FI68235C - FRAMEWORK FOR THERAPEUTIC ADMINISTRATION OF THERAPEUTIC EQUIPMENT 2-LORADENINDERDERAT - Google Patents

Description

68235

A process for the preparation of therapeutically useful 2-chloroadenine derivatives.

5 Separated from patent application 791 456

The invention relates to a process for the preparation of new 2-chloroadenine derivatives of the formula II and their pharmaceutically acceptable acid addition salts, 10 NH0 X. » 15 Lj „/>

Cl | R 120 in the formula is 2-cyclohexenyl or cyclohexyl.

The compounds of formula II have a beneficial bronchodilator effect.

Theophylline, which is normally administered as the ethylenediamine salt (aminophylline) or the choline salt, is an effective and useful non-adrenaline-induced bronchodilator commonly prescribed for the treatment of asthma. Due to its good solubility, aminophylline has for years been considered an effective oral bronchodilator 2,68235. However, aminofluorine is known to have certain disadvantages. For example, it causes intestinal disorders and side effects on the cardiovascular and central nervous systems, which has led to the search for 5 new non-adrenaline-acting bronchodilators with more advantageous properties, such as a stronger effect and / or fewer side effects.

A large number of different purine derivatives have been described in the patent and scientific literature. Examples) include the following publications: 1. J. Am. Chem. Soc., 81, 197-201 (1959), which describes the formula NH-ry>

k, V

Synthesis of compounds according to 20, wherein R is cyclohexyl or 2-cyclohexyl. These compounds are potential anticancer drugs.

2. U.S. Patent 3,917,837, which describes Formula 25

___ Λ OH

The use of a compound of claim 30 as an anti-inflammatory agent.

3. U.S. Patent 3,930,005, which describes compounds of the formula

II

68235 R2-> n ^ R3

X N

rV \\ CH2 o where R2 and can mean e.g. hydrogen and R 2 may mean e.g. lower alkoxy. The compounds are reported to have anti-inflammatory activity.

BE Patent 853,086 (Farmdoc 70719Y), which describes compounds of the formula f L) 20 wherein (a) X is C 1-6 alkoxy or -NHR, R is H or lower alkyl, Y is C 1-8 alkoxy -alkyl, C 3-8 -cycloalkyl or -hydroxycycloalkyl, phenyl, halophenyl, trifluoromethylphenyl, bicycloalkyl having up to 12 carbon atoms or hydroxy-bicycloalkyl, or -AR 1, A is methylene or ethylene, R 1 is phenyl, halophenyl, trifluoromethyl-phenyl, bicycloalkyl or hydroxy-bicycloalkyl having up to 12 carbon atoms, Q is H, C 1-6 alkyl, C 3-3 cycloalkyl or hydroxycycloalkyl, bicycloalkyl of up to 12 carbon atoms or hydroxy-bicycloalkyl , halophenyl, trifluoromethylphenyl or AR · * -; or (b) X is halogen or lower dialkylamino, Y is methyl, ethyl, cyclopentyl, phenyl, halophenyl, trifluoromethylphenyl or benzyl and Q is as defined above. The compounds are reported to be useful in the treatment of 68235 psoriasis.

5. DE-A-2 610 985 (Farmdoc 70863Y), which describes compounds of the formula nh2] T>

R

J COX 0 rH> i ° ft wherein and R2 represent OH or ONO2, or together form C2-6 alkylidene, aralkylidene or CR8R8, R1 is H or C1-4 alkyl; Rg is ORg or NR2Rg; R 9 is C 1-6 alkyl, R 6 and R 8 represent optionally substituted C 1-6 alkyl or C 1-6 cycloalkyl, or together form a C 2-6 alkylene group in which one CH 2 group may be replaced by a heteroatom, R 9 is C 1-6 alkyl or alkoxy, optionally substituted phenyl or H, X is OR 9 or N 1 R 11 'R 9 is C 1-7 alkyl-C 1-6 cycloalkyl, optionally substituted phenyl or aralkyl, R 1-4 and R ^ represents hydrogen, optionally substituted C 1-4 alkyl, alkenyl, or alkynyl, optionally substituted C 1-4 cycloalkyl, substituted phenyl, benzylamino, 2-methylfuryl or adamantyl, or one may be H and the other group of formula 3 ° | L / -, CH2ln-NH ~ OC O χ w R1 R2

K

5 68235 wherein n is 2-16, or R 1 q and together form a C 2-6 alkylene group in which one C 1-4 group may be replaced by a heteroatom. The compounds are reported to affect blood circulation, heart and metabolism.

5 6. Chem. Pharm. Bull., 23 (4), 759-774 (1975), in which e.g. describes compounds of the formula NH ~ I 2

OF

N I \ 10 1/15

Oil OH

wherein R is lower alkyl. The compounds are reported to have 20 coronary dilating effects.

JP Application Publication 52-71492 (Farmdoc 53190Y), which describes compounds of the formula NH-I 1 T f> R 3 wherein R 1 is straight or branched C 1 -C 4 alkyl, cycloalkyl, C 7-11 - aralkyl or piperazinoethyl of the formula -CH 2 -CH 2 -N 1 -R 2 wherein R 2 is C 1-6 aralkyl, monosubstituted aralkyl, cinnamyl or fluorenyl, R 2 is straight or branched C 1-10 alkyl, C 1-4 alkyl; cycloalkyl, C 1-6 aralkyl or piperazinoethyl as defined above, with the exception of those compounds in which R 1 is methyl, R 4 is methyl and R 2 is ethyl and R 2 is cycloalkyl and R 3 is C 1-6 alkyl, C 5-10 cycloalkyl or C 7 -C 4 aralkyl. The compounds are reported to have antiplatelet and coronary vasodilatory activity.

10 8. Chem. Pharm. Bull., 25 (7), 1811-1821 (1977), which describes the preparation of 2-thioadenosine derivatives such as a compound of formula Γ2 15 - \ L il / 20 C_ /.

The above compounds are reported to have some antiplatelet activity. It has been found that the corresponding compound having a ribose sugar group at the 9-position is considerably more potent, from which it can be concluded that the ribosyl group of 2-thioadenosine derivatives is essential for effectively inhibiting platelet aggregation and cannot be replaced by other substituents.

It has now been found that the 2-chloroadenine derivatives of formula II have a beneficial bronchodilator effect.

The 2-chloroadenine derivatives of formula II and their pharmaceutically acceptable acid addition salts li 7 68235 can be prepared by preparing a 2,6-dichloropurine derivative of the formula

Cl 5 I J) <v>

R 1 wherein R 2 is as defined above is reacted with ammonia in an inert solvent, and if desired, the resulting compound of formula II wherein R 1 is 2-cyclohexenyl is hydrogenated to give a compound of formula II wherein R 1 is cyclohexyl, and / or the resulting compound of formula II is converted into a pharmaceutically acceptable acid addition salt.

As used above, the term "pharmaceutically acceptable acid addition salts" refers to mineral acids such as hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric and phosphoric acids and the like, as well as organic acids such as acetic, citric, pivalic, lactic , salts formed with tartaric, oxalic, succinic, maleic and similar acids. Any non-toxic salt that forms a salt with these compounds comes into play.

To prepare compounds of formula II, the 6-chloro substituents of a compound of formula V are replaced by a 6-amino group, which can be carried out in a manner known per se. e.g., Chem. Pharm. Bull., 23, 759-774 <1975) _7 · In a preferred embodiment, the compound of formula V is suspended in an inert solvent (e.g. water, methanol, ethanol), the suspension is saturated with ammonia gas (preferably at a reduced temperature such as ^0 ° C). and the saturated reaction mixture is heated to a temperature slightly above room temperature and the boiling point of the reaction medium is 35 ° C. The most preferred amination process involves heating intermediate 68235 dissolved in ammonia in methanol in a sealed tube to about 100 ° C.

A compound of formula II wherein R 1 is cyclohexyl may also be prepared by catalytic hydrogenation of a compound of formula II having cyclohexenyl.

For example, a suitable procedure is one in which the compound to be hydrogenated is dissolved in a suitable non-reducing inert solvent (e.g., methanol, ethanol, water, aqueous methanol, aqueous ethanol) and then hydrogenated using a conventional hydrogenation catalyst. Examples of suitable catalysts are palladium carbon, Pd-BaSO 4, Pd-C, PtCl 2, Ru-C, Rh-C, Raney nickel, CuCrO, RhCl / ΐ5 (CgH3) 373 and RuCl2P (C2H2) 373 · The recommended catalyst is palladium on carbon. Although temperature and pressure are not critical in the hydrogenation step, preferred results have been obtained at room temperature and ambient pressure.

The free base compounds of formula II may be converted into pharmaceutically acceptable acid addition salts by conventional methods. Thus, for example, the free base may be dissolved in an inert solvent, reacted with approximately one weight equivalent of a suitable organic or inorganic acid to produce the desired salt, and recovered by precipitation or lyophilization of the salt.

The preparation of the starting materials and 2-chloroadenine derivatives of formula II can be illustrated by the following reaction scheme.

II.

9 68235 ci M = "a, K, Tl, Ag N 2 M or HgCl

‘O-1 / O

x> v X = Cl, Br, I

Cl \ Ä ^ io JC ci I catalytic

Cl hydrogenation ^

Λ .. I

15 li v "i«, NH ^ 20 NH ~ 1

JT2 N ^ \ ^ N

catalytic I I /

I 11) ----> ci ^ N / ^ K

jk "" hydrogenation

“O O

10 68235

The compounds of the invention were tested against aminophylline to determine their bronchodilator effect in vitro and in vivo, and to determine their antihypertensive effect (to measure cardiovascular side effects) in vivo.

Guinea pigs were made into tracheal chains in A. Akcasu's Arch. Int. Pharmacodyn. Ther., 122, 201 (1959). The effect of each test compound 10 was recorded by the method of Magnus and expressed as a percentage of 0.1 μg / ml isoproterenol before the maximum reaction obtained for each experiment. The bronchodilatory effect (in vitro) of aminophylline and test compounds is shown in Table 1 as EC 50 g (micro-15 g / ml concentration causing relaxation of 50% of the maximum reaction obtained with 0.1 microgram / ml isoproterenol).

The bronchodilator effect of test compounds in vivo was evaluated by the increase in guinea pig tracheal pressure (ITP) using the method described by James Pharm in James. Pharmac., 21, 379 (1969). A cannula was inserted into the trachea of the anesthetized guinea pig and ITP was recorded on a polygraph with the guinea pig artificially breathing. Arterial blood pressure (ABP; to measure the antihypertensive effect) was also measured during the experiment. The data were collected as well as intravenously via the duodenum that the compounds provided. Table 1 expresses the in vivo bronchodilator effect (ITP) of each compound as the ED 2 g (tracheal intraocular pressure dose 50 mg / kg) and the antihypertensive effect (ABP) as the ED 2Q value (arterial blood pressure 20 % lowering dose in mg / kg).

To determine the difference between the desired bronchodilator effect and the undesired cardiovascular (antihypertensive) effect, the ratio of hypotensive ED ^ g / bronchodilator ED ^ g and li 68235 is shown in Table 1. For compounds with the highest ABP / ITP ratios , the difference in cardiovascular side effect from bronchodilator effect is greatest.

5 Table 1

Results of pharmacological tests

Compound in vitro in vivo ITC, EDj-q intravenously

10 (yag / ml) ITP, ED5Q ABP, ED5Q ABP / ITP

__ (mg / kg) (mg / kg) __

Formula II 0.12 0.15 2.5 17 (R 2 = 2-cyclohexenyl)

Aminophylline 16.6 0.58 1.18 2 15 __i ITC = Effect in an isolated tracheal chain ABP = Effect on lowering arterial blood pressure ITP = Effect in the tracheal pressure test.

20

The following examples illustrate the invention. Preparation of starting materials 25 rY> η-Ο ^ ΗγΟ.

30 and 12 68235

Example I

HgCl salt of 2,6-dichloropurine Λχ

Cl

To a solution of 7.38 g (27.2 mmol) of HgCl 3 in 100 ral of 50% ethanol was added with stirring 5.15 g (27.2 mmol) of 2,6-dichloropurine. After 5 minutes, 10% NaOH (1010 mL) was added to the solution until no more color reaction occurred (yellow caused by HgO). The mixture was stirred for 30 minutes and the precipitate was filtered, washed successively with water, ethanol and diethyl ether and dried to give 6.91 g (64% yield) of the title salt.

Example II

9- (2-cyclohexenyl) -9H-2,6-dichloropurine 20

Cl 1 1> 25

Cl 30 X ^ i

A mixture of 6.91 g (16.3 mmol) of the product of Example I and 6.91 g of "Celite" (diatomaceous earth) in benzene was azeotroped to remove moisture. To the resulting mixture were added 100 mL of dry xylene 11 686835 and 4 mL (339 mmol) of 3-bromocyclohexene. The mixture was refluxed with stirring for 2.5 hours, cooled and filtered. The filter cake was washed with a small amount of CHCl 3. The filtrate and washings were evaporated to dryness. The residue was dissolved in 50 ml of benzene and the solution was washed with 20% KI solution (3 times) and aqueous NaCl solution (once) and dried over Na 2 SO 4. The filtrate was evaporated and the residue was purified by chromatography on silica gel to give 3.87 g (88%) of the title intermediate, m.p. 133-135 ° C. IR (KBr): 2930, 1590, 1565, 1405, 1355, 1315, 1210, 875, 835 cm -1. UV: λ MeOH 276 nm (ε 9500).

Δ 3.Χ NMR (CDCl 3): 2.00 (6H, m), 5.60 (1H, m), 6.00 (2H, m), 8.11 (1H, s).

Analysis for chhioN4Cl2: 15 Calculated: C 49.09 H 3.75 N 20.82 Cl 26.35

Found: C 48.54 H 3.48 N 20.34 Cl 25.54

By replacing 3-bromocyclohexene with an equivalent weight of cyclohexyl bromide as described above, 9-cyclohexyl-9H-2,6-dichloropurine was obtained.

20 Preparation of compounds of formula II

Example 1 2-Chloro-9- (2-cyclohexenyl) -9H-adenine NHg 25 w N Λ i i>

Cl 0

Ammonia gas was bubbled into a mixture of 2.8 g (10.3 mmol) of 9- (2-cyclohexenyl) -9H-2,6-dichloropurine in 50 mL of CH 2 OH at 0 ° C until gas 14 68235 no longer absorbed. The mixture was heated in a sealed tube to 100 ° C for four hours, then cooled and concentrated to form crystals, the crystals were filtered to give 2.39 g of the title compound. A second crop (112 mg) was obtained from the filtrate by chromatography on silica gel. Total yield = 2.50 g (96%), m.p. 195-197 ° C.

IR (KBr): 3120, 1640, 1590, 1320, 1300, 1225, 1190, 920 cm-1. UV: λ · MeOH 266 nm (6 14600). NMR (CDCl 3): δ 0.89

ItdX j (1H, m), 1.26 (1H, m), 2.00 (4H, m), 5.30 (1H, m), 6.00 (2H, m), 8.11 (1H) , s).

Substitution of 9- (2-cyclohexenyl) -9H-2,6-dichloropurine with 9-cyclohexyl-9H-2,6-dichloropurine as described above gave 2-chloro-9-cyclohexyl-9H-adenine.

Example 2 2-Chloro-9-cyclohexyl-9H-adenine An ethanol mixture of 2-chloro-9- (2-cyclohexenyl) -9H-adenine (252 mg, 1.0 mmol) was hydrogenated with 10% palladium / carbon. (93 mg) at room temperature and ambient pressure. The reaction mixture was filtered and the filtrate was evaporated. The residue was purified by silica gel chromatography to give 139 mg (55%) of the title compound, m.p. 206-209 ° C IR (KBr): 3360, 3150, 2905, 1645, 1595, 1570, 1540 cm-1. UV: XC2H5 ° H 267 nm (6 15300). NMR (CDCl 3): δ / 1.80 (10H, m), 4.47 (1H, m), 6.23 (2H, s), 7.82 (1H, s).

Claims (1)

Process for the preparation of therapeutically useful 2-chloroadenine derivatives of the formula II and their pharmaceutically acceptable acid addition salts, NH 2 (II) 10 R 1 in which R 1 is 2-cyclohexenyl or cyclohexyl, characterized in that 2,6-dichloro of formula J 20 (V) R 18 wherein is as defined above is reacted with ammonia in an inert solvent and, if desired, the resulting compound of formula II with 2-cyclohexenyl is hydrogenated to give a compound of formula II wherein R 1 is cyclohexyl, and / or the resulting compound of formula 30. ii is converted into a pharmaceutically acceptable acid addition salt.