RU2333212C9 - 1- AND 7-[ ω -(BENZHYDRYL-4-PIPERAZINYL-1)ALKYL]-3-ALKYLXANTINE DERIVATIVES WITH ANTIHISTAMINIC AND ANTIALLERGENIC EFFECT - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention concerns new derivatives of 1- and 7-[ω-(benzhydryl-4-piperazinyl-1)alkyl]-3-alkyloxantines of the general formulae I and II, including their pharmaceutically acceptable salts and/or salt hydrates, the derivatives showing antihistaminic and antiallergenic effect. In the general formulae I

and II

: R = H, Me, CH₂Ph; R¹ = Me, "н" - C₄H₉; n = 0-3; X = H, OH, OCOCH₂CH₂COOH; Y = Y¹ = H, Cl, F; on the condition that R and R¹ are not both methyl. Compounds of the invention feature high antihistaminic and antiallergenic activity. E.g., 7-[4-(benzhydryl-4-piperazinyl-1)butyl]-3-methyloxantine dihydrochloride surpasses most efficient antihistaminic and antiallergenic medications, such as cetirizine, loratadine and azelastine, in activity and lasting effect.

EFFECT: obtaining a compound with high antihistaminic and antiallergenic activity.

2 cl, 3 tbl, 8 ex

Description

Despite the rather large range of anti-histamine drugs used in medical practice as antiallergic drugs, the search for new histamine receptor H-1 blockers remains an urgent task due to the fact that most of the existing drugs of this class are not without drawbacks, such as: short duration of action, presence side effects from the central nervous system, etc. (MD Mashkovsky, Drugs, Moscow, "New Wave", 2005, 15th edition, pp. 285-297). In this regard, of particular interest is the search for original anti-histamine (antiallergic) drugs with a new chemical structure and, in particular, in a number of xanthine derivatives, among which there are a number of highly active natural compounds (theophylline, theobromine, caffeine) with valuable pharmacotherapeutic properties.

The aim of the invention is the expansion of the range of antihistamine (anti-allergic) drugs.

This goal is achieved by the synthesis and evaluation of the biological activity of the original chemical compounds, which are based on the structure of xanthine, in particular, derivatives of 1- and 7- [ω- (benzhydryl-4-piperazinyl-1) alkyl] -3-alkylxanthines, as well as their pharmaceutically acceptable salts and / or their hydrates, the General formulas I and II:

where R = H, Me, CH ₂ Ph; R ¹ = Me, n - C ₄ H ₉ ; n = 0-3

X = H, HE, OOSCH ₂ CH ₂ COOH; Y = Y ¹ = H, Cl, F;

provided that R and R ¹ do not simultaneously mean Me

which possess antihistamine and anti-allergic activity and can be used in medicine for the manufacture on their basis of new highly active and low-toxic anti-allergic drugs.

The inventive compounds are synthesized by the following methods:

Method A.

Xanthine derivatives of general formulas III and IV, where R = H, Me, CH ₂ Ph; R ¹ = Me, n —C ₄ H ₉ ;

which are obtained according to the classical Traube method (K.V. Vatsuro, G.L. Mishchenko, Named reactions in organic chemistry, Moscow, Iz-voy Chemistry, 1976, p.400; P.M. Kochergin et al., HGS , 1995, No. 9, p.388), alkylate in the form of a salt with an alkali metal (Na, K) α, ω-dibromoalkanes of the general formula V:

Br (CH ₂ ) _n Br (V, where n = 2-5).

The resulting ω-bromoalkylxanthines of the general formulas VI and VII, where R = H, Me, CH ₂ Ph; R ¹ = CH ₃ , nC ₄ H ₉ ; n = 2-5

treated in the presence of potassium iodide with substituted benzhydrylpiperazines of the general formula VIII:

где Y и Y¹=H, Cl, F.

where Y and Y ¹ = H, Cl, F.

you get the claimed compounds I and II, where X = H (table 1).

Method B.

) или 1- и 7- (3-хлор-2-оксипропил)-ксантины (IX и X, где Z=-СН(ОН)-СН₂Cl)According to this method, xanthine derivatives III and IV, where R = H, Me, CH ₂ Ph; R ¹ = Me, n — C ₄ H ₉ ; treated with epichlorohydrin. In this case, depending on the reaction conditions (anhydrous or aqueous medium), substituted 1- or 7- (2,3-epoxypropyl) xanthines are formed (IX and X, where

) or 1- and 7- (3-chloro-2-hydroxypropyl) -xanthines (IX and X, where Z = -CH (OH) -CH ₂ Cl)

(H.J.Roth, Reaction of theophylline and theobromine with 1,2-epoxides, Arch. Pharm., 1959, 292, 234-238; J. Med. Chem., 1985, 28, No. 5, 652).

By reacting IX and X with benzhydrylpiperazine and its derivatives, the claimed compounds I and II are obtained, where X = OH; n = 1 (table 1).

Biological activity of 1- and 7- [ω- (benzhydryl-4-piperazinyl-1) alkyl] -3-alkylxanthines derivatives (I and II)

The study of the antihistamine activity of the claimed compounds was carried out according to known methods (Guidelines for the experimental study of new pharmacological substances, Moscow, 2005, p. 489) on the isolated ileum of guinea pigs (suppression of the spasmogenic effect of histamine) and on anesthetized guinea pigs (antagonism against bronchoconstrictor effect of histamine). In experiments on whole animals, substances were administered intravenously (5 minutes before the introduction of histamine) and inside (2 hours before the start of the study).

When assessing the duration of the antihistamine action, the compounds were administered orally 24-72 hours before the start of the study.

The most active compound IIh (where R = H; R ¹ = CH ₃ ; n = 2; X = H; Y = Y ¹ = H) was also studied in awake guinea pigs using the itch model caused by instillation of an animal histamine solution into the eye ( anti-histamine action), as well as in rats on the model of passive cutaneous anaphylaxis (anti-allergic effect); (Manual on experimental study of new pharmacological substances, Moscow, 2005, p.511)

The inventive compounds I and II were studied in comparison with drugs similar in pharmacology and widely used in medical practice: cetirizine, loratadine and azelastine (Mashkovsky MD, Drugs, Novaya Volna, 2005, 15th edition, p. 285-297)

The results of the study of antihistamine activity and toxicity of the claimed compounds I and II are presented in table 2.

As follows from the presented data, the majority of the claimed compounds in in vitro and in vivo conditions for anti-histamine activity (indicators IC ₅₀ and ED _50, respectively) are not inferior to cetirizine and loratadine, but less active in comparison with azelastine. The exception is compound IIzh, which in the isolated guinea-gut of the guinea-pig significantly exceeds the activity of cetirizine and loratadine, although it is slightly inferior to azelastine. However, in vivo when administered intravenously, Compound IIzh is more active than all of the above reference drugs; when administered orally (2 hours before the start of the study), compound IIzh is superior in strength to cetirizine and loratadine and is similar to azelastine.

It should be emphasized that the duration of the antihistamine action of compound IIg exceeds all comparison drugs, including azelastine. So, on the histamine bronchospasm model, compound IIzh, cetirizine, loratadine and azelastine after oral administration at a dose of 3 mg / kg provide an effective blockade of the H ₁ -histamine receptors of the bronchi for 72, 48, 18 and 48 hours, respectively. In the model of pruritus caused by histamine, the protective effect of compound IIg at a dose of 3 mg / kg orally remains stable for 2 days and decreases only after 72 hours, whereas the similar effect of cetirizine and azelastine at the same dose decreases significantly after 48 hours , and after 72 hours it completely disappears. On the model of passive skin anaphylaxis, compound IIzh and cetirizine in doses of 1 and 3 mg / kg, respectively, have a moderate and similar antiallergic effect.

A very important fact is the fact that Compound II is less toxic than Azelastine and Cetirizine. Compound IIg is thermally stable, readily soluble in water and, unlike loratadine, can be used to prepare both solid dosage forms and eye drops.

The results obtained allow us to conclude that the series of 1- and 7- [ω- (benzhydryl-4-piperazinyl-1) alkyl] -3-alkylxanthines (I and II) found and studied by us was found among which substances with a high antihistamine and antiallergic activity, opens up new perspectives in the treatment of allergic diseases (Table 2).

Example 1

Preparation of 1- (4-bromobutyl) -3-methyl-7-benzylxanthine (VIc, R = CH ₂ Ph; R ¹ = CH ₃ , n = 4).

To 60 ml abs. CH ₃ OH containing 2.79 g (0.0517 mol) of sodium methoxide, 10.0 g (0.039 mol) of 3-methyl-7-benzylxanthine (III. R = CH ₂ Ph, R ¹ = CH ₃ ) are added.

The suspension is boiled with stirring for 30 minutes; the reaction mass is evaporated to dryness; at the end of the process, methanol residues are removed with toluene to distill off, 10.86 g of 1-sodium salt of 3-methyl-7-benzylxanthine are obtained.

To a solution of 42.3 g (24.4 ml; 0.196 mol) of 1,4-dibromobutane in 100 ml of dimethylformamide (DMF) add 10.86 g (0.039 mol) of the 1-sodium salt of 3-methyl-7-benzylxanthine and boil ( -150 °) while mixing for 3.5 hours. The mass is evaporated in vacuo, water and benzene are added to the residue, stirred, the benzene layer is separated, washed with water, dried over sodium sulfate and filtered through a layer of aluminum oxide. The filtrate is evaporated to a volume of ~ 30 ml and an equal amount of hexane is added. The precipitate formed is filtered and dried. 12.16 g (79.6%), 1- (4-bromobutyl) -3-methyl-7-benzylxanthine, m.p. 90-92 ° (from methanol), M ^+. 91.

Example 2

Preparation of 3-methyl-7- (4-bromobutyl) xanthine (VIIk, R = H, R ¹ = CH ₃ , n = 4).

To a solution of 42.3 g (0.196 mol; 23.4 ml) of 1,4-dibromobutane in 100 ml of acetonitrile add 10.0 g (0.049 mol) of the 7-potassium salt of 3-methylxanthine. The suspension is boiled under stirring for 28 hours, cooled, the precipitated precipitate is filtered off, washed until neutral with water, then with methanol and dried. Get 9,0 (61%) technical 3-methyl-7- (4-bromobutyl) xanthine (VII, R = H, R ¹ = CH ₃ , n = 4), after twice cleaning the technical sample by crystallization from a mixture of benzene and methanol and then dimethisulfoxide, so pl. 218-220 °, M ^+. 301.

Other VI and VII are synthesized in the same way (see Table 3).

Example 3

, R=R¹=СН₃). Суспензию 3 г (0,148 моль) натриевой соли 3,7-диметилксантина (III, 1-Na соль; R=R¹=СН₃) и 20 мл эпихлоргидрина нагревают при перемешивании при 65-70° в течение 20 часов. По охлаждении осадок отфильтровывают и промывают хлористым метиленом. Полученный раствор IX в хлористом метилене упаривают, маслообразный остаток растирают в абсолютном эфире, получают 2,7 (77%) 1-(2,3-эпоксипропил)-3,7-диметилксантина, т.пл. 115-119°, M^+. 236 (J-C. Pascal et al, J. Med. Chem., 1985, №28, №5, 647-652, т.пл. 116-117°).Getting 1- (2,3-epoxypropyl) -3,7-dimethylxanthine (IX, where

R = R ¹ = CH ₃ ). A suspension of 3 g (0.148 mol) of sodium salt of 3,7-dimethylxanthine (III, 1-Na salt; R = R ¹ = CH ₃ ) and 20 ml of epichlorohydrin are heated with stirring at 65-70 ° for 20 hours. After cooling, the precipitate is filtered off and washed with methylene chloride. The resulting solution IX in methylene chloride is evaporated, the oily residue is triturated in absolute ether, to obtain 2.7 (77%) of 1- (2,3-epoxypropyl) -3,7-dimethylxanthine, so pl. 115-119 °, M ^+. 236 (JC. Pascal et al. J. Med. Chem., 1985, No. 28, No. 5, 647-652, mp. 116-117 °).

, R=CH₂Ph; R¹=СН₃), выход 80%, т.пл. 90-95°, М^+. 312.Similarly, from the Na-salt of 3-methyl-7-benzylxanthine (III, 1-Na-salt, R = CH ₂ Ph; R ¹ = CH ₃ ) synthesize 1- (2,3-epoxypropyl) -3-methyl-7- benzylxanthine (IX, where

, R = CH ₂ Ph; R ¹ = CH ₃ ), yield 80%, so pl. 90-95 °, M ^+. 312.

Example 4

Preparation of 3-methyl-7- [4- (benzhydryl-4-piperazinyl-1) butyl] xanthine dihydrochloride (II, where R = H, R ¹ = CH ₃ , X = H, n = 2, Y = Y ¹ = H).

A mixture of 2.0 g (0.006 mol) of 90% 3-methyl-7- (4-bromobutyl) xanthine (VII, where R = H, R ¹ = Me, n = 4), 1.5 g (0.006 mol ) benzhydrylpiperazine VIII (where Y = Y ¹ = H) and 0.05 g of potassium iodide in 40 ml of acetonitrile is boiled with stirring for 30 hours. The reaction mass is evaporated, 25 ml of 5% hydrochloric acid are added to the residue;

the undissolved precipitate is filtered off and the solution is extracted with chloroform. The hydrochloric acid solution obtained after extraction is alkalinized to pH 8 with solid sodium bicarbonate and extracted with chloroform. The extract is washed with a saturated solution of sodium chloride and dried with magnesium sulfate. A saturated solution of hydrogen chloride in methanol is added to the dried chloroform solution to pH ~ 2, the mass is evaporated and the residue is crystallized from ethanol with the addition of water; 1.95 g (56.7%) of 3-methyl-7- [4- (benzhydryl 4-piperazinyl-1) butyl] xanthine dihydrochloride (II, where R = H, R ¹ = CH ₃ , X = H, n = 2, Y = Y ¹ = H), so pl. 216-217 °.

Found%: C56.47; H6.75; N 14.63; H20 4.70.

C ₂₇ H ₃₂ N ₆ O ₂ ⋅2 HCl⋅1.5N ₂ 0

Calculated%: C56,47; H 6.50; N 14.63; H ₂ O 4.93.

3-methyl-7- [4-benzhydryl-4-piperazinyl-1) butyl] xanthine succinate, m.p. 187.5-189 °. Found%: C 62.95; H 7.06; N 14.28; C ₃₁ H ₃₈ N ₆ O ₆ ;

Calculated%: 63.04; H 6.48; N 14.23.

Under similar conditions, from 3-butal-7- (4-bromobutyl) xanthine (VII, where R = H R ¹ = n-Bu; n = 4) and benzhydrylpiperazine (VIII, where Y = Y ¹ = H) are synthesized by 3- butyl-7- [4- (benzhydryl-4-piperazinyl-1) butyl] xanthine dihydrochloride (II, where R = H, R ¹ = nC ₄ H ₉ , X = H, n = 2, Y = Y ¹ = H), yield 49.4%, so pl. 240-242 °; M ^+. 514.

Found%: C61.07; H 6.98; N14.21.

C ₃₀ H ₃₈ N ₆ O ₂ ⋅2 HCl

Calculated%: 61,32; H 6.86; N14.30.

Example 5

Preparation of 1- [4- (benzhydryl-4-piperazinyl-1) butyl] -3-methylxanthine dihydrochloride (I, where R = H, R ¹ = CH ₃ , X = H, n = 2, Y = Y ¹ = H ) from 7-benzyl-1- (4-bromobutyl) -3-methylxanthine (VI, where R = benzyl, R ¹ = Me).

A solution of 2.1 g (0.005 mol) of 95% 7-benzyl-1- (4-bromobutyl) -3-methylxanthine in 50 ml of methanol and 0.21 g of 20% palladium hydroxide on carbon is hydrogenated at 40 ° to termination of the absorption of hydrogen (~ 1.5 hours). The catalyst is filtered off, washed with hot methanol, the filtrate is evaporated to give 1.35 g of 1- (4-bromobutyl) -3-methylxanthine (VI, where R = H, R ¹ = Me, n = 4).

A mixture of 1.35 g of the latter, 1.13 g (0.045 mol) of benzhydrylpiperazine (VIII, where Y = Y ¹ = H), 0.036 (0.00022 mol) of potassium iodide and 30 ml of acetonitrile is boiled under stirring for 15 hours. The reaction mass is evaporated, the residue is dissolved in 25 ml of 5% hydrochloric acid, the solution is washed with chloroform and the hydrochloric acid solution is alkalinized with solid sodium bicarbonate to pH ~ 8. The resulting mass is extracted with chloroform, the extract is washed with a saturated aqueous solution of sodium chloride and dried with magnesium sulfate. The chloroform solution is evaporated, the residue is dissolved in 5 ml of isopropanol, a saturated solution of hydrogen chloride in isopropanol is added to the solution to pH 2. After cooling (5-7 °, 16 hours), the precipitate is filtered and crystallized from methanol-isopropanol, get 1, 38 g (50.7%) 1- [4- (benzhydryl-4-piperazinyl-1) butyl] -3-methylxanthine dihydrochloride, m.p. 198-198 °.

Found%: C59.41; H6.54; N15.06.

C ₂₇ H ₃₂ N ₆ O ₂ ⋅2 HCl

Calculated%: C59,45; H6.28; N15.40.

Similarly, from 1- (4-bromobutyl) -3-butyl-7-benzylxanthine (VI, where R = CH ₂ Ph; R ¹ = n-Bu; n = 4) and benzhydrylpiperazine (VIII, where Y = Y ¹ = H ) get 1- [4- (benzhydryl-4-piperazinyl-1) butyl] -3-butylxanthine dihydrochloride (I, where R = H, R ¹ = n-Bu, X = H, n = 2, Y = Y ¹ = H), yield 42.2%, so pl. 215-217 °; M ^+. 514.

Found%: C60.29; H7.44; N13.93; H ₂ O 2.55.

C ₃₀ H ₃₈ N ₆ O ₂ ⋅2HCl⋅ 0.75 H ₂ O

Calculated%: C59,94; H7.04; N13.98; H ₂ O 2.25.

Example 6

Preparation of 1,3-dimethyl-7- [2-hydroxy-3- (benzhydryl-4-piperazinyl-1) propyl] xanthine dihydrochloride (II, where R = R ¹ = CH ₃ , n = 1, X = OH, Y = Y ¹ = H).

A mixture of 2.45 g (0.009 mol) of 1,3-dimethyl-7- (2-hydroxy-3-chloropropyl) xanthine (X, where Z = -CH (OH) -CH ₂ Cl) (see HJRoth, Arch. Pharm., 1959, 292, 234-238), 2.27 g (0.009 mol) of benzhydrylpiperazine (VIII, where Y = Y ¹ = H), 1.38 g of potash, 0.08 g (0.00005 mol) potassium iodide and 50 ml of acetonitrile boil with stirring for 20 hours. The mass is evaporated, the residue is dissolved in chloroform, the solution is washed with water, dried with magnesium sulfate. After distilling off the chloroform, the residue is crystallized from ethyl acetate, 2.61 g of base II is obtained (where R = R ¹ = CH ₃ ; n = 1, X = OH, Y = Y ¹ = H), which is dissolved in 70 ml of isopropanol. To the resulting solution is added a solution of hydrogen chloride in isopropanol to pH ~ 2, the precipitated precipitate is filtered off and dried. 3.34 (66%) 1,3-dimethyl-7- [2-hydroxy-3- (benzhydryl-4-piperazinyl-1) propyl] xanthine dihydrochloride are obtained, m.p. 224-226 °.

Found%: C57,32; H6,10; N14.86.

C ₂₇ H ₃₂ N ₆ O ₃ ⋅2 HCl

Calculated%: C57,75; H6,10; N14.97.

Example 7

Preparation of 1,3-dimethyl-7- [2-carboxyethylcarbonyloxy-3- (benzhydryl-4-piperazinyl-1) propyl] xanthine (II, where R = R ^l = CH ₃ ; n = 1; X = OCOCH ₂ CH ₂ COOH; Y = Y ¹ = H).

A mixture of 2.0 g (0,004 mol) of 1,3-dimethyl-7- [2-hydroxy-3 (benzhydryl-4-piperazinyl-1) propyl] xanthine (II, where R = R ¹ = CH ₃ ; n = 1 ; X = OH; Y = Y ¹ = H), 0.5 g (0.005 mol) of succinic anhydride and 20 ml of dichloroethane are boiled for 4 hours and evaporated to dryness. The residue is crystallized from absolute ethanol to give 2.04 g (86.7%) of 1,3-dimethyl-7- [2-carboxyethylcarbonyloxy) -3- (benzhydryl-4-piperazinyl-1) propyl] xanthine, mp. 183-185 °.

Found%: C63.28; H6.53; N14.32.

C ₃₁ H ₃₆ N ₆ O ₂ .

Calculated%: C63.25; H6.16; N14.28.

Example 8

Preparation of 1- [2-hydroxy-3- (benzhydryl-4-piperazinyl-1) propyl] -3,7-dimethylxanthine dihydrochloride I (where R = R ¹ = CH ₃ ; n = 1; X = OH; Y = Y ¹ = H).

A mixture of 1 g (0.0042 mol) of 1- (2,3-epoxypropyl) -3,7-dimethylxanthine, 1.26 g (0.0044 mol) of benzhydrylpiperazine and 30 ml of isopropanol is boiled under stirring for 30 hours. After cooling, the precipitate is filtered off, washed with ether and dried. 1.96 g (95%) of 1- [2-hydroxy-3- (benzhydryl-4-piperazinyl-1) propyl] -3,7-dimethylxanthine are obtained:

- base, so pl. 120-122 °, M ^+. 488;

- dihydrochloride, so pl. 196-198 °; M ^+. 488.

Similarly synthesize:

- 1- [2-hydroxy-3- (4 ¹ -chlorobenzhydryl-4-piperazinyl-1) propyl] -3,7-dimethylxanthine (I, where R = R ^l = CH ₃ ; n = 1; X = OH; Y = Cl; Y ¹ = H):

- base, yield 67%, so pl. 152-155 °;

- dihydrochloride, so pl. 192-194 °.

1- [2-hydroxy-3- (benzhydryl-4-piperazinyl-1) -propyl] -3-methyl-7-benzylxanthine (I, where R = CH ₂ Ph, R ¹ = Me; n = 1; X = OH; Y = Y ¹ = H), yield 50%, m.p. 98-100 °.

1- [2-hydroxy-3- (4 ¹ -chlorobenzhydryl-4-piperazinyl-1) propyl] -3-methyl-7-benzylxanthine (I, where R = CH ₂ Ph, R ¹ = Me; n = 1; X = OH; Y = Cl; Y ¹ = H), yield 50%, so pl. 170-172 °.

Table 3. Compound n R R ¹ Output, % M.p. Mass spectrum, EI, m / z; M ^+. one 2 3 four five 6 7 VIa 2 CH ₂ Ph CH ₃ 65 77-79 363 VIb 3 CH ₂ Ph CH ₃ 70 81-83 377 Vi 3 4-FC ₆ H ₄ CH ₂ CH ₃ 66 123-125 395 VIL four 4-FC ₆ H ₄ CH ₂ CH ₃ 67 92-94 409 VI five CH ₂ Ph CH ₃ 59 96-98 405 Wh four CH ₃ CH ₃ 60 120-122 315 VI four CH ₂ Ph NH ₄ H ₉ 75 88-90 433 VIIa 2 CH ₃ CH ₃ 70 143-145 287 VIIg 3 CH ₃ CH ₃ 60 131-133 301 VIId 3 H CH ₃ 60 126-128 287 VIIi four CH ₃ CH ₃ 65 123-125 315 VII four H NH ₄ H ₉ 59 86-88 343

Claims (4)

1. Derivatives of 1- and 7- [ω- (benzhydryl-4-piperazinyl-1) alkyl] -3-alkylxanthines of general formulas I and II:

where R = H, Me, CH ₂ Ph; R ¹ = Me, n - C ₄ H ₉ ; n = 0-3; X = H, HE, OOSCH ₂ CH ₂ COOH; Y = Y ¹ = H, Cl, F, provided that R and R ¹ do not simultaneously mean methyl, including their pharmaceutically acceptable salts and / or their hydrates. 2. A compound according to claim 1, namely 7- [4- (1-benzhydrylpiperazine family) butyl] -3-methylxanthine dihydrochloride (II _g, wherein R = H; R ¹ = Me; n = 2; X = H; Y = Y ¹ = H), which has antihistamine and anti-allergic effects.