethyl acetate. The aqueous layer is made alkaline with 28% aqueous ammonia and extracted with ethyl acetate. After washing the organic layer with water and drying with magnesium sulfate, remove the desiccant. Separate by F. The filtrate was concentrated, and the resulting residue was recrystallized from hexane-dichloromethane to yield 7-zoacetyl-7-(3-dimethylminoroprionyl)forskolin (283).

(41% from 1-(t-butyldimethylsilyl)-7-diacetylforskolin) mp 150-153°C MSm/z (relative intensity): 467 (M", 2), 2
02(2).

159(8), 118(29), 92(61), 91(
81), 58(100).

%25 using diethylamine instead of dimethylamine
The compound was obtained as a colorless oil.

Yield 69.1% MS m/z: 495 (M”) Example 3 7-Zoacetyl-7-(4-pyrrolidinobutyryl) forskolin (Compound N, 8) 7-Diacetyl forskolin (1,3 g ), pyridy (700111g)% dichloromethane 7 (40ml)
4-chlorobutyryl chloride (soo
mg) in dichloromethane (10 ml) and stirred at room temperature for 3 hours. After the reaction is completed, the reaction solution is concentrated under reduced pressure, and the resulting residue is purified by silica gel chromatography. Elution with hexane-ethyl acetate gave 7-(4-chlorobutyryl)-7-diacetylforskolin (1.27 g) as an oil.

'H-NMR (CDC13) δ: 5.53 (I H
, d, J=5Hz).

4.58 (IH, brs), 4.48 (IH, brs)
.

3.64 (2H, t, J=6Hz), 2.62
(2H, m).

2.18 (,4H, m), 1.73 (3H, s), 1.
45 (3H, s), 1.35 (3H, s), 1.2
7 (3H, s).

1.04 (3H, s).

This oil (1.27g), pyrrolidine (20ml),
A mixture of dichloromethane (50 ml) is stirred at room temperature for 5 days. After the reaction is completed, the reaction mixture is concentrated under reduced pressure. Add water to the residue and extract with ethyl acetate.

The organic layer is washed with water, dried with magnesium sulfate, and then the desiccant is removed from the house. Liquid F was concentrated under reduced pressure, and the residue was purified by silica gel chromatography. Elution with chloroform-methanol yields 7-deacetyl-7-(4-pyrrolidinobutyryl)forskolin (109flK, 6% from 7-diacetylforskolin).

'HNMR (CDCb) δ: 5.37 (I H, d,
J=4Hz).

4.56 (IH, m), 4.50 (IH, m),
2.53 (8)-1, m), 1.93 (2H,
m), 1.79 (41-1, m).

1.73 (3H, s), 1.44 (3H, s), 1.3
5(3H,s), 1.26(:3H,sL 1.03(
3H,s).

MS m/z (relative intensity): 507 (M”, 4), 1
99(3).

156 (26), 140 (10), 92 (40), 91
(52), 84(100).

Example 4 6-dimethylaminoacetyl-7-deacetylforskolin (compound h9) 7-Diacetyl-thu-dimethylaminoacetylforskolin (200 rag) obtained in Example 1 was mixed with acetonitrile-water (45:55). Dissolve in a mixed solvent (20 ml), add IN aqueous sodium hydroxide solution (0.8 ml), and stir at room temperature for 25 minutes. After the reaction is completed, one reaction solution is marred under reduced pressure. Water is added to the resulting residue and extracted with ethyl acetate. Organic layer? After washing with water, dry with magnesium sulfate and remove the desiccant from door to door. The P solution was concentrated under reduced pressure, and the resulting residue (242 cm) was purified by silica gel chromatography. By elution with acetonitrile, 6-dimethylaminoacetyl-7-deacetylphorscholin (
1761! Ig, 88%).

mp 116-117℃ (hexane-ethyl acetate I
R (nujol) ν: 3410.3200.175
0°1720 cm"" MS m/z (relative intensity): 453 (M, 5),
350(2).

237(2), 219(2), 104(15), 58(
100).

The hydrochloride salt is obtained by dissolving the crystals in dioxane and preparing a 1 equimolar hydrogen chloride-dioxane solution.・mp 263-265℃ (EtOH) IRt Nujorun ν: 3490, 3230.2680゜1745
．． 1710 cm-' Using the corresponding 7-substituted forskolin, the compounds shown in Table 4 are obtained by a similar rearrangement reaction.

Example 5゜6-Dimethylaminoacetyl phorskolin (compound tooth) 0) 6-dimethylaminoacetyl-7-deacetyl phorskolin (compound 9.587■) and dichloromethane (2
Pyridine (Ig) in a mixture of 0 ml).

Boil acetyl chloride (750 rng) in 4 portions.

Stir at room temperature for 7 hours. After the reaction was completed, water was added and the mixture was made basic with mW of sulfated sodium bicarbonate water.

Extract with dichloromethane. Dry the organic layer with magnesium sulfate and remove the desiccant. The filtrate was concentrated, and the resulting residue i (811) was purified by silica gel chromatography. Elute with hexane-ether (1:3), 6-
Dimethylaminoacetylphorskolin C444■,6
9%) I got it.

ml) 190-193°C (Toluene) IR (Nujol) ν: 3100. 1750.1730゜1
720 cm-''HNMR(CDCl3') δ: 586 (I I-
1, Q, J-4Hz.

J=2.7HzL 5.5 6 (I I-1,
d, J=4.9l-(z).

4.61 (IH, brs), 3.18 (2H, s),
2.31 (6H, s), 2.04 (3H, s), 1.6
4 (3H.

s), 1.42 (3H, s), 1.35 (3H, s).

1.04 (3H,s), 0.96 (3H,s
).

The hydrochloride is obtained in the same manner as in Example 4.

mp 255-260℃ (EtOH) IR (Nujol) ν: 3240.3130.2400゜1750
．． 1725 cm-' In this example, by using propionyl chloride or butyryl chloride in place of acetyl chloride, a compound with %]1°12 is obtained (see Table 5).

In addition, in this example, 6-dimethyl-minoacetyl-7
- 6-dinithylaminoacetyl-7-deacetylphorskolin (%6 compound), 6-(3-dimethyl-minopropionyl)-7 instead of zoacetylphorskolin
- diacetylforskolin (compound of Nn23), 6
-(3-diethylaminopropionyl)-7-diacetylforskolin (Arashi 24 compound), 6-(4-dimethylaminobutyl)-7-deacetylforskolin (
The results are shown in Table 5 by using the compound ffi19). Compounds of Na 15.17.18.20 can be obtained.

Table 5 Example 6゜6-dimethylaminoacetyl-7-deacetyl-7-dimethylaminoacetylforskolin (compound layer) 3-dimethylaminoacetyl-7-deacetylforskolin (compound tooth 9.700111), Pyridine (14
6ff@), dichloromethane 7 (10ms),
While cooling with water, chloroacetyl chloride (209 cm) was added dropwise.

The mixture was stirred for 3 hours under water cooling, and after the reaction was completed, one reaction solution was concentrated. The resulting residue is diluted with water, made basic with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The organic layer is washed with water, dried with magnesium sulfate, and then the desiccant is removed from the house. Concentrate the filtrate to obtain 7-chloroacetyl- as a white solid.
7-Diacetyl-6-dimethylaminoacetylforskolin (749).

A dichloromethane solution (20 cm) of this white solid (749 cm)
ml)'Q, 1 drop was added to a dichloromethane bath solution (20 ml) of excess dimethylamine under water cooling, and the mixture was stirred at room temperature for 1 hour. After the reaction is completed, water is added to the reaction solution and extracted with dichloromethane. After drying the organic layer with magnesium sulfate, the desiccant is removed in a furnace. Concentrate Fα to obtain residue 1 (728
11W) is purified by silica gel chromatography.

Bathe with dichloromethane-acetone (2:1) to obtain 6-dimethylaminoacetyl-7-deacetyl-7-dimethylaminoacetyl phorskolin (186ff1g, 23% from compound compound 9).

mp 180-183℃ (hexane-ethyl acetate) M
s m/z (relative intensity): 538 (M, 58),
454(8), 104(100), 102(100).

In a similar manner, 6-acetyl-7-diacetylforskolin was converted to 6-acetyl-7-chloroacetyl-7-diacetylforskolin, and then by reaction with dimethylamine, 6-acetyl-7-diacetyl- Two-dimethylaminoacetylforskolin (compound m2
88% from 1,6-acetyl-7-derocetylphorskolin.

'I-I NMR (CDCl5) δ: 5.82 (I
H, Q, J=4.711z.

J=3.0Hz), 5.62 (I H,d, J=4.
4Hz).

4.61 (IH, brs), 3.15 (2H, c
enterofAB qnartet, J=17Hz
), 2.37 (6H,s).

2.09 (3H, s), 1.66 (3H, s), 1.4
4 (3H, s), 1.33 (3H, s), 1.03 (3
H.

s), 0.98 (3H, s).

In a similar manner, 6-acetyl-7-cyacetylforskolin was converted to 6-acetyl-7-cyacetylforskolin using 4-chlorobutyryl chloride.
Convert to 7-(4-chlorobutyryl)7-cyacetylforskolin.

'HNMR (CDC13) δ: 5.83 (l H,
Q, J = 4.3Hz.

J = 3.1 Hz), 5.55 (l
H, d, J = 4.6Hz).

4.63 (IH, brs), 3.52 (2H, m).

2.38-2.6 (4H, m), 2.10 (3H
,s).

2.04-2.2 (3H, m), 1.6.7 (3
H,s).

1.44 (3H, s), 1.36 (3H, s), 1.0
4 (3H, s), 0.98 (3H, s).

This compound was reacted with pyrrolidine to produce 6-acetyl-7-zoacetyl-7-(4-pyrrolidinobutyryl)forskolin (compound 1'h 22.6-acetyl-7
- diacetylforskolin (14%).

'HNMR(CDCl3)δ: 5.81 (IH
, Q, J=4.3Hz.

J=2.9Hz), 5.54 (IH,d, J=4
．． 6Hz).

4.60 (IH, brs), 2.62 (6H, m).

2.28-2.44 (3H, m), 2.09 (3H, s
).

1.75-1.95 (68, m), 1.65 (3H).

1. 44 (3H, s), 1.35 (3H, s), 1.
03 (3H, s), 0.98 (3H, s).

Example 7゜7-zoacetyl-7-hemiglutaryl forskolin (
Compound 1'11k126) 7-cyacetylforskolin (369rng).

Glutaric anhydride (3421r@), pyridine (5ml
) is heated at 110°C for 2 hours. After the reaction 1
The reaction solution was concentrated under reduced pressure, water was added to the resulting residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous solution of copper sulfate,
After drying with magnesium sulfate, separate in a desiccant oven. The P solution is concentrated under reduced pressure, and the resulting residue is purified by silica gel chromatography. Elution with hexane-acetic acid (2:1) and then chloroform-methanol (9:1) gives 7-zoacetyl-7-hemiglutaryl forskolin (combined ventilation 26.270 cm, 56%) as an oil.

'HNMR (CDCl3) δ: 5.4 9 (
I H, d, J = 4.0 Hz).

4.58 (IH, brs), 4.47 (IH, t, J=
3.7Hz), 2.50 (4)1. m), 2.
20 (2H, m).

2.05 (2H, m), 1.73 (3H, s), 1.4
5 (3H, s), 1.35 (3H, s), 1.
27 (3H.

S), 1.04 (3H, s).

MS m/z (relative intensity): 482 (M, 7), 46
4 (62).

436 (sO), 227 (41), 115 (84)
.

81 (100).

Example 8゜7-zoacetyl-7-(2,3-dihydroxypropionyl)forskolin (compound rSkL27) 7-cyacetylforskolin (500 mg)% biridin (3
00111g), 2,2-dimethyl-1,3-dioxolane-
A dichloromethane solution (4 ml) of 4-carboxylic acid chloride (360q) is added and the mixture is stirred at room temperature for 4 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a residue [(950
(2) Purify by 7a-silica gel chromatography. 7-Cyacetylforskolin-7-(
A diastereomeric mixture of 2,2-dimethyl-1,3-dioquinrane-4-carboxilade is obtained.

(557■, 83%) mp 160-165°C MS m/z (relative intensity): 496 (M, 2), 47
8 (40).

131 (32), 123 (36), 101 (100).

59(30).

A mixture of this 7-zoacetyl phorskolin-7-(2,2-dimethyl-1,3-dioxolane-4-carboxylade) (300 μl) and 70% acetic acid (10 ml) was added to
Borrow for 2 hours at 0℃. After the reaction is completed, the reaction solution is concentrated under reduced pressure, and the resulting residue (470 cm) is purified by silica gel chromatography.

Elution with dichloromethane-ethyl acetate (2:1) gives a diastereomeric mixture of 7-derocetyl-7-42,3-dihydroxypropionyl)forskolin (A:B=3:2).

(250■, 91%) mp 160-172℃ IR (nujol): 3440, 3320.1750
, 1730° 1700 cm-' MS m/z (relative intensity: 456 (M, 5L 4
38 (77).

123 (94), 99 (80), 81 (100).

Example 9゜6-hesuccinylphorscholin (compound % (1j
A mixture of forskolin (Ig), t-butyldimethylsilyl chloride (i, 2g), imidazole (1,25g) and N,N-dimethylformamide (2ml) was mixed with 6
Leave at 0°C for 2 hours.

The reaction solution was poured into ice water and extracted with ether. The ether layer is washed with water and dried over anhydrous sodium sulfate. After removing the desiccant, the P solution was concentrated under reduced pressure to obtain 1-(t-butyldimethylsilyl)forskolin (1.2 g)* as a colorless oil.

(2) Obtained oil (t, 2g) u methanol (IO
mJ), add IN Na Of-1, and stir at room temperature for 3 hours. After the reaction is complete, the reaction solution is diluted with water and extracted with ethyl acetate. After washing the organic layer with water, it is dried with anhydrous sodium sulfate and the desiccant is removed in an oven.

The P solution is concentrated under reduced pressure, and the residue (1.0 g) is purified by silica gel chromatography. Hexane-ethyl acetate (
% 1-(t-butyldimethylsilyl)-7-diacetylforskolin (0.85 g) is obtained as a colorless oil.

f311-(t-butyldimethylsilyl)-7-diacetylforskolin (0,44+; l*pyridine (2,
0ml), add co-phosphoric anhydride (4g) and
Reflux for an hour. After the reaction is complete, pyridine is concentrated under reduced pressure.
The residue is thoroughly washed and extracted with ethyl acetate and 0,1 N HCl. The organic layer is washed with water and dried over anhydrous sodium sulfate. desiccant? After IP separation, the filtrate was concentrated under reduced pressure and 1-(t-
Butyldimethylsilyl)-7-hemisuccinyl-7-deacetylphorscholin (0.53 g, target) is obtained as an oil.

(4) Dissolve this oil (zsoiv) in a mixed solvent (IOmJ) of acetonitrile-water (1:l).

Add an aqueous solution (1 ml) of IN hydroxide.

Stir for 30 minutes at room temperature. After the reaction was completed, the reaction solution was diluted with water, adjusted to pH 3 with 0.5 NHC1, and extracted with ethyl acetate. The organic layer is washed with water and dried over anhydrous sodium sulfate. The desiccant is removed, the filtrate is concentrated, and the resulting residue is purified by silica gel column chromatography.

1-(t-7''Tyldimethylsilyl)-6-hemisuccinyl-7-deacetylphorscolin was dissolved as a colorless oil (1
78■, 71.2%).

(5) This oil (178■) was mixed with pyridine (Q,
4 ml) and diluted with acetic anhydride (0.4 ml) under water cooling.
Leave it at 4℃ overnight. The reaction solution was poured into ice water and extracted with ethyl acetate. After washing the organic layer with water, anhydrous acidification) I
Dry with Jum. After removing the desiccant, it is concentrated in a furnace under reduced pressure. The resulting composition was purified by silica gel column chromatography to obtain 1-(t-butyldimethylsilyl)-
6-Hemisuccinylphorscolin (183■, 96.
3%) as a colorless oil.

(6) This oily substance (75cm) was mixed with methanol (1ml
), add trifluoroacetic acid (1.5ml) and stir at room temperature for 4 hours. A saturated Na HC03 aqueous solution was added to the reaction mixture to neutralize it, and then extracted with ethyl acetate. After washing the organic layer with water, 1175m was concentrated under reduced pressure.

6-Hemisuccinyluorscholine (compound N1N2
9.32%, 52.2%, was obtained as a colorless oil.

NkiR(CDCl3)δ: 1.01.1.38
．． 1.42.1.61゜1.69.2.01 (each, 3
H,s, Me), 2.01(3H,s, 0A
c), 2.60-2.80 (4I(, rn.

COCH2CH2Co), 4゜6 1
(IH, broad.

s, lβ-H), 4.98 (l I-1,d,
J=8I-1z.

15-H), 5-28 (IH, d, J=17.5
Hz.

15-H), 5.52 (J H, d, J=3Hz
, 72-H), 5.83 (I H, t+ 3
．． 5Hz, 62-H).

5.97 (IH, dd, J=811117.5Hz
, 14-H) Example] 0゜6-hemisuccinyl-7-deacetylphorscolin (
Compound 28) I-(t-butyldimethylsilyl)-6-hemisacudiny-7-deacetylforskolin (260) obtained in Example 9 (4) was decomposed in the same manner as in Example 9 (6). protection, yielding 6-hemisuccinyl-7-deacetylphorscholin (compound 111h28.140, 67%) as a colorless oil.

MS m/z (relative intensity): 468 (M).

Example 11゜forskolin-1-hemisuccinate (compound ventilation 31
) Forskolin t1g), succinic anhydride (4.9g)%
A mixture of 4-morpholino-N,N-dicyclohexylcarbodiimide (1.1 gJ and pyridine (8 ml)) is heated at 100°C for 1 hour. After the reaction is complete, the reaction solution is concentrated under reduced pressure to obtain a residue. Add 0.5N hydrochloric acid to the solution and extract with ethyl acetate. Wash the ethyl acetate layer with saturated brine, dry over anhydrous sodium sulfate, and remove the desiccant. Concentrate solution F under reduced pressure to obtain a residue. was purified by silica gel column chromatography, eluting with chloroform-methanol (96:4) and then with chloroform-methanol-acetic acid (18:2:0.5) to obtain forskolin-1-hemisuccinate (compound N31°0). .7g)
is obtained as a colorless oil.

'H-NMR (sodium salt, CDCl5) δ:
5.50 (IH, d.

J=4Hz), 5.50(IH,s), 4.46(J
H, brs).

2.50-2.30 (4H, m), 2.16 (3
H,s).

1.67 (3H, s), 1.51 (3H, s), 1.
31 (3H.

s), 1.25 (3H, s), 1.02 (3H
,s).

MS (El, 70eV, methyl ester derivative)
m/'z (relative intensity): 5os((:M-183,
5), 243(7).

191 (33), 151 (31), 115 (
100).

307(45).

The sodium salt of forskolin-1-hemisuccinate is obtained by dissolving it in a 5% aqueous solution of sodium bicarbonate, adsorbing it on Amberley) XAD-n, washing with water, and eluting with methanol.

In a similar manner, forskolin-1-hemicultarate (compound v32 Jy) can be prepared using glutaric anhydride in place of succinic anhydride.

'I (-NMR (+ IJ lamb salt, CDCl5)
a: 5.57 (lH,brS), 5.4
8 (-J H, d, J=4Hz 4.55 (I
H.

t, J=3.7Hz), 2.5~2.2 (4H
, m), 2.0 to 1.8 (2H, m), 2. J8(
3H,s 1.71 (3H.

S)・1.54(3H,S), 1.34(3)1
．． Sno.

1.28L3H,s), 1.05(3H,s).

MS (El, 70eV, methyl ester derivative)
m/z (relative intensity) 52ou:M-ts]:3o)
.

259(7), 219(5), 191(3,1,175
(6L J29(100).

Example 12 Forskolin-1-hemiadipate (compound ventilation 33 Forskolin (0,] 2 g) and adipic acid dichloride (0,5 g) in dichloromethane solution (LOml)
Add pyridine (0.2 ml) under ice cooling. Add one reaction solution and stir at room temperature for 4 hours. The reaction solution was poured into an ice-cooled 5% sodium bicarbonate aqueous solution, and the acid chloride was decomposed with W water, and then the pH was adjusted to 3 with 0.5N hydrochloric acid.

Add ethyl acetate to this and extract. The organic layer was washed with saturated brine and then diluted with anhydrous sodium sulfate. The extract is concentrated under reduced pressure, and the resulting residue is purified by silica gel thin layer chromatography.

Develop with chloroform-methanol-acetic acid (9:1:0.1) and separate the portion with pHHO23-0.5.
), forskolin-1-hemiadibate (compound ff133.0.065 g) is obtained as a colorless oil.

'H-NMR (sodium salt, CDC1a) δ: 5
．． 56 (IH, brs), 5. ri 1 (IH, d,
J=4Hz), 4.46 (IH.

t, J=3.2Hz), 2.5~2.0 (4H,
m), 1.8-1.5 (4H, m), 2.18 (
3H,s), C70(3H.

S), 1.53 (3H, s), 1.33 (3H
,s).

1.24 (3H,s), 1.05 (31-1
,s).

MS (El, 70eV, methyl ester derivative m/z (relative intensity)' 5.34 ((M 18), 6
8 no.

282(7), 259(]4), 2]9(]3).

1! IN(61L 343(jOO).

Next, it is made into a sodium salt in the same manner as in the case of compound type 31.

Forskolin-1-hemioxalate (
Compound %30) can be prepared.

MS (FABJm/z: 483 (M+H),
591 (MH+108).

Example: 3°Forskolin-1-(N,N-dimethylaminobutyrate (Compound N36) Forskolin (0.20g), N,N-dimethylaminobutyrate (0.25g), dicyclohexylcarbodiimide ( A mixture of 0.40 g), 4-dimethylaminopyridine (0.30 g), and dichloromethane (5 ml) was reacted at room temperature for 2 hours. After separating the precipitated crystals, the filtrate was diluted with 7al-5% sodium bicarbonate aqueous solution. After making alkaline, extract with ethyl acetate. Wash the organic layer with water and dry with anhydrous sodium sulfate. Remove the desiccant from door to door.
Compress liquid F under reduced pressure.

The resulting residue is purified by silica gel column chromatography. Ethyl acetate, then ethyl acetate-methanol-
Elution with triethylamine (,95:5:J) yields forskolin-1-(N,N-dimethylaminobutyrate) (compound type 36.O, 19 g) as a colorless oil.

'HNMR (CDCh) δ: 5.55 (IH,s
), 5.53 (IH.

d, J=4.8Hz), 4.47 (JH,
br s), 2.5-2.1 (4H, m), 2
．． J 8 (6H,s), 217 (3H,s)
.

1.71 (3H, sL 1.85~1.65 (2H
, m).

1.54 (3H, s), 1.35 (3H, s), 1.2
8 (3H.

S), 1.06 (3H, s).

MS (FAB) m/z (relative, intensity Noni 524 (M
+H, 100).

632 (MH+I08.78).

Example 14 Forskolin-1-glycinate (compound type (1)
Forskolin (0.3 gJ, t-butoxycarbonylglycine (0.3 g), dicyclohexylcarbodiimide (0.4 g), 4-dimethylaminopyridine (0.3
g), a mixture of dichloromethane (5 ml) χ2 at room temperature
Stir for an hour. After precipitated crystals are separated from each other, the p liquid is extracted with ethyl acetate. After washing the organic layer with water, it is dried over anhydrous sodium sulfate. After removing the desiccant, the P solution is concentrated under reduced pressure, and the residue is subjected to silica gel column chromatography. Forskolin-1-BOC-glycinate (0.31 g) was eluted with ethyl acetate-benzene (5:95 J, then ethyl acetate-benzene (10:90)).
is obtained as a colorless oil.

'HNMR (CDCl2) δ: 5.61 (]H
,br S), 5.42(JH,d, J=4Hz
), 4.45 (JH, s).

3.80 (2H, d, J=5.3HzL 217
(3H.

s), 1.74 (3H, S), 1.55 (3H
, sLl, 45 (9H, s), 1.34 (3H, s),
1.29 (3H, s), 1.05 (3H, s).

(2) Next, this forskolin-1-BOC-glycinate (0.31 g) was dissolved in acetic acid (0.5 ml), and a hydrobromic acid-acetic acid solution (0.5 ml) was added under water cooling for 10 minutes at room temperature. put. After neutralizing excess hydrobromic acid with 5% sodium bicarbonate.

Adsorb onto Amberlite XAD-2 resin. After washing the column with water, it was eluted with MeOH and forskolin-1
-Glycinate (compound % 34° 0.32 g) is obtained as a colorless oil.

MS (FAB) m/z (relative intensity V 468 (MI
-IL576 (MH-z08).

By a similar method, forskolin-1-(6-aminocaproate) (compound %37), forskolin-
I-(4-aminoptylate (compound part 35)) can be produced.

Forskolin-J-16-minocaproate) (Compound Nh37) Oil MS (FAB) m/z: 524 (M+H)
.

632(Ml(+108J.

Forskolin-1-(4-aminobutyrate) (Compound 35) Oil MS (FAB) m/z: 496 (M+H)
-604 (MH-1108).

Example 15゜6-(4-aminobutyryl)forskolin (compound %
38) (1) 7-derocetylphorscholin (3,OOg, l
, 4-(t-butoxycarbonylamino)butyric acid (8,2
0g), 4-dimethylminopyridine (6.40g),
Dicyclohexylcarbodiimide (J2.60gJ 4
Add a few minutes at a time and leave at room temperature overnight. After the reaction is complete, water (
0.5ml) was added and the reaction solution was concentrated under reduced pressure. Add dichloromethane to the concentrate and separate the residue. FiM is concentrated and the resulting residue is purified by silica gel column chromatography. Dichloromethane-ethyl acetate (10
:J) to give 7-[4-(t-butoxycarbonylamino)butyryl]-7-zoacetylphorskolin (compound %38a: 1.60 g, 36%) as an oil.

MS m/z (relative intensity): 535 ((MI
(zO], 23).

479(23), 104(34), 86(81L57(
300].

(2) This oily substance (38a, 1.50 g),
Add 1N aqueous sodium hydroxide (6 ml) to a mixed solution of setonitrile (90 ml) and water (60 ml) and stir at room temperature for 40 minutes. After the reaction is complete, immediately concentrate the reaction solution, add water, and dilute with ethyl acetate. Extract. Dry the extract with magnesium sulfate, remove the desiccant, and concentrate the filtrate. The resulting residue (1.43 g) is purified by silica gel column chromatography. Dichloromethane-ethyl acetate (4:1 ~ 2:I) and 6-[4-(t-
butoxycarbonylamino)butyryl]-7-zoacetylfluoroscholine (Compound 38b, 1.12g, 7
5%). mp188-190℃ (Ethyl acetate IR (Nujorun ν: 3350.1735.17
10cm-'(3) This compound (t'h38b:1
．． 12g) was dissolved in dichloromethane (80mJ), and to this solution was added pyridine (1,52gJ) and acetyl chloride (675mJ).
■) Add three times. The mixture was stirred at room temperature for 8 hours, and water was added to complete the reaction.

Extract with dichloromethane and dry the organic layer over magnesium sulfate. The desiccant is removed, the filtrate is concentrated, and the resulting residue fi (1.97 g) is purified by silica gel column chromatography. Dichloromethane-ethyl acetate (10
:I to 5:1) to obtain 6-(4-(t-ptoxycarbonylaminanoptyryl)forskolin (compound size 38c: 414, 34%).

Compound % 1c: mp 162-165°C (hexane-toluene (4)) This compound (Na 38c, 123■) is dissolved in 85% formic acid under water cooling, and the mixture is stirred at room temperature for 2 hours. Reaction completed. After that, the reaction solution is concentrated, water is added and washed with ethyl acetate.The aqueous layer is made basic with 3N aqueous sodium carbonate solution and extracted with ethyl acetate.The organic layer is dried over magnesium sulfate, and the drying agent is separated by kW. Concentrate the filtrate and
The resulting residue is recrystallized from ethyl acetate-methanol to obtain 6-(4-aminobutyryl)forskolin (compound lN1138.31, 30%).

mp 191-192℃ IR (Nujiak) ν: 3360,1725cm
-''HNMR (CD30D) δ: 5.76 (I
H, Q, J = 4.7Hz.

J=3.3Hz), 5.39 (I H,d, J=
:4.3HzL4.42 (IH, brs), 2.59
(2H, to J=6.0Hz), 2.2-2.4
(2H,m), 1.88 (3H,s).

1.8~1.6 (3H, m), ! , 56 (3H
, s), 1.37 (3H, s), 1.23 (3H, s)
, 0.91 (6H, 5iNS m/z (relative intensity)
:495(M, 14), 146(32L 304(1)
00], 99 (13L 86 (74).

Example 16゜6-pyrrolidinoacetylforskolin (Compound Arashi 39
) (1) 7-Diacetyl-two-pyrrolidinoacetyl obtained in the same manner as in Example 1(I) except that pyrrolidinoacetic acid was used instead of 4-(t-butoxycarbonylamino)butyric acid in Example 1(1). Forskolin (4.20g
, ) in a mixed solvent of acetonitrile-water (4:l) (15
Dissolve the mixture in 0 ml of hydroxide and add an aqueous solution of IJ (9.63 ml) under water cooling. Stir at room temperature for 6 hours, then add water to complete the reaction. The reaction solution was extracted with ethyl acetate, and the organic layer was concentrated. Dissolve the concentrate in ether and make 1N
Extract with hydrochloric acid. The aqueous layer was made basic by adding aqueous ammonia dropwise under ice cooling, and extracted with ether. Dry the organic layer with magnesium sulfate and remove the desiccant. Concentrate the F belly,
The resulting residue is purified by silica gel column chromatography. Elution with dichloromethane-methanol (20:I) yielded 7-derocetyl-6-pyrrolidinoacetylforskolin (compound 1% 39a, 900■, 21
%).

IR(KBr)v: 3460.3210. J7
45°1710 cm-' MS m/z (relative intensity): 479 (M, I)
, 130 (87, 84 (Joo).

(2) This compound (1'439 a, 100tn
g), dichloromethane (loml), pyridine (72 .mu.) and acetyl chloride (72 .mu.) were added in 4 portions over a period of 6 hours under water cooling. Stir overnight at room temperature and extract with dichloromethane. After washing the organic layer with saturated saline, drying with magnesium sulfate. lI-'r. The desiccant is distributed from house to house, and the filtrate is concentrated to obtain rel.fiffi (1
20 ml of the product was purified by silica gel column chromatography. Elution with chloroform-methanol (20:]) yielded 6-pyrrolidinoacetylforskolin (compound IV).
1k139.53■, 50%).

mp 166 168°C (methylene chloride-hexane) IR (KBr) I': 3450.3230,17
50゜17 j 5 cm-' Example 17゜7-zoacetyl-7-(4-dimethylaminebutyryl)
Forskolin (compound elJm40) in a mixture of 7-diacetylforskolin (8,00g), 4-dimethylaminobutyric acid hydrochloride (14,56g), 4-dimethylaminopyridine (21,21g), and dichloromethane (150ml). , under water cooling, dicyclohexylcarbodiimide (
A mixture of 35.82 gJ and dichloromethane (120 ml) was added dropwise, and the mixture was stirred at room temperature for 4 hours. After the reaction is completed, the reaction solution is extracted with diluted hydrochloric acid. The aqueous layer is made basic with concentrated aqueous ammonia and extracted with diethyl ether. The organic layer is washed with water and dried over anhydrous magnesium sulfate. The desiccant was removed from door to door, and the resulting P solution was concentrated under reduced pressure to obtain 7-derocetyl-7-(4-dimethylaminobutyrylnophorscholine) (5.41 g) as an oil.

52% more than 7-diacetylforskolin
MS rn/z: 481 (M).

Example: 8゜6-(4-dimethylaminobutyryl)-14゜15-dihydroforskolin (compound Nn 41 ) 6-(4
-dimethylaminoptyrilnophorscholine (30ff
A mixture of 5% palladium-carbonate catalyst (Ig), 5% palladium-carbonate catalyst (6 ml), and methanol (8 ml) was entrained under a hydrogen atmosphere at room temperature for 5 hours. After the reaction was completed, the catalyst was taken from door to door, and the resulting P"H Concentrate to obtain 6-(4-dimethylaminobutyryl)-14,
15-dihydro-forskolin (compound number 41.30
ff1g, 100%).

mp 210-212℃ (Methanol IR (nujol) ν: 3160.1730.1710cm-'(
The data of NMR and MS are shown in Table 7) In the same manner as in this example, Table 6 and Table 7 (as shown (No.,
Compounds 42-45 are obtained.

In addition, in Example I7, the starting material for the compound of rVh42 was - instead of 4-dimethylaminobutyric acid hydrochloride.
It can be obtained in the same manner except that monodimethylaminoacetic acid hydrochloride is used.

In addition, the starting materials for the compounds of Nn43, 44.45 are
Example J (In 31, 4-dimethylaminobutyric acid hydrochloride, dimethylaminoacetic acid or 3-dimethylaminopropionic acid was used instead of 4-(t-butoxycarbonylaminobutyric acid, and the other conditions were the same as in Example 15. You can get it.

Example 19゜13-cyclopropyl-6-dimethylaminoacetyl-
14,35-dinorforskolin (compound tooth 46) 6-dimethylaminoacetylforskolin (100
), palladium acetate (J 4q), and anhydrous tetrahydrofuran (5 ml) was added with ethereal diazometha solution under water cooling, and the mixture was further stirred for 3 hours under water cooling. After the reaction is complete, remove the water and pHJO with 3N sodium carbonate aqueous solution.
and extract with ethyl acetate. The organic layer is dried over magnesium sulfate, and the drying agent is removed in an oven. Concentrate the obtained furnace liquid,
The residue is purified by silica gel column chromatography. Elution with dichloromethane-ether (4:1 to 2:1) yielded 13-cyclopropyl-6-dimethylaminoacetyl-14,35-dinorforskolin (compound 46
．． 16ryg, 16%).

IR (Nujol) ν: 3570, 3180, 373
5゜J 715 cm 'HNMR (CDC13) δ: 0.30 (2H, m
), 0.4 J (IH.

m), 0.75 (IH, m), 0.9J (JH, m)
, 0.95 (3H, s), 1.03' (3H, s)
, 1.32 (3H,s).

1.44 (3H, S), 1.54 (3H, S), 2.0
1 (3H.

S), 2.43 (6H, s), 3.23 (2H, s),
4.5J (IH, brs), 5.5 1 (J
H, d, J=5Hz).

5.83 (lH, t, J=4Hz).

MS m/z (relative intensity): 510 (M”, 2
3J, 109(49), 104(101,83(49)
, 59(1('10), 58(100).

In a similar manner, 13-cyclopropyl-7-deacetyl-7-dimethylaminoacetyl-34,35-
-) norforskolin (compound 1'1 & 147.60
%) You can get it.

IR (Nujoorno v: 325 (1, J740.1
705cm-''H-NMR (CDC13) δ:O,J
8 (2H, m), 0.49 (JI (.

m], 0.89 (JH, m), 0.96 (J
H, m), 1.0J (3H, s), 1.28 (3H
, s), 1.30 (3HT S).

1.50 (3H, s), 1.66 (3H, s),
2.38 (6H.

S), 3.27 (2H, s), 4.43 (JH, brs
Ha4.47 (jH,br s ], 5.43
(JH,d, J=4.5Hz).

MS m/z (relative intensity): 467 (M, 4), JO
9(26).

304 (58), 102 (60), 85 (43), 58
(100).

Example 20゜7-zoacetyl-7-(3-dimethylaminopropionyl)forskolin (compound ff17) 7-diacetylforskolin (2,00 gJ of dichloromethane solution (
60ml) and 4-dimethylminopyridine (3,00g)
), 3-dimethylaminopropionic acid hydrochloride (3,8
0g), dicyclohexylcarbodiimide (7,0Og)
) was divided into three portions over 47 hours and stirred at room temperature. After the reaction is completed, the solvent is concentrated under reduced pressure, and the resulting residue is treated with ethyl acetate and filtered. Concentrate the filtrate to obtain a residue i
(6, (15 g) is purified by silica gel chromatography. Dichloromethane-methanol (20 Co1~JO
:J,) and eluted with 7-zoacetyl-7-(3-dimethylaminepropionylnophorscholine (compound N11
47.1.72g, 68%] was obtained.

Table 7

Claims (1)

[Claims] General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, I and R^1 are hydrogen atoms, R^4 is a vinyl group,
If it is an ethyl group or a cyclopropyl group, (1) Either R^2 or R^3 has a partial structural formula ▲ Numerical formula, chemical formula, table, etc. ▼ (Here, R^5, R^6
is a hydrogen atom, a lower alkyl group, or a lower alkylene group in which R^5 and R^6 are bonded and which may contain an oxygen atom or a nitrogen atom in the bonded chain, and m is an integer of 1 to 5. ), and the other is a hydrogen atom or a partial structural formula CO (
CH_2)_nA group represented by
^7 and R^8 are bonded together to form a lower alkylene group which may contain an oxygen atom or a nitrogen atom in the bonded chain, and n is an integer of 1 to 5. ) is shown. ), or (2) R^2 is a hydrogen atom or -COCH_2CH_2
When CO_2H, R^3 is a hydrogen atom, the formula -COC
H_3, -COCH_2CH_2CH_2CH_2CO_2H,
or -COCH(OH)CH_2OH (however, R^2
When is a hydrogen atom, R^3 is a hydrogen atom and COCH_3
It is a group other than ), and R^1 is the partial structural formula CO
(CH_2)_pCO_2H, or ▲mathematical formula, chemical formula,
There are tables, etc. The group represented by ▼ (here R^9, R^
1^0 is a hydrogen atom or a lower alkyl group, p is 0
~5, g is an integer from 1 to 5. ), R^2
is a hydrogen atom, R^3 is an acetyl group, and R^4 is a vinyl group] and its physiologically acceptable salts