CS272221B2 - Method of new forskolin derivatives production - Google Patents

Abstract

PURPOSE:To provide a new compound having strong positively inotropic action, hypotensive action and adenylic acid cyclase activation action and high water- solubility and useful as an agent for the treatment of cardiac insufficiency. CONSTITUTION:The compound of formula I [one of R<2> and R<3> is CO(CH2)mNR<5> R<6> (R<5> and R<6> are H, lower alkyl, etc.; (m) is 1-5) and the other is H, CO(CH2) mX (X is H etc.; (n) is 1-5), etc., when R<1> is H and R<4> is vinyl, ethyl or cyclopropyl; R<2> is H, R<3> is acetyl and R<4> is vinyl when R<1> is CO(CH2)pCO2H, or CO(CH2)qNR<9>R<10> (R<9> and R<10> are H or lower alkyl; (p) is 0-5; (q) is 1-5)], e.g. 7-deacetyl-7-dimethylaminoacetylforskolin. The compound of formula can be produced by condensing 7-deacetylforskolin, 7-deacetyl-14,15-dihydroforskolin or 13-cyclopropyl-7-deacetyl-14,15-dinorforskolin with a compound of the formula R<5>R<6>N(CH2)nCO2H.

Description

A process for the preparation of novel forskolxine derivatives of formula (VII) wherein r 4 is vinyl, ethyl or cyclopropyl, r 5 _and r 6 are each hydrogen or C 1-4 alkyl or R 6. and R c together represent a C 1-4 alkylene chain which optionally contains an oxygen or nitrogen atom, m and n are from 1 to 5 and X is a hydrogen atom or "a group of the formula -N" wherein r ⁷ and R c are each independently ^R or Cý_4alkyl or R 'and R ⁸ together represent Ci_4alkylenový chain which optionally contains oxygen or nitrogen, or its physiologically acceptable salts, characterized in that the 7-deacetylforskolinový derivative of the formula VIII wherein R, R 5 _(R 6 and _m are as above, reacted with a carboxylic acid of formula IX, wherein X is as defined above, or a halide or anhydride thereof, and optionally the resulting compound of formula VII is converted to another compound within the scope of control and optionally allowed to react free the base of the resulting compound of formula VII with a physiologically acceptable acid to give the corresponding Novel forskolin derivatives have positive inotropic, hypotensive and adenylate cyclase stimulating effects.

HOOC (CH ₂ ) _n X (VII) tvxxx) (XX)

The present invention relates to a novel forskolin derivative having positive ionotropic, hypotensive and adenylate-cyclase stimulating effects.

Forskolin is already known to have positive ionotropic, hypotensive, and adenylate cyclase stimulating effects / Japanese Patent Laid-open No. 79,015/77 and Arzneim. Forsch. 31, 1248 (1981)].

However, forskolin is only soluble in water at room temperature at 0.0026% concentration. A special pharmaceutical device is therefore required for its administration. Thus, it is desirable to develop a water-soluble derivative of forskolin.

For this reason, the present inventors have conducted extensive studies. As a result of these studies, the following forskolin derivatives and their physiologically acceptable salts are more soluble in acid, basic or neutral solutions than forskolin and have positive ionotropic, hypotensive and adenylate cyclase stimulating effects. These forskolin derivatives are compounds of formula VII,

In which it is a vinyl, ethyl or cyclopropyl group,

R @ ⁵ and R @ ⁵ are each independently hydrogen or C1 -C4 alkyl or R @ 1 and R @ 2 together represent an alkylene chain of 1 to 4 carbon atoms, which optionally contains a hydrogen atom or a nitrogen atom; and

X represents a hydrogen atom or a group of the general formula

Wherein R @ 1 and R @ 2 are each independently hydrogen or C1 -C4 alkyl or R @ 1 and R @ 2 together represent a C1 -C4 alkylene chain optionally containing an oxygen or nitrogen atom, or a physiologically acceptable salt thereof .

In the above formula (VII), a C 1 -C 4 alkyl group is a methyl, ethyl, propyl or butyl group. C 1 -C 4 alkylene optionally containing an oxygen or nitrogen atom is, for example,

- ((Ή ₂ ) ₃ -, - (CH ₂ ) ₄ -, - (CH ₂ ) ₂ -NH- (CH ₂ ) ₂ - or - (CH ₂ ) ₂ -O- (CH ₂ ) ₂ -.

6

--CO _{(CH2) ni} t R (R) R represents for example dimethylamínoacetylovou group diethylaminopropionylovou group butylaminoacetylovou group dimethylaminopropionylovou group dimethylaminobutyrylovou group pyrrolidinbutyrylovou group pyrrolidinacetylovou group piperazinacetylovou

CS 272221 'B2 or morpholinacetyl. The group -CO (CH ₂ ) _n X represents, for example, an acetyl, propionyl or butyryl group or any of the above-mentioned different aminoacyl groups.

According to the invention, the forskolin derivatives of the general formula (VII) are prepared by reacting a 7-deacetylforskolin derivative of the general formula (VIII)

(VIII), wherein R 1, R 1, and m are as defined above, are reacted with a carboxylic acid of formula IX

Η000 (0Η _{2) η} X (IX) in which on X are as defined above, or a halide or anhydride in an organic solvent such as dichloromethane, 1,2-dichloroethane, chloroform and diethyl ether or a mixture thereof with water for temperatures, for example between -20 ° C and + 200 ° C, preferably between -5 ° C and the boiling temperature of the solvent used.

6-Aminoalkylcarbonyl-7-deacetylforskolin, 6-aminoalkylcarbonyl-7-deacetyl-14,15-dihydroforskolin or 13-cyclopropyl-6-aminoalkycarbonyl-7-deaetyl-14,15-aminorforskolin, i.e. the starting material of formula VIII, can be produced by reaction bases with 7-aminoalkylcarbonyl-7-deacetylforskolin or with 13-cyclopropyl-7-aminoalkylcarbonyl-14,15-dinorforskolin of formula X

(Wherein R, R, R ° and _m are as described above in a polar solvent, whereby the group -CO (CH ₂ ) _m N (R 5) R 6 is dislocated to the 6-position.

A compound of formula VII wherein R 1 is ethyl or cyclopropyl and R 1, r 6, X, m and n are as defined above can be prepared by hydrogenation of a forskolin derivative of formula VIIa

CS 272221 ’B2

wherein R 1, R 1, X, m and n are as defined above by reaction with diazomethane in the presence of a catalyst.

From the reaction product solution, the compound of the invention is isolated and purified by conventional means. It is thus obtained in the form of the free base, free acid or salt, depending on the reaction conditions and the post-reaction treatment method. If desired, both the free base and the free acid can be converted to a salt in a normal manner. The free base can be converted into an inorganic acid editorial salt such as hydrochloride, hydrobromide, sulfate or phosphate, or an organic acid editorial salt such as formic acid, acetic acid, fumaric acid, malic acid, citric acid salts. , tartaric acid, lactic acid or methanesulfonic acid. The free acid may be converted to a metal salt, for example, sodium, potassium, magnesium or calcium salt, or to an organic base salt, such as quaternary ammonium salts or pyridinium salts.

Compounds of this invention which have an asymmetric carbon atom in the groups -CO (CH _{2) n} N (R 5) R ^ and X ^ -COÍCHgJ, theoretically exist as optical isomers. These optical isomers are therefore included within the scope of this invention. The optical isomers may be resolved in a known manner, for example by chromatography or fractional crystallization.

Table 1 describes examples of compounds of the invention prepared according to the above procedure.

Table 1

compound no. OCO (CH 2) N. (R ⁵ ) R ⁶ 2 m. OCO (CH ₂ ) _n X R ⁴ 1 OCOCHpNXCHPp OCOCH ₃ CH = GH ₂ 2 OCCH ₂ N. (CH 2) _? OCCH ₂ CH ₃ ch == ch ₂ 3 OCCH ₂ N (CH ₃ ) ₂ OCO (CH ₂ ) ₂ CH ₃ ch = ch ₂ 4 OCO (3H; N (CH3) ₂ ) _; OCCH ₂ N (CH ₃ ) ₂ ch = ch ₂ 5 OCCH ₂ N (CH ₂ CH ₃ ) ₂ OCOCHij ch = ch ₂ 6 0C0 (CH ^) ₂ N (CH _{3) 2} OCOCH ₃ ch = ch ₂ 7 0C0 _{(CH) 9} N _{(CH 2} CH.p OCOCH ₃ ch = ch ₂ 8 OC (CH ₂ ) ₃ N (CH ₃ ) ₂ ococh ₃ Cffe = CH ₂

CS 272 221 B2

Table 1 (continued)

9 10 OCO (CH ₂ ) ₃ Nl · 2 OCOCII ₃ ch = ch ₂ OCOCHg / OCOCH ₃ ch = ch ₂ 11 OCO (CH ₂ ) ₃ N. (CH ₃ ) ₂ ococh ₃ CH ₂ CH ₃ 12 OCOCH ₂ N, (CH ₃ ^ 2 ococh ₃ CH ₂ CH ₃ 13 OCOCHgN ^ _ ococh ₃ CH ₂ GH ₃ 14 OCO (CH ₂ ) ₂ N. (CH ₃ ) ₂ ococh ₃ CH ₂ CH ₃ 15 Dec OCOCH ₂ N (CH ₃ ^ 2 ococh ₃ ch (ch ₂ )

The physiological activity of the compounds of this invention is determined by the following methods:

A. Positive ionotropic activity and hypotensive activity

Adult animals, either male or female, beagle dogs or mixed breed dogs are used as test animals. Under anesthesia with sodium pentobarbital, a polyethylene tube is placed in the left ventricle of each animal by its carotid artery to measure the left ventricular internal pressure. The polyethylene tube is also inserted into the animal's femoral artery to measure blood pressure. Each polyethylene tube is connected to a pressure sensor. The pressure is continuously recorded on the recorder using a pressure gauge. Further increase in left ventricular internal pressure (dp / dt) is determined using a differential meter and continuously recorded in a similar manner. It serves as an index of ionotropic efficiency.

The potency of the test compounds is represented by relative values to the maximal effects given by forskolin. The maximum increase in velocity (dp / dt) and the maximum reduction in mean blood pressure (MIBP), which result from intravenous administration of 30 µg / kg of forskolin, is taken as 1; the potency of test compounds is expressed as relative values resulting from intravenous administration of 300 µg / kg or 30 µg / kg of test compounds.

B. Adenylate Cyclase Stimulating Activity. A membrane fraction obtained from guinea pig heart muscle homogenate was used as an authentic adenylate cyclase sample (see: G. I. Drummond, D. L. Severson and L. Kuncan: J. Biol. Chem. 246, 4166 (1971)]. Labeled cyclic adenosine monophosphate (cAMP), which is produced by the action of adenylate cyclase on labeled adenosine triphosphate (ATP) as a substrate, is determined by the method of Salomon Y., London C, and Rondell M.: Anal.

CS 272221 32

Biochem. 58, 541 (1974). The reaction was initiated by adding the authentic enzyme to a solution of 25 mM Tris-HCl (pH 7.5) containing 5 mM MgCl 3, 20 mM creatine phosphate, 100 units per milliliter creatine phosphokinase, 1 mM cAMP, 1 mM / ml. ^ C (U) / ATP (approximately 7 counts per minute / picomol) and either forskolin or test compound (1 χΐιΜ) so that the final volume of the reaction mixture was 100 µl. The authentic enzyme is used in an amount of 150 to 200 micrograms per 100 microliters as a membrane protein. After 10 minutes at 37 ° C, the reaction is stopped by adding 100 µl of a solution (pH 7.5) containing 2% sodium dodecyl sulfate (SDS), 40 mM ATP and 1.4 mM cAMP. To measure the percent cAMP formed, 50 µl / ^µ H / cAMP (about 20,000 counts per minute) was added. The cAMP is then isolated by chromatography on a Dowex 50 resin column and an alumina column and the radioactivity of cAMP is measured.

The adenylate cyclase stimulation activity of the test compounds (1 µM) is expressed as a percentage of forskolin activity (1 µm), / a denotes 4 (n denotes number 6 for compound 1 and 6 and n denotes number 2 for compound no. 9, 10 and 11), the mean value.

Table 2 shows the results of tests A and B for typical compounds of the invention.

Table 2

Pysiological efficacy of forskolin derivatives

compound C. A. positive inotropic and hypotensive efficacy B. adenylate cyclase activating activity (%) dose (g / kgj iv) positive inotropm efficiency, (dp / dt) hypoten- gray efficiency 1 300 1.1 2,0 90.4 + 4.7 2 300 0.8 1,2 45 _r l ± 6.9 3 300 0.8 1.0 40.2 _ 7.1 4 300 0.9 0.7 19.5 + 0.5 6 30 1,2 0.8 107, -4 ± 7.1 7 300 1.0 1.5 .27.9 + 16.2 8 30 1.0 0.9 91.1 ± 14.6 9 30 0.9 0.7 214.9 10 30 0.6 0.6 57.8 11 30 0.5 0.6 114.7 15 Dec 300 0.8 0.8 -

C. Solubility

The results of water solubility measurements show that all of the compounds of the invention exhibit higher solubilities than forskolin.

Thus, the compounds of the invention have excellent inotropic, hypotensive and adenylate cyclase stimulating activity and are more water soluble than forskolin. The compounds of the invention are expected to be effective as a medicament for chronic cardiac insufficiency, as a hypotensive agent and as a brain vasodilator, and as a medicament in diseases such as glaucoma, asthma, immune deficiency, tumors and digestive system diseases that are caused by abnormal cAMP regulation. Suitable doses of the compounds of this invention in the treatment of diseases usually are from 0.01 to 30 mg / kg per day, although the dosage depends on the condition of the disease, the age of the patient to be treated and the route of administration.

Preferred compounds of this invention are 6-dimethylaminoacetylforskolin (compound number 1), 6- (3-dimethylaminopropionyl) forskolin (compound number 6),

6- (4-dimethylaminobutyryl) forskolin (compound number 8),

6- (4 * aminobutyryl) forskolin (compound number 9),

6-pyrrolidinoacetyl) forskolin (Compound No. 10) a

6- (4-dimethylaminobutyryl) -14,15-dihydroforskolin (Compound No. 11). Of these, compounds No. 6, 8 and 9 are particularly preferred for their therapeutic efficacy and other properties.

The compounds of the invention may be admixed with suitable pharmaceutically acceptable carriers. This provides tablets, granules, finer granules, powders, capsules, injectables, suppositories, eye drops, gypsum, ointments and other forms of pharmaceutical compositions which can be administered orally or parenterally. The compounds of this a

of the invention are more water soluble than forskolin so that they can be prepared as an aqueous solution suitable for infusion or intravenous administration. Thus, parenteral administration is expected to have great therapeutic effects.

The present invention is illustrated in more detail in the following examples, in which, in addition to the preparation of the compounds of the invention, i.e. compounds 1 to 15, also the preparation of compounds 16 to 33 described in Table 3, many of which serve as starting materials for the preparation of the compounds of the invention. However, these examples do not limit the scope of the invention.

Table 3

CS 272221 82

Table 3 (continued)

R ^c

R

IC

H

H

H

H

H

H

C00H ₂ E (CH ₃ ) ₂ COGH ₂ KH (CH ₂ ) ₃ CH ₃ COH ₂ MCÉ ₂ CH ₃ ) ₂ ·· HH = CH ₂ ch = ch ₂ ch = gh ₂ GOCH ₂ N CH = CH ₂ r ~ 0OGH ₂ N <\ _ of ™ ^- / NH ch = ch ₂ C0CH ₂ n / IN CHF = CH ₂

22nd H 23 H 24 COCH ₂ Ni (CH ₃ ) ₂ 25 coch ₂ (oh ₂ ch ₃ ) ₂ 26 COCH ₂ NH (CH ₂ ) ₃ CH ₃ 27 Mar: O (CH ₂ ) ₃ N (CH ₃ ) ' ₂ ' 28 co (ch ₂ ) ₂ n (ch ₃ ) ₂ 29 CO (OH ₂ ) ₂ N (CH ₂ CH ₃ ) 30 COGH ₃ 31 H 32 H 33 COCH ₃

co (gh ₂ ) ₂ n. (ch ₃ ) ₂

CO (CH ₂ ) ₃ N

H

H

H

H

H coch ^; 2n; (ch ₃ ) ₂ co (ch ₂ ) ₃ ni (ch ₃ ) ₂ co (ch ₂ ) n (ch ₃ ) ₂ gh = oh ₂ ch = ch ₂

CH = CH ₂ CH = CH ₂

CH = CH ₂

CH = CH ₂

CH = CH ₂

CH = CH ₂ CH = CH ₂ OH = CH ₂ CH ₂ CH ₃

CH = <2H-

CO (CH ₂ ) ₃ N

Example 1

7-Deacetyl-7-dimethylaminoacetylforskolin (Compound No. 16)

A solution (1 mL) of chloroacetyl chloride (250 mg) in dichloromethane was added to a mixture of 7-deacetylforskolin (500 mg), pyridine (250 mg) and dichloromethane (10 mL) with ice-cooling and stirring at room temperature for one hour. A further solution of pyridine (75 mg) and ethyl acetate (75 mg) in dichloromethane (1 mL) was added under ice-cooling.

The mixture was stirred at room temperature for three hours to quench the reaction. Then the product solution is evaporated to dryness in vacuo to remove dichloromethane and unreacted components. There was thus obtained an oily 7-deacetyl-7-chloroacetylforskolin which was subjected to the following reaction without further purification: This means that the oily product was dissolved in dichloromethane (10 ml), dimethylamine (3 ml) was added under ice-cooling, Stir one hour to quench the reaction. This product solution was concentrated in vacuo and after addition of water the mixture was extracted with ethyl acetate. The organic layer (extract solution) was washed with water, dried over magnesium sulfate and filtered to remove the drying agent. The filtrate was concentrated in vacuo. The concentrate (780 mg) was purified by silica gel chromatography. Elution with ethyl acetate gave 7-deacetyl-7-dimethylaminoacetylforskolin (468 mg, 76% yield based on 7-deacetyl-forskolin), mp 162-166 ° C (recrystallized from hexane-ethyl acetate). IR (nujol): 3450, 3200, 1735 and 1705 cm @ ^-1 . Mass spectrum (m / z, relative intensity): 453 (M ⁺ , 5), 357 (6), 102 (71), 59 (52), (100). This crystalline product was dissolved in dioxane. Addition of an equimolar amount of hydrochloric acid dissolved in dioxane gives the product hydrochloride, mp 284-287 ° C (ethanol). IR (nujol): 1740 and 1710 cm @ ^-1 . Compounds Nos. 17 to 21 are also obtained according to the above procedure, but using the amines listed in the table instead of dimethylamine. In the table, the yields are based on 7-deacetylforskolin, IR (nujol) is measured in cm <^'1' and the mass spectrum is indicated m / z (relative intensity).

Table 4 Compound no.

butylamine ethylamine

yield (%) m.p. C 0) IR mass spectrum 14 175-8 5610 481 (M ^& lt ^{; +} & gt ^; , 10) (hexane- ethyl- 5520 585 (6) acetate) 5520 550 (4) 1750 524 (6) 1710 152 (99) 86 (100) 90 150-5 5500 482 (M ⁺ , 12) (hexane • ethyl- 5180 585 (5), 150 (71) acetate) 1740 88 (100) 1710 58 (61)

CS 272221 B2.

Table 4 (continued)

19 ' pyrrolidine 71 178-182 (hexane- ethyl- acetate) 5000 5440 5160 1750 1710 479 (M ⁺ , 1), 150 (6), 128 (9), 85 (7), 84 (100) 20 May piperazine 32 oil 494 (M ^& lt ^{; +} & gt ^; , 5), 452 (2), 582 (10), 145 (28), 99 (100). '21 fflorfolin 28 182-185 (hexane- ethyl- acetate) 549Ο 5140 1755 1715 495 (M ⁺ , 2), 599 (2), 146 (9), 144 (10), 100 (100)

Example 2

7-Deacetyl-7- (3-dimethylaminopropxonyl) forskolxine (Compound No. 22)

A mixture of forskolin (15 g)> tert-butyldimethylchlorosilane (11.25 g), itnidazole (5.25 g) and N, N-dimethylformaniide (45 mL) was stirred at 70 ° C for 21 hours until the reaction was complete. The product solution is then poured into water. This mixture was extracted with ethyl acetate. The organic layer was washed with water, dried (MgSO4) and filtered. The filtrate was concentrated in vacuo. Crude (tert-Butyldimethylsilyl) forskolin (21.62 g) was obtained.

This oily product (21.62 g) was dissolved in methanol (250 mL). To this solution was added 1ΪΓ aqueous sodium hydroxide (40 mL) under ice-cooling. The reaction mixture was stirred overnight at room temperature to complete the reaction. The reaction mixture was then concentrated in vacuo. The concentrate was extracted with ethyl acetate after addition of water. The organic layer was washed with water, dried over magnesium sulfate and the desiccant was filtered off. The filtrate was concentrated in vacuo. The concentrate was purified by silica gel chromatography (concentrate weight: 20 g). Elution with 5: 1 hexane-ethyl acetate gave 1- (tert-butyldimethylsilyl) -7-deacetylforskolin (17.42 g, 99% yield forskolxin) as an oil. IR (neat): 3500, 3300 and 1710 cm ^-1 . MS: m / z (relative intensity): 482 (M ⁺ , 0.8), 466 (100), 407 (8), 311 (20), 191 (36), 75 (100).

To a mixture of the oily product (1.5 g), pyridine (320 mg) and dichloromethane (10 ml) was added dropwise 3-chloropropxonyl chloride (513 mg). After stirring at room temperature for 5 hours, pyridine (320 mg) and 3-chloropropionyl chloride (513 mg) were added to the mixture. The reaction mixture was stirred at room temperature overnight to quench the reaction. The product solution was extracted with ethyl acetate after addition of water. The organic layer was washed with water, dried and the desiccant removed by filtration. Concentration of the filtrate affords crude 1- (tert-butyl-dimethylsilyl) -7- (3-chloropropionyl) -7-deacetylforskolin (2.09 g) as an oil,

To a solution (10 mL) of this oily product in dichloromethane was added excess dimethylamine under ice-cooling. The mixture was stirred at room temperature for two hours to complete the reaction. The product solution is then concentrated. The crude 1- (tert.

butyldimethylsilyl) -7-4-acetyl-7- (3-dimethylaminopropionyl) forskolin (877 mg) as an oil.

CS 272221 .32

NMR Spectrum (CDCl3) .delta. 5.44 (1H, d, J = 4.6 Hz), 4.62 (1H, broad / br / s),

4.60 (1H, br s), 2.86 (6H, s, 1.70 (3H, s), 1.45 (3H, s), 1.33 (3, H, s), 1.26 (3H, s), 1.05 (3H, s), 0.87 (9H, s), 0.14 (3H, s), 0.02 (3H, s).

To a methanolic solution (10 mL) of this oily product (865 mg) was added trifluoroacetic acid (4 mL) under ice-cooling. The mixture was stirred at room temperature for 43 hours, then concentrated. This concentrate was diluted with dilute hydrochloric acid and washed with ethyl acetate. The separated aqueous layer was basified with 28% aqueous ammonia and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and the desiccant was filtered off. The filtrate was concentrated and recrystallized from hexane-dichloromethane. 7-Deacetyl-7- (3-dimethylaminopropionyl) forskolin (283 mg) was obtained. Yield 41% based on 1- (tert-butyldimethylsilyl) -7-deacetylforskolin. Melting point: 150-153 ° C. Mass Spectrum: m / z (relative intensity): 467 (M ⁺ , 2), 202 (2), 159 (8),

118 (29); 92 (61); 91 (81); 58 (100).

Example 3

7-Deacetyl-7- (4-pyrrolidinobutyryl) forskolin (Compound No. 23)

To a mixture of 7-deacetylforskolin (1.3 g), pyridine (700 mg) and dichloromethane (40 mL) was added a solution (10 mL) of 4-chlorobutyryl chloride (800 mg) in dichloromethane under ice-cooling. The reaction mixture was stirred at room temperature for 3 hours to quench the reaction. The product solution is concentrated in vacuo and the product is purified by silica gel chromatography. Elution with hexane-ethyl acetate gave (7- (4-chlorobutyryl) -7-deacetylforskolin (1.27 g) as an oil. 1 H NMR spectrum (CDCl 3 Cl 0):

5.53 (1H, d, J = 5Hz), 4.58 (1H, broad band), 4.48 (1H, br s), 3.64 (2H, triplet,

J = 6 Hz, 2.62 (2H, ra), 2.18 (4H, m), 1.73 (3H, s), 1.45 (3H, s), 1.35 (3H, s) 1.27 (3H, s); 1.04 (3H, s).

A mixture of this oil (1.27 g), pyrrolidine (20 mL) and dichloromethane (50 mL) was stirred at room temperature for five days to complete the reaction. The product solution was concentrated in vacuo, water was added and the product was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and the drying agent was filtered off. The filtrate was concentrated in vacuo. The product was purified by silica gel chromatography. Elution with chloroform-methanol gave 7-deacetyl-7- (4-pyrrolidinobutyryl) forskolin (109 mg, 6% yield based on 7-deacetylforskolin). 1 H NMR Spectrum (CDCl 3):

5.37 (1H, d, J = 4Hz), 4.56 (1H, m), 4.50 (1H, m), 2.53 (8H, m), 1.93 (2H, m), 1.79 (4H, m), 1.73 (3H, s), 1.44 (3H, s), 1.35 (3H, s), 1.26 (3H, s), 1.03 (3H) , s). Mass spectrum m / z (relative intensity): 507 (M ⁺ , 4), 199 (3), 156 (26), 140 (10), 92 (40), 91 (52), 84 (100).

Example 4

6-Dimethylaminoacetyl-7-deacetylforskolin (Compound No. 24)

7-Deacetyl-7-dimethylaminoacetylforskolin (200 mg of the compound of Example 1) was dissolved in 20 ml of a mixture of acetonitrile and water (45:55), 0-.8 ml of 1N aqueous sodium hydroxide was added and the solution was stirred for 25 minutes. of room temperature to terminate the reaction. The product solution was concentrated in vacuo. Water was added and the product was extracted with ethyl acetate. The organic layer was washed with water and dried over magnesium sulfate. The drying agent is filtered off. The filtrate was concentrated in vacuo and the concentrate was purified by silica gel chromatography. Elution with acetonitrile gave 6-dimethylaminoacetyl-7-deacetylforskolin (176 mg, 88% yield), mp 116-117 ° C. IR (nujol): 3410, 3200;

1750 and 1720 cm ^-1 . Mass spectrum m / z: 453 (M ^& lt ^{; +} & gt ^; , 5), 350 (2), 237 (2), 219 (2), 104 (15), 58 (100). This crystalline product was dissolved in dioxane and an equimolar amount of hydrochloric acid dissolved in dioxane was added. The product hydrochloride is obtained, mp 263-265 ° C (ethanol). IR (nujol): 3490, 3230, 2680, 1745, and 1710 (cm ^-1 ).

The following compounds are obtained by the same rearrangement using the corresponding 7-substituted 7-deacetyl-forskolines.

Table 5 Compound

C.

yield

m.p.

@ 1 H-NMR (CDCl3): .delta.

Weight spectrum

3θ%

Mp 84-86 ° 0 (hexane-ethyl acetate) for 159-162 ° 0

5.89 C1H, q, J = 4Hz,

J = 2.7 Hz).

4.66-ClH, br s)

4-, 29 (1H, d, J = 4Hz) 3.54 (2H, AB quartet center, J = 17.5Hz)

4-81 (M +, 5)

87 · (25)

2.71 (4H, 1.62 (5H, 1.4-2 (5H, 1.40 (5H, 1.08 pH, 1.06 (5H, 0.98 C3H),

q.-J = 7Hz)

J = 7Hz)

5.94 (1H, quartet, J = 481 (M ⁺ , 2))

4.8-Hz, J = 5.1 Hz) 465 (0.8)

4.66 (1H, broad s) 152 (35)

4.51 (1H, d, J = 4.5 Hz) 86 (100) 5.45 (2H, AB quartet center, J = 17.5 Hz)

2.65 (2H, t, J = 7.6 Hz)

1.59 (3H, s); 1.49 (2H, ni);

1.42 (5H, s), 1.59 (3H, a), 1.55 (2H, m), 1.08 (5H, s), 0.98 (5H, s),

0.91 (5H, t, J = 7.5Hz)

5.90 (1H, triplet, 481 J = 6.7 Hz), 175

4.65 (1H, broad s) 132 4.26 (1H, d, J = 4Hz) 114 2.33 (4H, m). 91

2.20 (6H, s), 1.78 (2H, m), 1.62 (3H, s), 1.42 (3H, s), 1.41 (3H, s), 1.0? ( 3Η, s), 0.97 (3H, s) (M +, 12) (13) · (100) (50) (19)

2Q 87.1% colorless oil - 467 (M ⁺ ) material ·

33.9% colorless oily - 495 (M +) material

Example 5

6-Dimethylamino-acetylforskolin (Compound No. 1)

To a mixture of 6-dimethylaminoacetyl-7-deacetylforskolin (Compound No. 24, 587 mg) and dichloromethane (20 mL) was added a mixture of pyridine (1 g) and acetyl chloride (750 mg) in four portions. The mixture was stirred at room temperature for 7 hours to quench the reaction. The product solution was basified with saturated aqueous sodium bicarbonate (NaHCO 3) after the addition of water and the product was extracted with dichloromethane. The organic layer was dried over magnesium sulfate and the desiccant was filtered off. The filtrate was concentrated and the concentrate (811 mg) was purified by silica gel chromatography. Elution with hexane-ether (1: 3) gave 6-dimethylaminoacetylforskolin (444 mg, 69% yield), m.p. 190-193 ° C (toluene). IR (nujol): 3100, 1750, 1730 and 1720 cm @ ^-1 . ¹ H NMR Spectrum (CDCl 3): 5.86 (1H, quartet, J = 4Hz, J = 7.2Hz), 5.56 (1H, doublet, J = 4.9Hz), 4.61 ( 1H broad singlet), 3.18 (2H, singlet), 2.31 (6H, singlet), 2.04 (3H, singlet), 1.64 (3H, singlet), 1.42 (3H, singlet), 1.35 (3H, singlet), 1.04 (3H, singlet), 0.96 (3H, singlet).

The hydrochloride of this product was prepared in the same manner as described in Example 4, mp 255-260 ° C (ethanol). IR (Nujol): 3240, 3130, 2400, 1750, 1725 cm ^1st

Compounds # 2 and # 3 were prepared according to this example except that propionyl chloride and butyryl chloride were used instead of acetyl chloride.

Compounds Nos. 5, 6, 7 and 8 were also prepared according to this example except that 6-dimethylaminoacetyl-7-deacetylforskolin (Compound No. 25), 6- (3-dimethylaminopropionyl) was used in place of 6-dimethylaminoacetyl-7-deacetylforskolin. -7-Deacetylforskolin (Compound No. 28, 6- (3-diethylaminopropionyl) -7-deacetylforskolin (Compound No. 29) and 6- (4-dimethylaminobutyryl) -7-deacetylforskolin (Compound No. 27)).

Table 6 compound δ yield tt ¹ H NMR (CDCl 3)

Mass spectrum%

3, 38%

5.81 (1H, quartet, J = 4.3 ^Hz)

. (3h ’, t, J = 7.4Hz)

Table 6 (continued)%

5.84 (1H, quartet, J = 523 (M> 1) 4 Hz , _J = 2.7 Hz) 508 (0,5) 5.55 (1H, ï, J = 4.3 Hž) 316 (2I 4.61 (1K, wide s) 132 Italy (26) 2.70 (4H, q, J = 6.9 Hz) 130 (17) 3.33 (2H, s), 2.02 (3H, s) 95 Italy (11) 1.66 3H, s), 1.43 (3H, s) 87 (42) 1.35 (3H, singlet) - 86 (100) 1.07 (6H, triplet, J = 6.9 Hz) 1.03 (3H, s), 0.96 (-3H, s)

% 176 - ^ C 5.54 (1H, q, J = 4 ', 3 Hz, (diethyl-J = 7.2 Hz) • ether) 5.52 (1H, doublet, J = 4 Hz)

4.62 (1H, broad singlet) 2.46-2.73 (5H, mt)

2.25 (6H, s), 2.02 (3H, s)

1.66 (3H, s). 1.44 (3H, s) 1; 35 (3H, s), 1.03 (3H, s) 0.97 (3H, s)

509 (M ⁺ , 3)

118 (17) (25) (38) (100)

34% 5.84 (1H, q, d = 4.3 Hz).

J = 2.7Hz)

5.52 (1H, doublet, J = 4.4 Hz) 4.61 (1H, broad singlet)

2.85 (2H, multiplet)

2.51 (6H, m), 2.02 (3H, s)

1.66 (3H, s), 1.44 (3H, s)

1.35 (3H, s),

1.04 (6H, triplet, J = 7.1 Hz) ‘1.03 (3H, s), 0.97 (3H, s)

8 31% 238 to 5.84 (1H; quartet, J = 523 (M ⁺ , 5) Mp 240 ° C = 4: Hz, J = 3 Hz) 174 (4) (tetrahy- 5,52 (1H, doublet, J = 4 Hz) 132 Italy (20) . drofuranj- 4.61 (1H, wide singlet) 114 Italy (23) (methanol) 2.35 (4H ,. multiplet) 92 Italy (11) 2.22 (6H, s), 2.02 (3H, s) 91 (17) 1.81 (2H, m), 1.65 (3H, s) 58 (100) 1.43 (3H, s), 1.35 · (3H, s) • 1.03 C3H, s), 0.97 (3H, s)

Example 6

6-Dimethylaminoacetyl-7-deacetyl-7-dimethyleminoacetyl-forskolin (Compound No. 4)

Chloroacetyl chloride (209 mg) was added dropwise to a mixture of 6-dimethylaminoacetyl-7-deacetyl-forskolin (Compound No. 24, 700 mg), pyridine (146 mg) and dichloromethane (10 mL) under ice-cooling. The reaction mixture was stirred under ice-cooling for three hours until the reaction was complete. The mixture is then concentrated. Concentrate ^- after dilution with water, basified with saturated aqueous sodium bicarbonate, and ^- the product is extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and the drying agent was filtered off. Concentration of the filtrate gave a white solid of 7-Chloroacetyl-7-deacetyl-6-dimethylaminoacetylforskolin (749 mg).

A solution of this white solid (20 mL, 749 mg) in dichloromethane was added dropwise to a solution (20 mL) of excess dimethylamine in dichloromethane under ice-cooling. The mixture was stirred at room temperature for one hour to complete the reaction. The product solution was extracted with dichloromethane after the addition of water. The organic layer was dried over magnesium sulfate and the drying agent was filtered off. The filtrate was concentrated and the concentrate (728 mg) was purified by silica gel chromatography. Elution with dichloromethane / acetone (2: 1) .4 gave 6-dimethylaminoacetyl-7-deacetyl-7-dimethylaminoacetylforskolin (186 mg, 23% yield based on compound 24). 180 DEG-183 DEG C. (hexane-ethyl acetate). Mass spectrum m / z (relative intensity): 538 (M ⁺ , 58), 454 (8), 104 (100),

102 (100).

According to the above procedure, 6-acetyl-7-deacetylforskolin is converted to 6-acetyl-7-chloroacetyl-7-deacetylforskolin, which is further reacted with dimethylamine to give 6-acetyl-7-deacetyl-7-dimethylaminoacetylforskoline (Compound No. 30, yield 88% based on 6-acetyl-7-deacetylforskolin). NMR Spectrum (CDCl3):

5.82 (1H, quartet, J = 4.7 Hz, J = 3.0 Hz), 5.62 / 1H, doublet, J = 4.4 Hz), 4.61 (1Ξ, broad singlet), 3.15 (2H, AB quartet center, J = 17 Hz), 2.37 (6H, singlet), 2.09 (3H, singlet), 1.66 (3H, singlet), 1.44 (3H, singlet), 1 33 (3H, singlet), 1.03 (3H, singlet), 0.98 (3H, singlet).

In the same way, 6-acetyl-7-deacetylforskolin is converted to 6-acetyl-7- (4-chlorobutyryl) -7-deacetylforskolin using 4-chlorobutyryl chloride. @ 1 H NMR Spectrum (CDCl3) .delta.

5.83 (1H, quartet, J = 4.3Hz, J = 3.1Hz), 5.55 (1H, doublet, J = 4.6Hz), 4.63 (1H, broad singlet), 3.52 (2H, multiplet), 2.38-2.6 (4H, multiplet), 2.10 (3H, singlet), 2.04-2.2 (3H, multiplet), 1.67 (3H, singlet), 1.44 (3H, singlet), 1.36 (3H, singlet), 1.04 (3H, singlet), 0.98 (3H, singlet).

This product was reacted with pyrrolidine. There was thus obtained 6-acetyl-7-deacetyl-7- (4-pyrrolidinobutyryl) -forskolin (Compound No. 33, 14% yield based on 6-acetyl-7-deacetylforskolin). NMR Spectrum (CDCl3, Z): -...

5.81 (1H, quartet, J = 4.3 Hz, J = 2.9 Hz), 5.54 (1H, doublet, J = 4.6 Hz), 4.60 (1Ξ, broad singlet), 2 62 (6H, multiplet), 2.28 to 2.44 (3H, multiplet), 2.09 (3H, singlet) 1.75 to 1.95 (6H, multiplet), 1.65 (3H), 1 44 (3H, singlet), 1.35 (3Ξ, singlet), 1.03 (3H, singlet), 0.98 (3H, singlet).

Example 7

6- (4-Aminobutyryl) forskolin (Compound No. 9) (1) A mixture of 4- (t-tert-butoxycarbonylamino) butyric acid (8.20 g), 4-dimethylaminopyridine (6.40 g) and dicyclohexylcarbodiimide (12.60) g) is added to the mixture in 4 portions

Of 7-deacetylforskolin (3.00 g) and dichloromethane (100 mL) under ice-cooling. The reaction mixture was stirred overnight at room temperature to quench the reaction. The product solution was concentrated in vacuo after addition of water (0.5 mL). Dichloromethane was added to the concentrate and the undissolved material was removed by filtration. The filtrate was concentrated and the residue was chromatographed on a silica gel column. Elution with dichloromethane / ethyl acetate (10: 1) afforded 7- (4- (tert-butoxycarbonylamino) butyryl) -7-deacetylforskolin (Compound No. 9a, 1.60 g, 36% yield) as a colorless oil. Mass spectrum m / z (relative intensity): 535 ((MH ₂ O) ⁺ , 23), 479 (23), 104 (34), 86 (81, 57 (100)).

(2) To a mixture of this oily product (Compound No. 38a, 1.50 g), acetonitrile (90 mL) and water (60 mL) was added 1 N aqueous sodium hydroxide solution (6 mL). The mixture was stirred at room temperature for 40 minutes. Immediately after completion of the reaction, the product solution was concentrated and extracted with ethyl acetate after addition of water. The extract solution was dried with magnesium sulphate and the drying agent was filtered off. The filtrate was concentrated and the concentrate (1.43 g) was purified by silica gel column chromatography. Elution with dichloromethane / ethyl acetate (4: 1 to 2: 1) gave 6- (4- (tert-butoxycarbonylamino) butyryl) -7-deacetylforskolin (Compound No. 9b, 1.12 g, 75% yield), m.p. 190 ° C (ethyl acetate). IR (nujol): 3350, 1735 and 1710 cm @ ^-1 .

(3) This compound (number 38b, 1.12 g) was dissolved in dichloromethane (80 mL).

To this solution was added a mixture of pyridine (1.52 g) and acetyl chloride (675 mg) in three portions. The reaction mixture was stirred at room temperature for 8 hours. Water is added to the end of the reaction. The product solution was extracted with dichloromethane, the organic layer was dried over magnesium sulfate and the filtrate (after removal of the drying agent by filtration) was concentrated. The concentrate (1.97 g) was purified by silica gel chromatography. Elution with dichloromethane / ethyl acetate (10: 1 and 5: 1) afforded 6- (4- (tert-butoxycarbonylamino) butyryl) forskolin (compound number 9c, 414 mg, 34% yield), mp 162-165 ° C (mixture hexane with tuluene).

(4) This compound (number 9c, 123 mg) was dissolved in 85% formic acid under ice-cooling to react together. This solution was stirred at room temperature for two hours to complete the reaction. The product solution was concentrated, diluted with water and washed with ethyl acetate. The aqueous layer was basified with 3N aqueous sodium carbonate. The product was extracted with ethyl acetate. The organic layer was washed, dried with magnesium sulfate and filtered to remove the drying agent. The filtrate was concentrated and the residue was recrystallized from ethyl acetate-methanol. There was thus obtained 6- (4-aminobutyryl) forskolin (Compound No. 9, 31 mg, 30% yield). Mp 191-192 ° C, IR (nujol): 3360, 1725 cm ^-1 . NMR spectrum (CD 3 OD,

5.76 (1H, quartet, J = 4.7 Hz, J = 3.3 Hz), 5.39 (1H, doublet, J = 4.3 Hz), 4.42 (1H, broad singlet), 2 59 (2H, triplet, J = 6.0 Hz), 2.2 to 2.4 (2H, multiplet), 1.88 (3H, s), 1.8 to 1.6 (3H, multiplet), 1.56 (3H, s), 1.37 (3H, s), 1.23 (3H, s), 0.91 (6H, s). Mass spectrum m / z (relative intensity): 495 (M ⁺ , 14), 146 (32, 104 (100), 99 (13), 86 (74)).

Example 8

6-Pyrrolidinoacetylforskolin (Compound No. 10) (1) 7-Deacetyl-7-pyrrolidinoacetylforskolin (4.20 g), which was prepared in the same manner as in Example 7 (1) except that instead of 4- (tert-butoxycarbonylamino) ) butyric acid, using pyrrolidine acetic acid, is dissolved in a mixture of acetonitrile and water (4: 1) (150 ml). To this solution was added dropwise 1N aqueous sodium hydroxide (9.63 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 6 hours. Water was added to quench the reaction. The product solution was extracted with ethyl acetate, the organic layer was concentrated and dissolved in ether. The ether solution was extracted with 1N aqueous hydrochloric acid. Aqueous ammonia was added dropwise to the aqueous layer of the extracted solution under ice-cooling. The solution was basified and extracted with ether. The organic layer was dried over magnesium sulfate. The drying agent was removed by filtration. The filtrate was concentrated and the residue was purified by silica gel column chromatography. Elution with dichloromethane / methanol (20: 1) gave 7-deacetyl-6-pyrrolidinoacetyl-forskolin (Compound No. 10a, 900 mg, 21% yield). IR (KBr): 3470, 3210, 1745, 1710 cm @ -1. Mass spectrum m / z (relative intensity): 479 (M ⁺ , 1), 130 (8), 84 (100).

Pyridine (72 mg) and acetyl chloride (72 mg) were added in four portions to the mixture of the above compound (# 10a, 100 mg) and dichloromethane (10 mL) under ice-cooling over 6 hours. The reaction mixture was stirred overnight at room temperature. It is then extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and filtered to remove the drying agent. The filtrate was concentrated in vacuo (120 mg) and purified by silica gel chromatography. Elution with chloroform / methenol (20: 1) gave 6-pyrrolidino-acetylforskolin (Compound No. 10, 53 mg,

50% yield). Melting point 166-168 ° C (dichloromethane-hexane). IR (KBr):

3450, 3230, 1750, 1715 cm ^-1 .

Example 9

7-Deacetyl-7- (4-dimethyl8minobutyryl) forskolin (compound number 31)

A mixture of dicyclohexylcarbodiimide (35.82 mg) and dichloromethane (120 mL) was added dropwise to a mixture of 7-deacatylforskolin (8.00 g), 4-dimethylaminoboric acid hydrochloride (14.56 g), 4-dimethylaminopyridine (21.21 g) The reaction mixture was stirred at room temperature for four hours to complete the reaction. The product solution was extracted with dilute hydrochloric acid. The aqueous layer basified with concentrated aqueous ammonia was extracted with diethyl ether. The organic layer was washed with water, dried The filtrate was concentrated in vacuo to give oily 7-deacetyl-7- (4-dimethylaminobutyryl) forskolin (5; 41 g, 52% yield based on 7-deecetylforskolin). m / z: 481 (M).

Example 10

7- (4-Dimethylaminobutyryl) -14,15-dihydroforskolin (Compound No. 11)

A mixture of 6- (4-dimethylaminobutyryl) forskolin (30 mg), 58% palladium on carbon (6 mg) and methanol (8 mg) was stirred under hydrogen atmosphere at room temperature for five hours to complete the reaction. The product solution is filtered to remove the catalyst. The filtrate was concentrated to give 6- (4-dimethylaminobutyryl) -14,15-dihydroforskolin (Compound No. 11, 30 mg, 100% yield). Mp 210-212 ° C (methanol). IR (nujol) 3160, 1730 and 1740 cm @ ^-1 .

Compounds Nos. 32 and 12-14, as listed in Table 7, were prepared in the same manner as described above in this Example. The NMR and mass spectra of compounds 11, 12 and 14 are shown in Table 8.

Table 7

compound properties yield starting mater. C. name 32 .14> 15-dihydro-7- Λ m.p. 187-187 ° C 100% 7-Deacetyl-7- deacetyl-7-di- (ethyl acetate) dimethylamino- methylaminoace- (nujol): 34-70 » acetylforsko- tylforskolin 3180, 1750, 1700 cm ^-1 tench 12 6-dimethylamino- appearance: white 100% 6-dimethyla- acety1-14,15-di- solid minoacetyl- hydroforslcolin MS m / z: 497 (M ⁺ ) forskolin 13 '6_pyrrolidinoace- appearance: white 100% compound tulle-14,15-dihy- solid number 10 droforskolin MS m / z: 507 (M ^& lt ^{; +} & gt ^; )

Λ

CS 272221 ’Β 2

Table 7 (continued)

6- (5-dimethylaminopropionyl) -14,15-dihydroforskolin appearance white 100% 6- (5-dimethyl-aminopropionyl) MS m / z 511 (M ⁺ ) forskolin

Table 8

Mass Spectrum Combined, (m / z).

TI NMR Spectrum! (relative ^- intens.) mna c.

(solvent, DMSO-d6, < + &gt;) m.p.

5.64- (1H, triplet, J = 4-.0Hz),

5.54 (1H, doublet, J = 4.0 Hz),

4-, 54- (1H, br s), 2.4-2.5 (2H, m),

2.28 (2H, triplet, ’J = 7.0,)

2.09 (5H, s), 1.91 (5H, s),

1.8 to 1.6 (2H, A), 1.6 to 1.4- (2H, m),

525 (M ⁺ , 26) 200 (6), 174 (9), 152 (64) · ’* 114 (52) 58 (100)

1.4-9 (3 H, s); 1.57 OH, s),

1.15 (5H, s), 0.92 (5H, s),

0.91 OH, s), 0.81 OH (t, Γ = 6.88 Hz) (solvent, CDCl 3 OD, t) i 4-97 (M ⁺ )

5.9 to 5.3 (1H, multiplet)

5.4-9 (1H, triplet, J = 5.5Hz);

4.41 (1H, broad s), 1.99 OH, s),

1.98 (6H, s), 1.98 (6K, s), 1.58 OH, s),

1.4-7 OH, s), 1.22 OH, s), 1.01 OH, s),

1.00 OH, s), 0.89 OH, t, J = 7.5 Hz) (solvent, GDGl, 511 (M ⁺ , 7))

5.85 (1H, quartet, J = 4-, 3 Hz, 3 → 1 Hz), 160 (7)

5.4-9 (1H, doublet, J = 4.4 Hz), 118.09)

4-, 55 (1H, broad s), 2.75 (2H, n), 116 (10)

2.57 (2H, m), 2.52 (6H, W) ', 2.01 (3H, s) 53 (100)

1.58 (3H, s), 1.46 OH, s), 1.24 OH, s),

1.02 OH, s), 0.97 OH, s), 0 * 90 OH, t, J _g 7 Hz)

The starting material for the preparation of compound 32 can be prepared according to the procedure of Example 9 except that Ν, Ν-dimethylglycine hydrochloride is used instead of 4-dimethylaminobutyric acid hydrochloride.

Starting materials for the preparation of compounds 12, 13 and 14 can be prepared according to the procedure of Example 7, substituting Ν, Ν-dimethylglycine hydrochloride, pyrrolidineacetic acid and 3-dimethylaminopropionic acid for 4- (tert-butoxycarbonylamino) butyric acid.

Example 11

13-Cyclopropyl-6-dimethylaminoacetyl-14,15-dinorforskolin (Compound No. 15)

To a mixture of 6-dimethylaminoacetylforskolin (100 mg), palladium acetate (14 mg) and anhydrous tetrahydrofuran (5 mL) was added an ethereal solution of diazomethane under ice-cooling. The reaction mixture was stirred under ice-cooling for three hours to complete the reaction. Water was added to the product solution. The pH of the mixture was adjusted to 10 with 3N aqueous sodium carbonate solution and the product was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the drying agent was removed by filtration. The filtrate was concentrated and the residue was purified by silica gel column chromatography. Elution with dichloromethane / ether (4: 1 to 2: 1) afforded 13-cyclopropyl-6-dimethylaminoacetyl-14,15-dinorforskolin (Compound No. 15, 16 mg, 16% yield). IR (nujol):

3570, 3180, 1735 and 1715 cm ^-1 , or NMR (CDCl3):

0.30 (2H, m), 0.31 (1H, m), 0.75 (1H, m), 0.91 (1H, m), 0.95 (3H, s), 1.03 (3H) , s),

1.32 (3H, s), 1.44 (3H, s), 1.54 (3H, s), 2.01 (3H, s), 2.43 (6H, s), 3.23 (2H) s), 4.51 (1H broad singlet)), 5.51 (1H, d, J = 5Hz), 5.83 (1H, t, J = 4Hz). Mass spectrum m / z (relative intensity): 510 (M ⁺ , 23), 109 (49), 104 (100), 81 (49), 59 (100), 58 (100).

According to the above procedure, 13-cyclopropyl-7-deacetyl-7-dimethylaminoacetyl-14,15-dinorforskolin (Compound No. 19, 60% yield) was prepared from 7-deacetyl-7-dimethylaminoacetylforskolin. IR (nujol): 3250, 1740 and 1705 cm @ -1. @ 1 H NMR Spectrum (CDCl3): 0.18 (2H, m), 0.49 (1H, m), 0.89 (TH, m) 0.96 (1H, m). 1.01 (3H, s), 1.28 (3H, s), 1.30 (3H, s), 1.50 (3Ξ, s), 1.66 (3H, s), 2.38 (6H) (s), 3.27 2H, s), 4.43 (1H, broad s),

4.47 (1H, broad s), 5.43 (1H, d, J = 4.5 Hz). Mass spectrum m / z (relative intensity): 467 (M ⁺ , 4), 109 (26), 104 (58), 102 (60), 85 (41), 58 (100).

Example 12

7-Deacetyl-7- (3-dimethylaminopropionyl) forskolin (Compound No. 22)

A mixture of 4-dimethylaminopyridine (3.00 g), 3-dimethylaminopropionic acid hydrochloride (3.80 g) and dicyclohexylcarbodiimide (7.00 g) was added in three portions over 47 hours to a solution (-60 ml) of 7-deacetylforskoline (2). G) in dichloromethane. The reaction mixture was stirred at room temperature. After completion of the reaction, the solvent was evaporated in vacuo. The resulting residue was dissolved in ethyl acetate and the solution was filtered. The filtrate was concentrated and the concentrate was purified by silica gel chromatography (concentrate weight: 6.05 g).

Elution with dichloromethane / methanol (20: 1 to 10: 1) afforded 7-deacetyl-7- (3-dimethylaminopropionyl) forskolin (compound number 22, 1.72 g, yield: 68%).

*

Claims (4)

SUBJECT OF THE INVENTION 1. A process for preparing the novel forskolínových derivatives of formula VII (VII) in which A represents vinyl, ethyl or cyclopropyl, _and R ^ are each hydrogen or alkyl having 1 to 4 carbon atoms or R @ 56 _{and znameila} JF alkylene chain together and having 1 to 4 carbon atoms, optionally containing an oxygen or nitrogen atom, m and n are numbers from 1 to 5; X represents a hydrogen atom or a group of the general formula R ⁷ Wherein R 'and R' are each independently hydrogen or C 1 -C 4 alkyl or R 'and R' together are C 1 -C 4 alkylene chain optionally containing an oxygen or nitrogen atom, or their physiologically acceptable salts, characterized in that the 7-deacetylforskolin derivative of the general formula VIII (VIII) in which R ⁴ , R ⁶ and R ⁶ is as defined above is reacted with a carboxylic acid of the general formula IX ' HOOC (CH ₂ ) _n X (IX), wherein Hnal is as defined above, or a halide or anhydride thereof, and optionally the resulting compound of formula VII wherein R 6 is vinyl and R ⁶ , R ⁶ , m, X is as defined above, hydrogenated in the presence of a catalyst to form a compound of formula VII wherein R 1 is ethyl and R 1, r 6, m, X is as above, or reacted with diazomethane in the presence of a catelysator to form a compound of formula VII; to form a compound of formula (VII) wherein Ropr is cyclopropyl and R ·, R ^, m, n, and X are as defined above and optionally reacting the free base of the resulting compound of formula (VII) with a physiologically acceptable acid to formation of the corresponding salt. 2. The process of claim 1 wherein the carboxylic acid is acetic acid, the halide is acetyl chloride, and the like. acetic anhydride. 3. The process of item 1 for the preparation of novel forskolin derivatives of formula VII wherein X is hydrogen, m is 2, n is 1, R1 is vinyl and and r6 is each methyl, characterized in that 7- The deacetylforskolin derivative of the general Formula VIII, in which R 1 represents a vinyl group, and R 1 represents each methyl group and m is 2, is reacted with acetic acid, acetyl chloride or acetic anhydride. 4. The process of item 1 for producing the novel forskolin derivatives of the general formula 4 5 VII wherein X is hydrogen, mje3, njel, R represents a vinyl group and R and R6 are each a methyl group, characterized in that 7-deacetylforskolinový derivative of the formula VIII wherein R is a vinyl group, R ⁵ and R ⁵ is each methyl and m is 3, reacted with acetic acid, acetyl chloride