DE2543596A1 - NEW CYCLIC ADENOSINE MONOPHOSPHATES AND THE METHOD OF MANUFACTURING THEM - Google Patents

Description

FROM KREISLER SCHÖNWALD MEYER EISHOLD FUES FROM KREISLER KELLER SELTING

PATENT LAWYERS Dr.-Ing. by Kreisler ■ f 1973

Dr.-Ing. K. Schönwald, Cologne Dr.-Ing. Th. Meyer, Cologne Dr.-Ing. K. W. Eishold, Bad Soden Dr. J. F. Fues, Cologne Dipl.-Chem. AIeIc from Kreisler, Cologne Dipl.-Chem. Carola Keller, Cologne Dipl.-Ing. G. Selting, Cologne

5 Cologne, September 29th, 1975

DEICHMANNHAUS AT THE MAIN RAILWAY STATION

Fu / Ax

Asahi Kasei Kogyo Kabushiki Kaisha,

No.25-1, Dojima-hama-dori 1-chome, Kita-ku, Osaka-shi,

Osaka, Japan

Novel cyclic adenosine monophosphates and processes

for their manufacture.

The invention relates to new cyclic adenosine monophosphates with excellent biological and pharmacological properties Properties and effects and methods of their preparation. The invention is particularly directed to new 8-substituted ones cyclic adenosine derivatives of the general formula

O = P

A (CH ₀ ) CH

2 ' η

(D

OH

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in which A is -S- or -NH- and η is an integer from 2 to 12, the non-toxic salts of these compounds and Process for their preparation directed.

In 1957, Sutherland and co-workers found that when epinephrine and glucagon act on liver cells of higher animals, a low molecular weight nucleotide that activates the kinases is formed. Later, this substance was identified as adenosine j5 ', 5 ^f -cyolomonophosphate (hereinafter referred to as "c-AMP"). c-AMP is now referred to as the intracellular second messenger or "messenger" of the effects of hormones in higher animals. In particular, when a certain hormone is bound to a receptor of a target cell, an adenylate cyclase is activated to increase the c-AMP level. When the c-AMP level increases, c-AMP-dependent protein kinases are activated and a wide variety of biological reactions are intensified. In certain cases, the unmasking of nucleohistones is stimulated and the formation of various enzymes (proteins) is triggered. In another case, stored glucose or glycogen phosphorylase is activated to accelerate glycogenylose. Another number of biological reactions are influenced by the level of c-AMP. Asthma can be mentioned as one of these biological responses. The main cause of asthma is a reduced responsiveness of the ß-adrenalgic receptor, (one of the hormone receptors) of the smooth muscles of the respirators. The steroid increases the reactivity of the β-adrenergic receptor, and theophylline is effective as an antagonist and blocker of a c-AMP-degrading enzyme (phosphodiesterase for c-AMP, hereinafter referred to as "PDE"). Both chemical compounds influence the increase in the c-AMP level (A. Szentivanyi, J. Allergy, 42 (1968) 203-232). It is also believed that scabies, a skin disease, is caused by a decrease in c-AMP levels. this

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is a disease that is due to excessive overgrowth of abnormal Epithelial cells, which contain abundant glycogen, and is characterized in that the Puncture of the hormone receptor has already changed and not the effects of ß-adrenergic promoters, Adenylate cyclase activators and NaF (J.J. Voorhees and coworkers, Arch. Dermatol. 105 (1972) 695. A considerable number of diseases have already been reported, caused by disturbance of the c-AMP level.

c-AMP is converted to 5'-adenosine monophosphate by phosphodiesterase decomposed. In other words, the intracellular level of c-AMP is determined by the difference in activity between the synthesizing enzyme, i.e. adenylate cyclase, and the degrading enzyme, i.e. PDE. the biological activities of intracellular c-AMP are revealed by protein kinases. Given these facts research work on 8-substituted c-AMP derivatives was carried out by the applicant with the aim of producing medicaments te to alleviate and control diseases caused by abnormal c-AMP levels. As a result, 8-substituted derivatives that meet all of the following requirements were synthesized:

1. The derivatives must be stable under the action of PDE.

2. You have to specifically inhibit the PDE (as a competitive inhibitor for PDE be effective).

J. You must have excellent membrane permeability to have.

4. You need to activate protein kinases.

While carrying out chemical syntheses and biological experiments, the applicant developed a new biological

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gical fact, and on the basis of this fact, she succeeded in synthesizing new c-AMP derivatives with excellent properties that known compounds do not have.

Certain 8-substituted c-AMP derivatives are known. These known derivatives are described in the following Classified way. In this classification, alkyl derivatives, in which a linear alkyl radical is bonded to the carbon atom in the 8-position via an amino or thio group is referred to as alkylamino derivatives or alkylthio derivatives.

1.) 8-halogen-substituted derivatives (including the Cl- and Br-derivatives)

2.) 8-alkylamino derivatives (including the NH ₂ -,
CH, NH and CIUCHgNH derivatives).

3.) 8-Alkylthio derivatives (including the CH ^ S-
and CH ^ CHgS derivatives).

As the discussion above shows, in each of the known 8-alkyl-substituted derivatives of c-AMP, the G number in the alkyl radical up to 2.

The applicant has synthesized 8-alkyl-substituted c-AMP derivatives in which the C number in the alkyl radical is increased, but it has been found that new derivatives ^ in which the C number is 6 or more, namely the CH -, ( CH ₂ ) t- ~ NH- and CH, (CHg) ₁ -S-derivatives and higher alkyl-substituted derivatives, have a much stronger PDE-inhibiting effect than the known derivatives. It has also been found that the new derivatives in which the alkyl radical has a carbon number of
10 or more, namely the CH _x (CHo) _n NH- and CH, (CH ₀ O ₀ S derivatives and those substituted with higher alkyl radicals
Derivatives have a PDE-inhibiting effect and excellent
Have permeability through living membranes.

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In detail, the new c-AMP derivatives synthesized by the applicant, which contain a linear alkyl radical with 3 to 1J> C atoms (where η in the above general formula has a value of 2 to 12) as a substituent which has a Amino or thio group is bound to the 8-position, mainly as PDE inhibitors in vivo and increase the intracellular level of c-AMP. Furthermore, all new substances now synthesized by the applicant are not degraded by c-AMP PDE, but they are opposite the effects of PDE are very stable. Details of the main biochemical properties of these new derivatives are given in Table 1 below.

For the sake of simplicity, these new derivatives have been classified by the applicant according to their activities in the following three Divided into groups:

1.) Group I:

8-CH ₃ (CH ₂ ) ^ Hc-AMP (where η is 2 to 4) and 8-CH ₅ (CH ₂ ) ^ -C-AMP (where η is 2 to 4).

2.) Group II:

8-CH ₃ (CH ₂ ) _n NH-c-AMP (where η is 5 to 8) and 8-CH ₃ (CH ₂ ) _n Sc-AMP (where η is 5 to 8).

3.) Group III:

8-CH ₃ (CH ₂ ) _n NH-c-AMP (where η is 9 to 12) and 8-CH ₃ (CH ₂ ) _n Sc-AMP (where η is 9 to 12).

The derivatives of group II with an alkyl radical with 5 to 9 carbon atoms have a much stronger PDE-inhibiting effect than known c-AMP derivatives. Furthermore, this inhibiting effect is much stronger than that of the well-known theophylline. Theophylline and se ine derivatives are referred to as a ntiasthmatica

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turns. The new c-AMP derivatives will be group II take the place of these well-known anti-asthmatic drugs.

Group III derivatives have greater membrane permeability than the known derivatives. The results of experiments using protein kinases confirmed that the derivatives of this group do not have any activating effect on kinases. In short, the derivatives of this group are PDE inhibitors with excellent membrane permeability.

As mentioned earlier, scabies, a disease caused by lowering c-AMP levels, is characterized by: that the functions of both the hormone receptor and the adenylateyelase have changed and theirs Punctures generally cannot be normalized (restored). As a means of increasing the intracellular c-AMP concentration can inhibit PDE can be viewed. In this context, the Group III derivatives have a strong PDE-inhibiting effect with excellent membrane permeability. Therefore, a sufficient healing effect is to be expected when an ointment that contains a Group III derivative that is applied to scabie-affected skin.

In the following, biological tests are carried out with the new c-AMP derivatives according to the invention and their results were described.

1.) Tests using cultured CHO-Ki cells:

From A.W. Hsie and T.T. Puck was found in 1971

6 2 '
that with the addition of N, 0 -dibutylryl-c-AMP in one

Concentration of 10 "- ^ mol / liter to a medium, containing cultured Chinese hamster cells (CHO-Ki), CHO-Ki of the epithelial form. is regressed to the form of pibroblasts.

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(Proc. Nat. Acd. Sci. U.S. 68, 558-36I). Subsequent

6 In 2 minutes it was found that N, 0 -dibutyryl-c-AMP inhibits the PDE and thereby increases the intracellular e-AMP concentration and the protein kinases activated.

Using this method, the new derivatives were examined for the following two properties:

1.) Ability to increase the c-A MP concentration in CHO-Ki-Zones.

2.) membrane permeability.

The experiments were carried out according to the modified method of Hsie and Puck as follows:

1.) To determine the ability to increase the c-AMP concentration, the new derivatives were the above said medium was added at a concentration of 1 mmol / liter or 10 mmol / liter. After 24 hours microscopic analysis was carried out. The one containing the CHO-Ki cells was used as controls Medium which, however, did not contain any biologically active compound ^ and which contained the CHO-Ki cells Medium containing 10 "moles / liter of N, 0 -dibutyryl-c-AMP contained, tested in the same way.

2.) The membrane permeability was rated on the basis of the regression. In detail, the new derivatives were added to the above-mentioned medium in a concentration of 10, 5 χ 10, Kf ¹ , 2 χ ΙΟ " ¹ , 5 χ" ^{1 or 1 mmol / liter.} After 16 or 30 hours, the microscopic analysis was carried out and the limit concentration causing the regression (referred to as "LPC") was determined. Furthermore, the membrane permeability was evaluated on the basis of the LPC value determined in this way. The results obtained in these tests are below

mentioned in Tables 1 and 2.

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- 8 - Table 1

c-AMP derivatives according to the derivatives of group invention I II III

Stability against PDE *
Membrane permeability ***

Known connections

N ⁶ , O ² '-dibutyryl-c-AMP
[Ν ⁶ , O ² '- (CH ₃ CH ₂ CHpCO) 2-c-AMP]

Stability compared to PDE * +

PDE inhibition + ++ +

XXX

Membrane permeability + ++

8-bromo-c-AMP (8-Br-o-AMP)

Stability against PDE * + + +

PDE inhibition ** + ++ +

Membrane permeability *** + +

8-methylamino-c-APM
(8-CH ₃ NH-C-AMP)

Stability against PDE * + + +

PDE inhibition + ++ +

Membrane permeability ^^ - + ++

χ The Dy, .- fraction created by partial purification the phosphorodiesterase obtained from pig brain was used as a standard enzyme. The stability to PDE was evaluated by the degree of decomposition at a concentration of 1 mmol / l.

xx PDE inhibition was rated based on the relative inhibition observed when the test compound in the same molar concentration as the substrate (1 mmol / l) was added. The inhibition constant (ki) was determined by the enzymological method

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calculated (Lineweaver-Burk diagram).

XXX The membrane permeability was determined on the basis of I the minimum concentration that the regression of the cultured CHO-Ki cells. (The regression of CHO-Ki is caused by increasing the concentration of c-AMP.)

The characters in Table 1 intermediate the results of the comparison of the above properties the new derivatives according to the invention and the known compounds. They have the following meanings:

++: The new derivative according to the invention is far superior to the known compound.

+: The new derivative according to the invention is superior to the known compound.

+: The difference in properties between the new derivative according to the invention and the known ^ compound is immaterial.

-: The known compound is superior to the derivative according to the invention.

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1. - 10 - 2543596 2 Cells (CHO-Ki) through the at Regression L C. > R. C. I.
i 0.3- ^ 2. Tabel new 8-substituted c-AMP derivatives 10 " ⁴ at -10" ^ ( A. 10 "- ⁵ mol / l) I. Regression of cultured link Mol / l mol / l - 3. C. A. - - 4th C. A. 0.2 ^ 0.4 5. c-AMP C. - i 6th N ⁶ , O ² '(CH ₃ CH ₂ CH ₂ CO) ₂ - C. A. 0.2 ~ 0.08 ~ -> 7th C-AMP C. C. 0.5- 0. 05 ^ 8th. 8-Br-c-AMP C. C. 0.07 ^ 9. 8-CH ₃ NH-C-AMP C. C. 0.09 ^ 10. 8-CH ₃ (CH _{2) 2} NH-C-AMP C. C. 0.4 ~ 11. 8-CH ₃ (CH ₂ NH ₃ J C. C. 0.4- 12th 8-CH ₃ (CH ₂ J ₄ NH C. C (toxic) 0.4 13th 8-CH ₃ (CH _{2) 5} NH C. C (toxic) 0.3 14th 8-CH ₃ (CH ₂ J ₆ NH C. C (toxic) 0.3 15th 8-CH ₃ (CH ₂ J ₇ NH A. C (toxic) 0.02 16. 8-CH ₃ (CH ₂ J ₈ NH A. A. 0.01 17th 8-CH ₃ (CH ₂ ) gNH A. A. <0.005 18th 8-CH ₃ (CH ₂ J ₁₀ NH A. A. <0.005!
j 19th 8-CH ₃ (CH _{2) 1: L} NH C. A. <0.005 20th 8-CH ₃ (CH _{2) 12} NH C. A. 23 8-CH ₃ (CH ₂ ) ₂ Sc-AMP C. C (toxic) 24. 8-CH ₃ (CH ₂ ) ₃ S C. C (toxic) 25th 8-CH ₃ (CH ₂ ) ₄ S C. C (toxic) 26th 8-CH ₃ (CH ₂ J ₅ S A. C (toxic) 27 8-CH ₃ (CH ₂ J ₆ S A. C (toxic) 8-CH ₃ (CH ₂ ) ₇ S A. 8-CH ₃ (CH ₂ J ₈ S A. 8-CH ₃ (CH ₂ J ₉ S A. 8-CH ₃ (CH ₂ J ₁₀ S 8-CH ₃ (CH ₂ J ₁₁ S

A: Highest activity in regression. B: Capable of regression. C: No detectable regression

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These test results clearly show that in the derivatives according to the invention, when the C number of the alkyl radical is 9 or more, the LPC value falls regardless of whether the alkyl radical is attached to the 8-position via the amino group or the thio group. It is believed that the reason for this is that the greater the number of methylene groups in the alkyl group (ie, the greater the value of η in the above general formula), the greater the hydrophobicity and the improved permeability of the cell membranes to the compounds. Other experiments confirmed that the new derivatives with 8 or more carbon atoms in the alkyl radical no longer act like c-AMP on the protein kinases. In the case of these derivatives, the regression of CHO-Ki (increase in the intracellular c-AMP concentration) is caused exclusively by PDE inhibition. · ■

2. Experiments using phosphodiesterase (PDE) from I pig brain j

In general, c-AMP is caused by the PDE degraded to 5'-AMP, with the activity or function ι as c-AMP loses. This degradation often renders the c-AMP ineffective in various experiments and clinical investigations. So that the c-AMP derivatives are sufficiently effective, it is therefore especially important that they have high stability against

have the effects of PDE. On the other hand, they must have a strong inhibitory effect on the enzyme, ie PDE. Accordingly, the applicant used as the standard enzyme the phosphodiesterase extracted and partially purified from the pig brain cortex by the method of Teo, Wang et al., Which did not contain any other contaminating esterase (5 ¹ -nueleotidase).

The enzyme was purified by ammonium sulfate fractionation and passing through a DEAE cellulose column according to the modified method of TSTeo, TTWang and others. (J.Biol. Chem. 248 , 585). The reaction mixture (10 ml) contained 40 mmol Tris-HCl (pH 8.0), 3 mmol MgCl ₂ , 0,> 4.0 mmol c-AMP, 0.5 or 1.0 mmol c-AMP derivative and 82 ng of the enzyme as protein. The | The reaction and analysis were carried out according to the method of Bucher and Sutherland (J.Biol.Chem. .2JjZ (1962) 1244). The test results are shown in Table j5 below.

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Table 3

Inhibitory effect of 8-substituted c-AMP derivatives derivative 0 Inhibition II the hydrolysis of c-AMP ( 38.9 Escapement con
stante » by phosphodiesterase des 1.0 47.6 (mmol) link Pig brain 1.0 51.1 1.0 55.6 0.47 1.0 62.3 0.21 c-AMP Inhibition I 1.0 76.1 0.23 8-Br-c-AMP Concentration Relative.
(mmol / 1 reacti- inhibition + - '
on mixture {%) 1.0 78.2 0.12 8-CH ₃ NH-C-AMP c-AMP 1.0 80.0 0.072 8-CiI ₃ (CH ₂ ) ₂ NH-C-AMP 1.0 0.5 71.3 0.058 8-CH ₃ (CH _{2) 3} NH-c-AMP 1.0 0.5 67.6 0.026 8-CH ₃ (CH _{2) 4} NH-c-AMP 1.0 0.5 51.4 0.0093 8-CH ₃ (CH _{2) 5} NH-C-AMP 1.0 0.5 18.3 0.027 8-CH_ (CH ₀ ), .NH-c-AMP
Y / d O 1.0 0.5 11.3 0.082 8-CH ₃ (CH ₂ ) _? NH-C-AMP 1.0 0.5 60.1 0.17 8-CH ₃ (CH ₂ ) gNH-c-AMP 1.0 1.0 64.3 0.66 8-CH ₃ (CH ₂₎ NH-a-AMP 1.0 1.0 76. 7 0.84 8-CH ₃ (CH _{2) 1Q} NH-c-AMP 1.0 1.0 92.4 0.078 8-CH ₃ (CH ₂₎ NH-c-AMP 1.0 1.0 90.4 0.074 8-CH ₃ (CH _{2) 12} NH-c-AMP 1.0 0.5 05.0 0.040 8-CH ₃ (CH ₂ ) ₂ SC-AMP 1.0 1.0 74.9 0.019 8-CH ₃ (CH ₂ ) ₃ SC-AMP 1.0 0.5 68.2 0.0095 8-Ch ₀ (CH ₀ ). S-CtAMP
3 2 4 1.0 0.5 39.1 0.016 8-CH ₃ (CH ₂ ) ₅ SC-AMP 1.0 1.0 26.4
calibration 0.031 8-CH ₀ (CH ₀ ), SC-AMP
J Δ O 1.0 1.0 0.046 8-CH ₃ (CH ₂ ) ₇ SC-AMP 1.0 0.088 8-CH ₀ (CH ₀ ) _O SC-AMP
3 Za 1.0 following G 0.14 8-CH ₃ (CH ₂ ) _g SC-AMP 1.0 calculated: 8-CH ₃ (CH ₂ ) _1Q SC-AMP 1.0 8-CH ₃ (CH ₂ ) SC-AMP 1.0 1.0 1.0 1.0 + 'The values were after the
100 χ (1 - a / b)

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Here a means. the degree of hydrolysis of c-AMP im
Reaction mixture containing the inhibitor (the c-AMP derivative) and b the degree of hydrolysis of c-AMP im
Reaction mixture that does not contain an inhibitor.

The Ki values were obtained from the slope of the Lineweaver j Burk curve and the intersection of the Dixon curve j

calculated. |

None of the new derivatives were degraded by PDE, while N ⁶ , O ² -dibutyryl-c-AMP, 8-Br-c-AMP and 3-NH ₂ -C

have been degraded by PDE. It has been found that from I the new alkylamino-c-AMP derivatives according to the invention | the 8-CH ₅ (CH ₂ ) _n NH-c-AMP derivatives, in which η has a value J from 5 to 9, have a higher activity as PDE inhibitors than the known 8-CH ₅ NH-C-AMP and 8-CH ₅ CH ₂ NH-C-AMP. It was also found that the 8-CH ₅ (CHg) _n NH-C-AMP derivatives in which η is 3 or 4 have a somewhat
have a lower or comparable PDE-inhibiting effect; like the well-known alkylamino derivatives. With regard to the j new alkylthio derivatives according to the invention, it was found that although the PDE-inhibiting effect of j

8-CH ^ (CH ₀ ) Sc-AMP derivatives ^ in which η is 3 or! 4, with that of the known 8-CH ₅ SC-AMP and
8-CH ^ CHpS-c-AMP derivatives comparable or slightly lower
is, however, the PDE inhibitory activity of
8-CH ₅ (CH ₂ ) _n Sc-AMP, where η has a value from 5 to 8,
is much higher than that of the known alkylthio derivatives.
The inhibition constants of 8-CH ₅ (CH ₂ ) ^ NH-C-AMP and
8-CH ₅ (CHg) ₆ SC-AMP "were found to be 9.3 and 9.5 nmoles.
Each of these values is above the values of the previous ones
produced c-AMP derivatives.

To investigate the inhibition mechanism of 8-substituted c-AMP derivatives, the Lineweaver-Burk curve used for each derivative. The response was

609 8-15 / 1 219

at a substrate concentration (c-AMP) of 0.3 to 4.0
mmol / l and a derivative concentration of 0.5 mmol / l
carried out. It has been found that all new derivatives

according to the invention an antagonistic inhibition I mechanism (focused on Vmax (focusing on -p> max)) j

exhibit. It was thus confirmed that all of the derivatives prepared according to the invention contain the phosphodiesterase,
specifically inhibit the c-AMP-degrading Knzyme.

In particular, the new derivatives inhibit the above; group II, namely 8- _{CH- ^ (CH 2} ) J ₁ NH-C-AMP and, 8-CH-, (CH ₂ ) _n Sc-AMP, where η has a value from 5 to 8, i is the PDE antagonistically stronger than all previously known ι c-AMP derivatives. The new derivatives of group II are PDE inhibitors and all have a stronger inhibitory effect than the theophylline or its derivatives currently used as an anti-asthmatic. There is also the ability; for the activation of protein kinases in all derivatives
group II is essentially lost, they work

only as PDE inhibitors. It is therefore to be expected that I will take the place of theophylline as antiasthmatics
will kick.

The preparation of the new c-AMP derivatives according to
Invention is described below.

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The invention includes the new 8-substituted c-AMP derivatives the general formula

O = P

(D

OH

in which A stands for -S- or -NH- and η stands for an integer from 2 to 12, and the non-toxic inorganic ones and organic salts of these compounds and a process for their preparation.

The new 8-linear cyclic alkyl mercapto AMP derivatives of the formula (I), in which A is sulfur, in which η has the abovementioned meaning has, and their non-toxic inorganic and organic salts are obtained by reacting in the 8-position halogenated cyclic AMP derivatives of the general formula

(II)

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- Ib -

in which X is a halogen atom, e.g. a bromine atom, or its organic or inorganic salts with a Alkali metal salt of a linear alkyl meroaptan of the formula

CH ^ (CH ") SH, in which η is an integer from 2 to 12, made in an alcohol as a solvent.

Those used as starting material for the process according to the invention, halogenated in the 8-position cyclic AMP derivatives, e.g. 8-bromo-c-AMP, can be obtained by Treatment of c-AMP with bromine in acetic acid as a buffer can easily be prepared (M.Ikehara and coworkers, Chem. Pharm. Bull. 17 (1969) 348).

For this reaction, the 8-bromo-c-AMP derivative can be used in free form or in the form of an inorganic salt, e.g. of the sodium salt, or as the salt of an organic Base, e.g., triethylamine, can be used. An alcohol is used as the solvent. The alkali salts of the Alkyl mercaptans are produced by conventional methods, e.g. by converting the alkyl mercaptan into an alcohol serving as a solvent with an alkali metal alcoholate, e.g. methoxy sodium or tert.-butoxy potassium. The alkali salt of the alkyl mercaptan is used in an amount of at least 1 mole, preferably in an amount from 2 to 10 moles per mole of the 8-halo-c-AMP derivative is used. The use of the alkali salt of alkyl meroaptan in too large a surplus is for economic reasons which is inconvenient and also disadvantageous, since this makes aftertreatment and work-up difficult. the The reaction is carried out at the boiling point of the solvent used. The response time largely depends the other reaction conditions, for example the amount of the alkali salt of the alkyl mercaptan used and on the type of solvent used, but generally good results are obtained if the Reaction is carried out for 1 to 5 hours. Too long a reaction time is inappropriate because it causes

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Decomposition of the desired product takes place. The product can easily be in the form of crystals of the free Ester by conventional methods, e.g. by concentrating the resulting liquid reaction product at 40.degree under reduced pressure, dissolving the residue in cold water and adding concentrated hydrochloric acid for solution with cooling and stirring to adjust a pH in the acidic range.

The new 8-linear alkylamino-c-AMP derivatives of the Formula (i) in which A is the group of the formula -NH- in which η has the meaning given above, and their non-toxic inorganic and organic salts can be obtained by reacting halogenated cyclic AMP derivatives of the formula (II) or their organic or inorganic salts with a linear alkylamine of the formula CH- (CHp) NHp, in which η is an integer from 2 to is to be produced.

This reaction is carried out at 50 to 150 ° C for 1 to 24 hours. Any solvent which does not inhibit the progress of the reaction can be used, but water or an alcohol is preferred as the reaction solvent because of the solvency. If an alkylamine with 10 or more carbon atoms is assumed, particularly good results are obtained when using methoxyethanol. The alkylamine is used in an amount of 1 to 20 moles per mole of the 8-position halogenated c-AMP derivative. The use of the alkylamine in large excess is not appropriate because it makes the post-treatment difficult and the production costs are high, although the reaction is not adversely affected even if the alkylamine is used in large excess. The reaction product can easily be in the form of crystals of the free ester by conventional methods, for example by concentration of the liquid reaction product at 40 ⁰ C

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Under reduced pressure, dissolve the residue in aqueous 0.5N ammonia, extract the solution with Ether for removing contaminants soluble in ether, e.g. excess alkylamine, addition of concentrated Hydrochloric acid to set a pH value in the acidic range and, if necessary, by adding Isolate methanol, ethanol, acetone or the like.

The new 8-substituted c — AMP derivatives according to FIG Invention are very stable in vivo and in vivo mainly as antagonistic inhibitors for PDE, the c-AMP degrading enzyme; effective. Of these new derivatives, those that have 5 to 10 carbon atoms in the Substituting alkyl radical contain, a particularly high effectiveness as an antagonistic inhibitor for PDE. Furthermore, since the ability of these derivatives to activate protein kinases is greatly reduced, they are no longer effective as active type c-AMP even when administered to the living body. With others In other words, side effects of these derivatives can be eliminated or eliminated by directly increasing the c-AMP level be mitigated.

The compounds according to the invention are due to their ability to reduce the concentration of intracellular To increase intermediate bodies with hormone effect, valuable for the treatment of various disease states including metabolic disorders and endocrine gland disorders. They have an effect on different ones Target tissues have high biological activity and selectivity. They also show resistance to degradation Enzymes, e.g., cyclic phosphodiesterase. The compounds according to the invention are therefore valuable for example for the treatment of bronchial asthma, refractory congestive heart failure, diabetes mellitus, Pseudohypoparathyroidism, obesity, some neoplastic Appearances more resistant to vasopressin

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Diabetes insipidus and other disorders attributable to disorders of the function of the pituitary gland are.

The invention is also directed to pharmaceutical preparations containing a compound of formula (I) as contain essential active ingredient in admixture with a pharmaceutically acceptable, non-toxic carrier.

Solids, liquids and gases can be used as pharmaceutical carriers for the formulation of the medicaments. The formulations may for example take the form of tablets, pills, K _a pseln, powders, preparations have sustained release of the active ingredient, solutions, suspensions, elixirs, and aerosols. The various oils, for example oils from petroleum, oils of animal, vegetable or synthetic origin, for example peanut oil, soybean oil, mineral oil and sesame oil are suitable as carriers. Preferred liquid carriers are water, saline solutions, aqueous dextrose and glycols, in particular for injection solutions. Suitable pharmaceutical auxiliaries are, for example, starch and cellulose. Talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dry milk, glycerin, propylene glycol and water. In each case, the pharmaceutical preparations contain an effective amount of the active ingredient with a carrier, the amount of which is chosen so that the correct dosage form for the appropriate administration is obtained.

The amount of the compounds of the invention effective in treating biological disorders is generally in the range of about 1 to 100 mg / kg body weight of the recipient for once or several times a day Administration. The active ingredients can be used in any suitable manner, e.g., parenterally or orally, and in a any form suitable for administration, e.g.

60981 5 / 12-19

be administered as isotonic saline solution, suspensions, tablets, capsules and the like (see for example U.S. Patent 3,872,084).

The inventive c-AMP derivatives of group II, in particular 8-CH ₃ (CH ₂ ) ₆ Sc-AMP and 8-CH ₃ (CH ₂ ) _? NH-C-AMP, are highly effective as antiasthmatics and therefore can take the place of theophylline or its derivatives, which are currently widely used as antiasthmatics.

The group III c-AMP derivatives according to the invention are Antagonistic inhibitors for PDE and known c-AMP derivatives are far superior in terms of membrane permeability. When drugs containing these derivatives according to the invention are used by scabies or the like Diseases afflicted skin are applied, they are sufficiently absorbed to have a high healing effect to unfold. Furthermore, these derivatives become effective in administration even at low concentrations quickly absorbed by the cells so that they perform their functions effectively.

At the currently As the most effective method for treating scabies, the PDE is inhibited and the intracellular c-AMP concentration increased. Given this, it is easy to understand that the new c-AMP derivatives according to the invention are very effective for the medical treatment of scabies.

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The synthesis of the new 8-substituted c-AMP derivatives according to the invention is described in detail in the following examples.

example 1

400 mg (18 mmol) of metallic sodium were dissolved in 60 ml of anhydrous methanol, and 3.4 ml (24 mmol) of n-hexyl mercaptan were added to the solution. The mixture was stirred at room temperature for about 30 minutes. Then 2.46 g (6 mmol) of 8-bromo-c-AMP were added, whereupon the mixture was refluxed with stirring for one hour. The liquid reaction product was concentrated at 40 ⁰ C. 60 ml of cold water was added to the residue. The pH was then adjusted to 6 with concentrated hydrochloric acid with stirring. The mixture was extracted twice with 100 ml of ether each time. The aqueous layer was filtered and the filtrate was cooled. The pH was adjusted to 2 by adding concentrated hydrochloric acid with stirring. The mixture was cooled and stirred to crystallize. The precipitated crystals were filtered off and washed with small amounts of cold ethyl alcohol and ether to remove the thiol odor. The crystals were then dried at room temperature under reduced pressure to obtain 2.16 g (yield 81%) of crystalline 8-n-hexylmercapto-c-AMP having the following characteristics:
Decomposition point: 225 ° C

UV absorption maximum:

PH2 PH ₁₃ 285 mu

285 mu, Λ. 282.mu, 6. 19,400 _r E ", _n / E max ' _max ' P ^tt 2 ^ ⁵⁰

· = 0..48, E ₂₈₀ ZE ₂₆₀ = 2.36

Paper chromatography (n-butanol / acetic acid / water = 4: 1: 5 (upper layer): Rf value = 0.65.

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Elemental analysis for C.gH «N ₁ -OgSP:

Found: C = 43.24%, H = 5.95%, N = 15.57%, S = 7.02%, P = 6.73%

Calculated: C = 43.14%, H = 5.43%, N = 15.72%, S = 7.20%, P = 6.95%

Example 2

The experiment described in Example 1 was repeated in the same way, except that 2.9 ml (24 mmol) n-amyl mercaptan used instead of 3.4 ml of n-hexyl mercaptan became. This gave 2.22 g (85% yield) of crystalline 8-n-amylmercapto-c-AMP, which the had the following key figures:

Decomposition point: 226 C
UV absorption maximum:

PH ₂ PH ₁₃ 284 mu

Anax ^282m P' ^£ PH. ¹⁹ ' ⁶⁰⁰ ' ^E 250 ^{/ E} 260

= 0.45, E ₂₈₀ ZE ₂₆₀ = 2 ^ 46

Paper chromatography (n-butanol: acetic acid: water = 4: 1: 5 (upper layer): Rf value = 0.65

Elemental analysis for C ₁₅ Hp _{2 NcOcSPi}

Found: C = 41 37%, H = 5.44%, N = 16.03%, S = 7.23%,

* ■ / · U56

Calculated: c = 41.76%, H = 5.14%, N = 16.23%, S = 7.43%, P = 7.18%

Example 3

The experiment described in Example 1 was repeated in the same way with the difference that 2.6 ml (24 mmol) of n-butyl mercaptan were used in place of 3.4 ml of n-hexyl mercaptan. 1.79 g (yield 72%) crystalline 8-n-butylmercapto-c-AMP was obtained, which had the following key figures: Decomposition point: 224 ° C

60 ^ 81571219

UV absorption maximum:

PH ₂ pH 284 mu

A _max ²⁸⁴ * V. ^ _ma x 282 _mu.5 pH2 20,100,

= 0.44, E ₂₈₀ / E ₂₆₀ = 2.52

Paper chromatography (n-butanol: acetic acid: water = 4: 1: 5, upper layer): Rf value = 0.66

Elemental analysis for C .. Hp N ₅ O ₆ SP:

Found: C = 40.02%, H = 5.33%, N = 15.50%, S = 7.48%, P = 7.24%

Calculated: C = 40.29%, H = 4.83%, N = 16.78%, S = 7.68%, P = 7.42%

Example 4

In 80 ml of ethyl alcohol, 400 mg (18 mmol) became metallic Sodium dissolved. 4.2 ml (24 mmol) of n-octyl mercaptan was added to the solution. The mixture was 30 minutes stirred at room temperature. After adding 2.46 g (6 mmol) of 8-bromo-c-AMP, the mixture was turned on for 3 hours Heated reflux condenser. The reaction product obtained was worked up in the manner described in Example 1, whereby 2.32 g (yield 82%) of crystalline 8-n-octylmercapto-c-AMP obtained that had the following metrics:

Decomposition point: 223 C
UV absorption maximum:

pH2 P ^H 13 ²⁸ ^ ^m P

Λ 285 mu, λ 282 rough, ζ, 18,400, ~

= 0.48, E _oon ZE _ocn = 2.70

Paper chromatography (n-butanol: acetic acid: water = 4: 1: 5 (upper layer): Rf value = 0.65

Elemental analysis for ^c io ^H 28 ^N 5 ° 6 ^SP:

Found: c = 45.43%, H = 6.34%, N = 14.80%, S = 6.52%, P = 6.38%

^ 09815/1219 "

Calculated: C = 45.66%, H = 5.96%, N = 14.79%, S = 6.77% P = 6.54%

Example 5

The experiment described in Example 4 was repeated in the same manner with the difference that 3.8 ml (24 mmol) of n-heptyl mercaptan were used instead of 4.2 ml of n-octyl mercaptan. This gave 2.26 g (yield 82%) of crystalline Sn-heptylmercapto-c-AMP which had the following characteristics: Decomposition point: 228 ° C
UV absorption maximum:

pH ₁₃ 28 5 rough

^{285 m} P 'A _max 282 mu, ^ 19,300,

= 0.47, E ₂₈₀ ZE ₂₆₀ = 2.45

Paper chromatography (n-butanol: acetic acid: water = 4: 1: 5 (upper layer): Rf value = 0.65

Elemental analysis for C ^ ₇ Hp ₄ N ₅ OgSP:

Found: C = 44.45%, H = 5.9.8%, N = 15.13%, S = 6.78%, P - 6.65%

Calculated: c = 44.44%, H = 5.70%, N = 15.24%, S = 6.98%, P = 6.74%

Example 6

In 100 ml of anhydrous tert-butyl alcohol, 620 mg (20 mmol) of metallic potassium dissolved while heating to 40 ° C. After adding 5.0 ml (24 mmol) of n-decyl mercaptan the mixture was stirred for about 20 minutes to dissolve. Then 2.46 g (6 mmol) of 8-bromo-c-AMP dem The mixture was added and the mixture was refluxed for 1 hour. The reaction product obtained was worked up in the manner described in Example 1, leaving 2.60 g (yield 86%) crystalline 8-n-decylmercapto-c-AMP was obtained as follows Key figures had:

- 1

Decomposition point: 227 C UV absorption maximum:

pH ₂ PH ₁₃ 28 5 mu

^ ²⁸⁵ W ^ max ^{282 m} »> ^C _P H ₂ ¹⁷ ' ⁸⁰⁰ ' ^E 250 ^{/ E} 260

= 0.52, E ₂₈₀ ZE ₂₆₀ = 2.69

Paper chromatography (n-butanol: acetic acid: water = 4: 1: 5 (upper layer): Rf value = 0.75

Elemental analysis ^{for C 2o H} 32 ^N 5 ° 6 ^SP:

Found: C = 47.64%, H = 6.58%, N = 13.86%, S = 6.25%, P = 6.07%

Calculated: C = 47.90%, H = 6.43%, N = 13.96%, S = 6.39%, P = 6.18%

Example 7

The experiment described in Example 6 was repeated in the same way with the difference that 5.7 ml (24 mmol) of n-dodecyl mercaptan instead of 5.0 ml n-decyl mercaptan were used. This gave 2.70 g (yield 85%) of crystalline e-n-dodecyl-mercapto-c-AMP received that had the following metrics:

Decomposition point: 228 ° C.

UV absorption maximum:

285 mu ^ ¹⁷

_Λ PH ₂
^A max ^{285 1} ^ ' ^A max ²⁸²

= 0.53, E ₂₈₀ ZE ₂₆₀ = 2.70

Paper chromatography (n-butanol: acetic acid: water = 4: 1: 5 (upper layer):

Rf value = 0.80

Elemental analysis for 022 ^ 5N ₅ OgSP:

Found: C = 49.60%, H = 6.85%, N = 13.02%, S = 5.95% P = 5.76%

809 8 1 b / TT19

2543598

Calculated: C = 49.90%, H = 6.85%, N = 13.22%, S = 6.05%, P = 5.89%

Example 8

The experiment described in Example 4 was repeated in the same way with the difference that 2.18 ml (24 mmol) of n-propyl mercaptan instead of 4.2 ml n-Octyl mercaptan were used, 1.94 g (yield 80%). Crystalline 8-n-propylmercapto-c-AMP were obtained, which had the following characteristics:

Decomposition point: 225 C
UV absorption maximum:

PH2 _λ PH ₁₃ 284 mil

A _mav 284 rough, A_ 282

IU α. Χ

= 0.45, E ₂₈₀ ZE ₃₆₀ = 2.45

Paper chromatography (n-butanol: acetic acid: water = 4: 1: 5 (upper layer)):
RF value = 0.55

Elementary analysis for C ^ H ₁₈ N ₅ OgSP:

Found: C = 38.78%, H = 4.86%, N = 17.08%, S = 7.80%, P = 7.55%

Calculated: c = 38.71%, H = 4.50%, N = 17.36%, S = 7.95%, P = 7.68%

Example 9

The experiment described in Example 4 was repeated in the same way with the difference that 5.7 ml (30 mmol) n-nonyl mercaptan instead of 4.2 ml n-octyl mercaptan were used. Here, 2.49 g (yield 85%) of crystalline 8-n-nonylmercapto-c-AMP were included receive the following key figures:

Decomposition point: 225 C

60 15/1

UV absorption maximum:

PH ₂ pH ₁₃ 285 ταμ

285 ταμ, λ 282 mn, &"18,200, max 'P" 2

= 0.49, E _00n ZE ₂₆₀ = 2.70

Paper chromatography (n-butanol: acetic acid: water = 4: 1: 5 (upper layer)): Rf value = 0.68

Elemental analysis:

Found: _c = 46.70%, H = 6.45%, N = 14.20%, S = 6.48% P = 6.22%

Calculated: c = 46.81%, H = 6.20%, N = 14.37%, S = 6.57%, P = 6.35%

example

The experiment described in Example 1 was repeated in the same way with the difference that 5.4 ml (24 mmol) of n-undecyl mercaptan were used in place of 3.4 ml of n-hexyl mercaptan. Here were 2.32 g (yield 75%) of crystalline 8-n-undecylmercaptoc-AMP with the following key figures were obtained:

Decomposition point: 227 ° C UV absorption maximum:

_Λ PH2 _Λ ρΗχ3 285 um

Λ 285 mn, Λ. 282 rough. & 17 800 E / E max r ' max ° " ¹ ^' pH ₂ ^{1 / | ÖÜU} '^ 250 ^{/ i: i} 260

= 0.52, E _00n ZE ₀ ^ _n = 2.68

Paper chromatography (n-butanol: acetic acid: water = 4: 1: 5 (upper layer): Rf value = 0.75

Elemental analysis for ^C 21 ^H 34 ^N 5 ° 6 ^SP:

Found: C = 48.83%, H = 6.80%, N = 13.67%, S = 6.09%, P = 6.12%

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Calculated: C = 48.92% ', H = 6.65%, N = 13.58%, S = 6.22% P = 6.01%

Example 11

820 mg (2 mmol) were added to 20 ml of 2-methoxyethanol 8-bromo-c-AMP and 3.14 g (20 mmol) n-decylamine were added. The mixture was refluxed with stirring for 2 hours. The mixture was poured into 100 ml of aqueous Poured in ammonia and extracted twice with 200 ml of ether each time. The aqueous layer was taking at 40 C concentrated to 10 ml under reduced pressure. The residue was added dropwise to methanolic hydrochloric acid with stirring given, the pH of which had previously been adjusted to 1.5. Then it was over to crystallization Stirred overnight while cooling. The precipitated crystals were filtered off with small amounts of cold water and. Washed cold ethanol and dried at room temperature under reduced pressure, with 805 mg (Yield 83%) crystalline 8-n-decylamino-c-AMP with the following key figures were obtained:

Decomposition point: 226 C

UV absorption maximum:

- ■ PH ₂ pH ₁₃ 277 mu

^{A 277 1} ^ '^ _max 277 mu, S _pH2 12.700, = 0.74, E ₂₈₀ ZE ₂₆₀ = 1.34

Paper chromatography (n-butanol: acetic acid: water = 4: 1: 5 (upper layer)):
Rf value = 0.83 '

Elemental analysis for ^c po ^H 33 ^N 6 ° 6 ^P:

Found: _c = 48.96%, H = 7.03%, N = 17.40%, P = 6.21%

Calculated: ^c = 49.58%., H = 6.86%, N = 17.35%, P = 6.39%

609815/1219

Example 12

The experiment described in Example 11 was repeated in the same way with the difference that 3.43 g (20 mmol) of n-undecylamine instead of 3.14 g n-decylamine were used, with 705 mg (yield 79%) crystalline 8-n-undecylamino-c-AMP with the following Key figures were obtained:

Decomposition point 225 C
UV absorption maximum:
1 ^PH 2 ___. P ^H 13 ρ ²⁷⁷

^{λ 277 1} ^ '^ _max 277 _mp , ε

= 0.87, E ₂₈₀ ZE _26n = 1.31

Paper chromatography ~ (n-butanol: acetic acid: water = 4: 1: 5 (upper layer): Rf value = 0.86

Elemental analysis for Cp ^ .H, -Ν, -Ο, -Ρ:

Found: C = 50.18%, H = 7.23%, N = 16.65%, P = 6.14s

Calculated: C = 50.60%, H = 7.08%, N = 16.86%, P =

Example 13

The experiment described in Example 11 was repeated in the same way with the difference that 3.71 g (20 mmol) of n-dodecylamine were used in place of 3.14 g of n-decylamine, with 750 mg (yield 73%) crystalline 8-n-dodecylamino-c-AMP with the following Key figures were obtained:

Decomposition point: 227 ° C
UV absorption maximum:

Ί ^PH 2 ^ _n PH ₁₃ 277 mp

²⁷⁷ -Pl 277 mp, C ^ ^H 12,100,

⁸⁸ ' ^E 280 / ^E 260

609 815/1219

Paper chromatography (n-butanol: acetic acid: water = 4: 1: 5 (upper layer)):
Rf value 0.86

Elemental analysis for C ~~ H., "N, -O, P:

Found: c = 51.27%, H = 7.36%, N = 16.30%, P = 5.96% Calculated: _{c = 5} i. _{55% / H = Ί} . ₂ 8%, N = 16.40%, P = 6.04%

Example 14

The experiment described in Example 11 was repeated in the same way with the difference that 3.99 g (20 mmol) of n-tridecylamine were used in place of 3.14 g of n-decylamine. Here were 650 mg (Yield 62%) crystalline 8-n-tridecylamino-c-AMP obtained with the following key figures:

Decomposition point: 234 C
UV absorption maximum:

_Λ P ^H 2 _ PHl3 _c 277 m, u

⁷¹ max ^{277 1} ^ '^ max ²⁷⁷ ^' ^Z _P H ₂ ¹² ' ⁰⁰⁰ ' ^E 250 ^{/ E} 260 = 0.87, E ₂₈₀ ZE ₂₆₀ = 1.35

Paper chromatography (n-butanol: acetic acid: water = 4: 1: 5 (upper layer)):
Rf value = 0.90

Elemental analysis for Cp-H ^ gNgOgP:

Found: C = 51.30%, H = 7.32%, N = 16.04%, ρ = 5.75% Calculated: c = 52.46%, H = 7.47%, N = 15.96%, P = 5.88%

Example 15

820 mg (2 mmol) of 8-bromo-c-AMP and 2.59 g (20 mmol) of n-octylamine were added to 40 ml of n-butanol. The mixture was refluxed with stirring for 3 hours (the internal temperature was 120 ° C). The reaction mixture

609815/1 219

was concentrated at 40 ° C. under reduced pressure. The residue was dissolved in 50 ml of aqueous 0.5N ammonia. The solution was extracted twice with 100 ml of ether each time. The aqueous layer was filtered. Of the The filtrate was adjusted to pH 1.5 with concentrated hydrochloric acid while cooling and stirring became. 50 ml of methanol were then added dropwise to the solution, whereupon the mixture allowed to crystallize overnight 5 C was stirred. The deposited crystals were filtered off with small amounts of cold water and washed cold ethanol and dried at room temperature under reduced pressure, giving 420 mg (yield 46%) crystalline 8-n-octylamino-c-AMP with the following Key figures were obtained:

Decomposition point: 223 ° C UV absorption maximum:

PH ₂

n, ax = 0.53,

pH ₁₃

277 mi

277 mn, = 1.42

PH ₂ ¹³ ' ²⁰⁰ ' ^E 250 ^{/ E} 260

Paper chromatography (n-butanol: acetic acid: water = 4: 1: 5 (upper layer)):
Rf value 0.80

Elemental analysis ^{for c -id H} 29 ^N 6 ° 6 ^P:

Found: C = 46.29%, H = 6.52%, N = 18.20%, P = 6.53%

Calculated: c = 47.36%, H = 6.40%, N = 18.42%, P = 6.78%

Example 16

820 mg (2 mmol) of 8-bromo-c-AMP were added to 60 ml of ethanol and 2.02 g (20 mmol) of n-hexylamine. The mixture was reacted in a glass ampoule at 100 ° C. for 6 hours By working up the reaction mixture in the manner described in Example 15, 497 mg (yield

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58%) crystalline 8-n-hexylamino-c-AMP with the following Get key figures:

Decomposition point: 224 ° C
UV absorption maximum:

PH ₂ PH ₁₃ 277 mu

13.600, E _ocn / E = 0.52, E _oon / E ", _n = 1.45

Paper chromatography (n-butanol: acetic acid: water = 4: 1: 5 (upper layer))
Rf value 0.78

Elemental analysis for C .., -Η ,,, - Ν, -Ο, -Ρ:

Xo ^ O U Ό

Found: C - 44.75%, H = 6.01%, N = 19.35%, P = 7.02% Calculated: C = 44.86%, H = 5.88%, N = 19.62%, P = 7.23%

Example 17

The experiment described in Example 16 was repeated in the same way with the difference that 1.46 g (2 mmol) of n-butylamine were used instead of 2.02 g of n-hexylamine, with 520 mg (yield 65%) crystalline 8-n-butylamino-c-AMP with the following Key figures were obtained:

Decomposition point: 223 ° C
UV absorption maximum:

pH ₂ P ^H 13 277 ΐημ

^A max ^{277 ra} ^ '^ ax ^{277 1} ^' ^δ _P H, ¹³ ' ⁷⁰⁰ ' ^E 25 ₀ / ^E 260 = 0.53, E ₂₈₀ / E ₂₆₀ = 1.41

Paper chromatography (n-butanol-acetic acid: water = 4: 1: 5 (upper layer):

Rf value 0.70

Elemental analysis: for Ci / Hp-iNgOgP * found: C = 41.80%, H = 5.35%, N = 21.22%, P = 7.68% Calculated: c = 42.00%, H = 5.29%, N = 21.00%, P = 7.74 %

809815/1219

Example 18

820 mg (2 mmol) of 8-bromo-c-AMP were added to 40 ml of methanol and 2.36 g (40 mmol) of n-propylamine are added. The mixture was reacted in a glass ampoule at 80 ° C. for 5 hours. By working up the reaction mixture obtained in the manner described in Example 15, 540 mg were obtained (Yield 70%) crystalline 8-n-propylamino-c-AMP obtained with the following key figures:

Decomposition point: 226 ° C

UV absorption maximum:

_ P ^H 2 ~ PH ₁₃ 277 nui

^ ²⁷⁷ * ^ _max 277 mp, Z ^ 13,400, ZE = 0.49, E ₂₈₀ ZE ₂₆₀ = 1.45

Paper chromatography (n-butanol: acetic acid: water = 4: 1: 5 (upper layer)):
Rf value 0.56

Elemental analysis for ^ λ - \ ^ λο®pPc? '

Found: C = 40.30%, H = 5.13%, N = 21.65%, P = 7.86% Calculated: "C = 40.42%, H = 4.96%, N = 21.76%, P = 8.02%

Example 19

The experiment described in Example 11 was repeated in the same way with the difference that 2.87 g (20 mmol) of n-nonylamine were used in place of 3.14 g of n-decylamine, with 706 mg (yield 75%) crystalline 8-n-nonylamino-c-AMP with the following key figures were obtained:

Decomposition point: 225 ° C

UV absorption maximum:

_Λ P ^H 2 _ P ^H i3 _c 277 rough

'^ max ^{277 1} ^' ^ max ^{£ 277}

= 0.60, E ₂₈₀ ZE ₂₆₀ = 1.37

_ i3 _c
^{277 1} ^ '^ max ²⁷⁷ ™ »> ^£ pH ₂ ¹³ ' ⁰⁰⁰ ' ^E 25 ₀ / ^E 260

609815/1218

Paper chromatography (n-butanol: acetic acid: water = 4: 1: 5 (upper layer):

Rf value 0.75
Elemental analysis for C ₁₉ H ₃ ^ NgOgP:

Found: c = 48.25%, H = 6.86%, N = 17.70%, P = 6.23% Calculated: C = 48.51%, H = 6.64%, N = 17.86%, P = 6.58%

Example 20

The experiment described in Example 11 was repeated in the same way with the difference that 2.30 g (20 mmol) of n-heptylamine were used instead of 3.14 g of n-decylamine, 549 mg (yield 62%) of crystalline material 8-n-heptylamino-c-AMP with the following indicators were obtained:
Decomposition point: 223 ° C
UV absorption maximum:

λ ^pH 13 c ²⁷⁷ X ^ _x 277 ^

= 0.52, E ₂₈₀ ZE ₂₆₀ = 1.42

277 mp, ^ ¹³ ' ⁴⁰⁰ ' - ^E 25 (/ ^E 260

Paper chromatography (n-butanol: acetic acid: water = 4: 1: 5 (upper layer):

Rf value 0.72
Elemental analysis for C ₁₇ H ₂₇ NgOgP:

Found: C = 46.33%, H = 6.27%, N = 19.10%, P = 6.87% Calculated: C = 46.15%, H = 6.15%, N = 19.00%, P = 7.00%

Example 21

The experiment described in Example 16 was repeated with the difference that 1.74 g (20 mmol) of n-pentylamine instead of 2.02 g of n-hexylamine were used, with 406 mg (yield 49%) of crystalline 8-n-pentylamino c-AMP with the following key figures were obtained:

Decomposition point: 223 ° C

6098 15/1219

Claims (15)

UV absorption maximum: > ^pH 2 -ν P ^H 13 277 mu ^A max ²⁷⁷ * K _ax 277 6 = 0.52, E ₂₈₀ ZE ₂₆₀ = 1.43 > ^pH 2 13 ^A max ²⁷⁷ *? ' K 277 mu.6 ^ 13,600, Paper chromatography (n-butanol-acetic acid: water = 4: 1: 5 (upper layer): Rf value 0.60 Elemental analysis for ^c i5 ^H 23 ^N 6 ° 6 ^P: Found: c = 43.60%, H = 5.78%, N = 20.10%, P = 7.32% Calculated: C = 43.48%, H = 5.60%, N = 20.28%, P = 7.48% 609815/1219 Patent claims Cyclic adenosine monophosphates of the general formula O = P -0 OH in which A is -S- or -NH- and η is an integer from 2 to 12, and their non-toxic inorganic ones and organic salts. 2) Cyclic 8-alkyl mercaptoadenosine monophosphates der general formula NH O = P III in which η is an integer from 2 to 12, and its non-toxic inorganic and organic salts. 80 9 8 15/1219 3. Cyclic S-alkyl mercaptoadenosine monophosphates
of formula III and their non-toxic inorganic and organic salts, in which η is a whole Number is from 5 to 8. 4. Cyclic 8-alkyl mercaptoadenosine monophosphates
of formula III and their non-toxic inorganic
and organic salts in which η is a whole
Number is from 9 to 12. 5. Cyclic 8-alkylaminoadenosine monophosphates of
general formula y — NH (CH ₉ ) CH, / £ * XX -J IV O-CH2 H H ^{0 = P} · \ ■ \ O OH OH in which η is an integer from 2 to 12, and j their non-toxic inorganic and organic ' Salts. ! 6. Cyclic 8-alkylaminoadenosine monophosphates of j Formula IV and its non-toxic inorganic and: organic salts, in which η is an integer ' is from 5 to 8. j 7. Cyclic 8-alkylaminoadenosine monophosphates der
Formula IV and its non-toxic inorganic and | organic salts in which η is an integer ί from 9 to 12. 809815/1219 8. A process for the preparation of compounds according to claim 2, characterized in that in
8-position halogenated cyclic adenosine monophosphates of the general formula NH O = P OH in which X is a halogen atom, e.g. a bromine atom, or its inorganic or organic salts with a Alkali salt of a linear alkyl mercaptan of the general formula OH., (CHp) SH, in which η is an integer from 2 to 12 is, implements. 9.Verfahren for the preparation of compounds according to claim 5, characterized in that in the 8-position .halogenated cyclic adenosine monophosphates
the general formula O = P 609815/1219 in which X is a halogen atom, for example a bromine atom, or its inorganic or organic salts with a linear alkylamine of the general formula CH ₃ (CH ₂ ) NH ₂ , in which η is an integer from 2 to 12, is reacted. 10. The method according to claim 8, characterized in that that the reaction is carried out in the presence of an alcohol serving as a solvent. 11. The method according to claim 9, characterized in that the reaction is carried out in the presence of an alcohol or in the presence of water as a solvent. 12.Verfahren according to claims 8 and 10, characterized net that the alkali salt of the linear alkyl mercaptan in an amount of 1 to 10 moles per mole of the cyclic adenosine monophosphate halogenated in the 8-position is used. 13 · Process according to claims 9 and 11, characterized in that the linear alkylamine in one Amount of 1 to 20 moles per mole of the 8-halogenated cyclic adenosine monophosphate is used. 14. The method according to claims 8 to 13 * thereby marked j draws that the reaction occurs at the boiling point of < used solvent performs. ] 15. The method according to claims 8, 10, 12 and 14, characterized in that that the reaction is carried out for 1 to 5 hours. 609815/1219 l6. Method according to claims 9> Π, Ij5 and 14, thereby characterized in that the reaction 1 to 24 Hours. 17. Process according to Claim 9 *, characterized in that linear alkylamines of the formula CH-, (CH ₂ ) _n NH ₂ , in which η is an integer from 9 to 12, and methoxyethanol are used as the solvent. l8. Pharmaceutical preparations, characterized by a content of compounds of claims 1 to 7 609815/1219