US3896119A - Xanthines substituted in the 8-position - Google Patents

Xanthines substituted in the 8-position Download PDF

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US3896119A
US3896119A US292798A US29279872A US3896119A US 3896119 A US3896119 A US 3896119A US 292798 A US292798 A US 292798A US 29279872 A US29279872 A US 29279872A US 3896119 A US3896119 A US 3896119A
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methyl
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hydroxyl
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Karl-Heinz Klingler
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Evonik Operations GmbH
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Degussa GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
    • C07D473/08—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1 and 3, e.g. theophylline

Definitions

  • ABSTRACT Compound are prepared having the formula:
  • R is hydrogen or methyl
  • R and R are hydrogen, methyl, hydroxy, or hydroxymethyl
  • R is hydrogen or methyl
  • R is alkyl of l to 6 carbon atoms.
  • phenylalkyl of 7 to 12 carbon atoms or -NR R where R and R individually are hydrogen or alkyl'of l to 6 carbon atoms or R and R together with the nitrogen atom form a 5 to 7 membered ring which can have an additional oxygen, nitrogen or sulfur atom and also can contain 0 to 2 alkyl substituents with l to 4 carbon atoms or salts thereof.
  • the compounds have outstanding broncholytic activity.
  • R is hydrogen or methyl
  • R and R are hydrogen, methyl, hydroxy, or hydroxymethyL
  • R is hydrogen or methyl and R is alkyl of l to 6 carbon atoms
  • phenylalkyl of 7 to 12 carbon atoms or an additional oxygen, nitrogen or sulfur atom and also an alkyl substituted morpholino group are also especially suitable.
  • n is a member from I to 3 and X is a CH- group or in the case n is 2 or 3 X can also be either oxygen or nitrogen or R, can be a methyl substituted morpho- I lino group.
  • the compounds of the invention are pharmacologically active and especially have a strong broncholytic activity. There are also present valuable circulatory activity.
  • salts of the amines of formula I there'can be prepared and' employed salts of any non-toxic pharmacologically acceptable acids such as hydrochloric acid,
  • hydrobromic acid sulfuric acid, acetic acid, p-toluene sulfonic acid, propionic acid, succinic acid, maleic acid, malonic acid, fumaric acid, lactic acid, tartaric acid and citric acid.
  • the compounds can beconverted from the salts to the free bases again in customary-manner, forexample,
  • the compounds of the invention can be prepared by methods which are known in themselves. Thus, there can be used the procedures employed in Klingler U.S. Pat. application Ser. No. 163,468 filed July 16, 1971, now U.S. Pat. No. 3,728,346 and in Klingler U.S. Pat. application Ser.'No. 284,911 filed Aug. 30, 1972, now U.S. Pat. 3,855,221 entitled Hydroxyphenyl Hydroxyethylaminoalkyl Theophyllines (corresponding to Austrian application 7745/71 filed Sept. 6, 1971) by replacing the hydrogen nucleus in the 8-position of the theophylline nucleus of the starting material of those applications with the grouping R, as defined above.
  • the entire disclosures of the two above-mentioned Klinger U.S. applications is hereby incorporated by reference.
  • the compounds of the present invention can be prepared by reacting:
  • Y is oxygen or hydroxyl plus a hydrogen and X and Y are different one being a halogen and the other an amino group except that if Z is an amino group and Y is a hydroxyl group plus hydrogen X can also form an ethylene oxide ring; if a keto group is present in the compound obtained, it is reduced to a hydroxyl group;
  • the latter is the case if the amino group as well as, in a given case, the phenolic hydroxyl group also are protected by a benzyl group or a carbobenzoxy group and for example a keto group is hydrogenated.
  • the protective group is not split off during the reaction, a simple after treatment of the reaction product is necessary wherein then the splitting off of the protective groups takes place, for example under the conditions given above.
  • protective groups for the amino groups there can be used, for example: the benzyl group, a-phenylethyl group, benzyl groups substituted in the benzene nucleus such as, for example, the p-bromo or pnitrobenzyl group, the carbobenzoxy group, the carbobenzthio group, the trifluoroacetyl group, the phthalyl group, the trityl group, the p-toluenesulfonyl group and similar groups.
  • These same protective groups can be used for the phenolic hydroxyl groups; additionally there can be used simple acyl groups as, for example, the acetyl group.
  • Process (a) is suitably carried out in a solvent such as alcohols, e.g., methanol, ethanol, propanol, isopropanol, or butanol, alcohol-water mixtures, dimethyl formamide, aromatic hydrocarbons such as benzene, toluene, xylene and other aromatic solvents at elevated temperatures such as for example 50 to 200C.
  • a solvent such as alcohols, e.g., methanol, ethanol, propanol, isopropanol, or butanol
  • alcohol-water mixtures dimethyl formamide
  • aromatic hydrocarbons such as benzene, toluene, xylene and other aromatic solvents
  • an acid acceptor is employed such as alkali carbonates, for example, potassium carbonate and sodium carbonate, tertiary amines, e.g., tributylamine or excess amine reactant.
  • the process also can be carried out without a solvent.
  • the keto groups in the compound obtained must be reduced to the hydroxyl group.
  • catalysts there can be used, for example, the customary finely divided metal catalysts such as noble metal catalysts, for example, platinum and especially palladium.
  • the reduction can be carried out at normal temperature or elevated temperature.
  • a temperature range of about 40 to C in a solvent such as lower aliphatic alcohols, e.g., methanol, ethanol, isopropanol, propanol and butanol, alcoholwater-mixtures dimethyl formamide, etc.
  • solvent such as lower aliphatic alcohols, e.g., methanol, ethanol, isopropanol, propanol and butanol, alcoholwater-mixtures dimethyl formamide, etc.
  • free bases of formula II or the salts can be employed.
  • the phenolic hydroxyl groups as well as the secondary amino groups contain benzyl protective groups then these are split off simultaneously in the catalytic hydrogenation if, for example, a palladium catalyst is used.
  • the reduction of the keto group can also take place with the aid of other known reducing agents which reduce a keto group to the hydroxyl group.
  • reducing agents are, for example, nascent hydrogen, (for example zinc-acid such as zinc-glacial acetic acid or zinchydrochloric acid, aluminum amalgam, metal hydride or complex metal hydrides (such as LiH, LiAlH alkali borohydrides such as sodium borohydride or lithium borohydride, sodiumtriexthoxyaluminum hydride), aluminum alcoholates such as aluminum isopropylate-isopropanol (Meerwein-Ponndorf process), etc.
  • nascent hydrogen for example zinc-acid such as zinc-glacial acetic acid or zinchydrochloric acid, aluminum amalgam, metal hydride or complex metal hydrides (such as LiH, LiAlH alkali borohydrides such as sodium borohydride or lithium borohydride, sodiumtriexthoxyaluminum hydride), aluminum alcoholates such as aluminum isopropylate-isopropanol (Meerwein-Ponndorf process), etc.
  • R is the hydroxymethyl group under mild conditions, there is obtained the end product of formula I when R is CH OH and by stronger conditions the end product where R is CH If it is desired to maintain the CH OH group it is suitable to work at low or only slightly elevated temperatures as well as at normal pressure and to add the starting compound as the base. Another possibility is to reduce the ketone with a reducing agent which only attacks keto groups, especially complex metal hydrides such as sodium borohydride or lithium aluminum hydride and in a given case to subsequently split off the protective group by catalytic hydrogenation under mild conditions. This type of process is illustrated by example 2 of Klingler application Ser. No. 284,911, filed Aug. 30, 1972, now U.S. Pat. No. 3,855,221 entitled Hydroxyphenyl Hydroxyethylaminoalkyl Theophyllines".
  • the reduction step can take place simultaneously with the condensation or the Schiffs base can be first isolated and this reduced subsequently.
  • Those compounds which contain asymmetric carbon atoms and which as a rule are obtained as recemates can be split in known manner, for example, by means of optically active isomers, into optically active acid.
  • optically active or disastereometric starting materials whereby there is obtained as the final product a corresponding pure optically active form or a disastereomer configuration.
  • stereoisomer racemates since they are present in the compounds produced two or more asymmetrical carbon atoms. Separation is possible in the customary manner, for example, by recrystallization.
  • the pharmaceutical compositions or medicaments can contain one or more of the compounds of the invention or mixtures of these with other pharmaceutically active materials.
  • the customary pharmaceutical carriers and assistants can be used for the production of pharmaceutical preparations.
  • the medicines can be used enterally, parenterally, orally or perlingually. Dispensing can take place in the form of tablets, capsules, pills, dragees, plugs, ointments, powders, liquids or aerosols.
  • PROCESS (a) Compounds of Formula II in which Z is a halogen can be produced by reacting a compound of the following formula:
  • H oc C-N with a 1,3-dihalopropane, e.g., 1,3-dichloropropane or 1,3-dibromopropane with addition of an alkaline agent such as soda lye for example.
  • a 1,3-dihalopropane e.g., 1,3-dichloropropane or 1,3-dibromopropane with addition of an alkaline agent such as soda lye for example.
  • the reaction is carried out at 50 to 200C with solvents such as water, alcohols, e.g., methanol, ethanol, isopropanol. propanol or butanol, dimethyl formamide, dioxane or mixtures of these solvents.
  • the compounds of Formula II where Z is NH or, for example a benzylamino group are prepared from the corresponding halo compounds by reaction with excess ammonia in an autoclave at a temperature between and 150C or by reaction with benzylamine without pressure in the same temperature range.
  • solvents there can be used water, alcohols, e.g., methanol, ethanol, isopropanol, propanol or butanol, water-alcoholmixtures, dimethyl formamide, hydrocarbons such as toluene and xylene.
  • the mixture was heated for an additional 2 hours, made up to 800 ml with ethyl alcohol, acidified with alcoholic hydrochloric acid and filtered with suction after two days. To purify the product, it was boiled with ethyl alcohol and after cooling filtered with suction. The yield of the dried hydrochloride was 24 grams, M.P. 237239C.
  • EXAMPLE 3 12.8 grams of 7-(3-aminopropyl)-8-morph0linotheophylline were caused to react with 7.5 grams of 2- (3,5-dibenzyloxyphenyl)-2-hydroxyethyl bromide in the molten condition for 5 hours at 135C with stirring. The reaction product was heated with toluene, filtered with suction and stirred with a little water, again filtered with suction and dried at C.
  • the compounds of the invention are suited for the production of pharmaceutical compositions and preparations.
  • the pharmaceutical compositions or drugs contain as the active material one or several of the compounds of the invention, in a given case in admixture with other pharmacologically or pharmaceutically effective materials.
  • the production of the medicine can take place with the use of known and customary pharmaceutical carriers and diluents, as well as other customary assistants.
  • Such materials include gelatin, sucrose, pectin, starch, tylose, talc, lycopodium, silica, lactose, cellulose derivatives, micropulverized cellulose, stearates, e.g., methylstearate and glyceryl stearate, emulsifiers, vegetable oils, water, pharmaceutically compatible monoor polyvalent alcohols and polyglycols such as glycerine, mannitol, sorbitol, pentaerythritol, ethyl alcohol, diethylene glycol, triethylene glycol, ethylene glycol, propylene glycol, dipropylene glycol, polyethylene glycol 400, as well as derivatives of such alcohols and polyglycols, dimethyl sulfoxide, esters of saturated and unsaturated fatty acids with monoor polyvalent alcohols such as glycols, glycerine, diethylene glycol, perthaerythritol, sorbitol,
  • preservatives for example ethylenediaminotetraacetic acid
  • antioxidants there can be used for example sodium metal bisulfite and ascorbic acid
  • preservatives there can be used for example sorbic acid, phydroxybenzoic acid esters, e.g., methyl phydroxybenzoate and ethyl p-hydroxybenzoate and similar materials.
  • the drugs can be used enterally, parenterally, orally, perlingually or in the form of sprays.
  • the compounds of the invention have a good bronchospasmolytic activity as exhibited, for example, on the isolated tracheal spiral of the guinea pig.
  • the bronchospasmolytic activity is comparable to that of the known drug orciprenaline.
  • the compounds of the invention have utility in treating bronchial asthma, chronic asthmatic bronchitis, emphysema bronchitis with spasmic components and additional respiratory illnesses.
  • the compounds can be delivered in the form of tablets, capsules, pills, dragees, liquids or aerosols.
  • liquids there can be used oily or aqueous solutions or suspensions, emulsions, injectable aqueous or oily solutions or suspensions.
  • the preferred forms of use are tablets which contain between 1 and 50 mg. of active material or solutions which contain between 0.1 and 5% of active material.
  • the amount of active component of the invention can be used for example in an amount of 2 mg dispensed orally or 10 strokes of a 0.2% solution dispensed as an aerosol. These doses can be dispensed once or several times a day.
  • the acute toxicity of the compounds of the invention in the mouse is between 80 mg/kg and ISO mg/kg.
  • the drugs can be used in human medicine or in veterinary medicine, e.g., to treat cats, dogs, horses, sheep, cattle, goats and pigs.
  • R is hydrogen or methyl
  • R and R are hydrogen, methyl, hydroxy or hydroxymethyl
  • R is hydrogen or methyl
  • R is where R and R individually are hydrogen or alkyl of 1 to 6 carbon atoms or R and R collectively together with the nitrogen atom form a 5 to 7 membered heterocyclic ring with to 1 additional hetero atom and 0 to 2 alkyl substituents, said additional hetero atom being nitrogen, sulfur or oxygen, or a pharmacologically acceptable salt thereof.
  • R and R are hydrogen or alkyl of 1 to 6 carbon atoms.
  • R and R are alkyl of l to 6 carbon atoms.
  • R is hydrogen, methyl or hydroxyl
  • R is hydroxyl
  • R is dialkylamino wherein the alkyl group has 1 to 6 carbon atoms, morpholino, methylmorpholino or piperidino.
  • R is hydrogen, R and R are hydroxyl groups in the 3,4 or 3,5 position and R is a ring of the formula:
  • R is hydrogen, methyl or hydroxyl
  • R is hydroxyl
  • R is diethylamino, morpholino, or methyl morpholino.

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Abstract

Compound are prepared having the formula:

where R1 is hydrogen or methyl, R2 and R3 are hydrogen, methyl, hydroxy, or hydroxymethyl, R7 is hydrogen or methyl and R4 is alkyl of 1 to 6 carbon atoms, phenylalkyl of 7 to 12 carbon atoms or -NR5R6 where R5 and R6 individually are hydrogen or alkyl of 1 to 6 carbon atoms or R5 and R6 together with the nitrogen atom form a 5 to 7 membered ring which can have an additional oxygen, nitrogen or sulfur atom and also can contain 0 to 2 alkyl substituents with 1 to 4 carbon atoms or salts thereof. The compounds have outstanding broncholytic activity.

Description

United States Patent [1 1 Klingler XANTl-IINES SUBSTITUTED IN THE S-POSITION [75] Inventor: Karl-Heinz Klingler,Langen,
Germany [73] Assignee: Deutsche Goldund Silber-Scheideanstalt vormals Roessler, Germany [22] Filed: Sept. 27, 1972 [21] Appl. No.: 292,798
[30] Foreign Application Priority Data OTHER PUBLICATIONS Kubotz et al., Pharmaceutical Society of Japan, Vol. 89, pp. 441-444, 1969.
Primary ExaminerRobert Gerstl Assistant ExaminerPaul J. Killos Attorney, Agent, or FirmCushman, Darby & Cushman [451 July 22, 1975 [57] ABSTRACT Compound are prepared having the formula:
where R is hydrogen or methyl, R and R are hydrogen, methyl, hydroxy, or hydroxymethyl, R is hydrogen or methyl and R is alkyl of l to 6 carbon atoms. phenylalkyl of 7 to 12 carbon atoms or -NR R where R and R individually are hydrogen or alkyl'of l to 6 carbon atoms or R and R together with the nitrogen atom form a 5 to 7 membered ring which can have an additional oxygen, nitrogen or sulfur atom and also can contain 0 to 2 alkyl substituents with l to 4 carbon atoms or salts thereof. The compounds have outstanding broncholytic activity.
23 Claims, No Drawings XANTHINES SUBSTITUTEDVINITHVYAE 8-POSIJTION The present invention relates to compounds of the formula:
where R, is hydrogen or methyl, R and R are hydrogen, methyl, hydroxy, or hydroxymethyL R is hydrogen or methyl and R is alkyl of l to 6 carbon atoms,
, phenylalkyl of 7 to 12 carbon atoms or an additional oxygen, nitrogen or sulfur atom and also an alkyl substituted morpholino group. Also especially suitable are those compounds in which R, is hydrogen, R and R are hydroxy groups in the 3, 4 or 3,5 posi-, tions and R is a ring of the formula:
where n is a member from I to 3 and X is a CH- group or in the case n is 2 or 3 X can also be either oxygen or nitrogen or R, can be a methyl substituted morpho- I lino group.
The compounds of the invention are pharmacologically active and especially have a strong broncholytic activity. There are also present valuable circulatory activity.
As salts of the amines of formula I, there'can be prepared and' employed salts of any non-toxic pharmacologically acceptable acids such as hydrochloric acid,
hydrobromic acid, sulfuric acid, acetic acid, p-toluene sulfonic acid, propionic acid, succinic acid, maleic acid, malonic acid, fumaric acid, lactic acid, tartaric acid and citric acid.
The compoundscan beconverted from the salts to the free bases again in customary-manner, forexample,
, by treating a solution in an organic medium such as alcohols, e.g., methanol with sodium carbonate or soda .lye. A
'clude 7 I methylphenyl)-2-hydroxyethylamino]-propyl} 5 Examples of compounds within the invention in 'addi- 7 tion to those mentioned in the specific examples in- -{3-[2-(3-hydroxymethyl-4-hydroxy-5- 8-dirnethylamino-theophylline; {3-[2-(3,4-
di(hydro xymethyl)-phenyl)-2-hydroxyethylamino]- 7- {3-[2-(4- phenyl)-l-methyl-Z-hydroxye- -8-methyl aminotheophylline;
propyl}. '-8 -morpholinotheophylline; hydroxyrnethyl thylamino]-propyl} Z-(phenyl)-2-hydroxyethylamino]-propyl -8-(2,6- dimethyl) morpholino-theophylline; 7- {3-[2-(3,5- dihydroxyphenyl)-2-hydroxyethyl-amino]-propyl}-8- amino-theophylline; 7-{3-[2-(3,4-dihydroxyphenyl)-2- hydroxyethyl-amino]-propyl}-8-hexylaminotheophylline; 7-{3-[2-(3,4-dihydroxyphenyl)-2- hydroxyethylamino]-propyl}-8-hexylaminotheophylline; 7-{3-[2-(3,4-dihydroxyphenyl)-2- hydroxyethyl-amino]-propyl- -8-di sec. butylaminotheophylline; 7-{3-[2-(3,5-dihodroxyphenyl)-2- hydroxyethyl-amino]-propyl}-8-phenethyltheophylline; 7-{3-[2-(3,4-dihydroxyphenyl)-2- hydroxyethylamino]-propyl}-8-thiomorpholinotheophylline; 7- {3-[ 2-( 3,4-dihydroxyphenyl )-2- ,hydroxyethylamino ]-propyl} -8-piperidinotheophylline; 7-{3-[2-(2-hydroxyphenyl)-2- hydroxyethylamino]-propyl l-8-piperazinotheophylline; 7- {3-[ 2-( 3 ,5-dihydroxyphenyl)-2- hydroxyethyl-amino]-propyl} -8-(2-butyl) morpholinotheophylline; 7- 3-[ 2( 3 ,4-dihydroxyphenyl )-2- hydroxyethylamino]-propyl} -8-pyrrolidinotheophylline; 7- 3-[2-( 3 ,4-dihydroxylphenyl)-2- hydroxyethylamino]-propyl} -8-azacycloheptyltheophylline; 7-{3-[2-(3,5-dihydroxyphenyl)-2- hydroxye'thylamino] propyl-8-( l-oxa-4-azacycloheptyl)-theophylline.
The compounds of the invention can be prepared by methods which are known in themselves. Thus, there can be used the procedures employed in Klingler U.S. Pat. application Ser. No. 163,468 filed July 16, 1971, now U.S. Pat. No. 3,728,346 and in Klingler U.S. Pat. application Ser.'No. 284,911 filed Aug. 30, 1972, now U.S. Pat. 3,855,221 entitled Hydroxyphenyl Hydroxyethylaminoalkyl Theophyllines (corresponding to Austrian application 7745/71 filed Sept. 6, 1971) by replacing the hydrogen nucleus in the 8-position of the theophylline nucleus of the starting material of those applications with the grouping R, as defined above. The entire disclosures of the two above-mentioned Klinger U.S. applications is hereby incorporated by reference.
Thus, the compounds of the present invention can be prepared by reacting:
a. a compound of the formula:
with a compound of the formula:
2 XCHY lll.
where Y is oxygen or hydroxyl plus a hydrogen and X and Y are different one being a halogen and the other an amino group except that if Z is an amino group and Y is a hydroxyl group plus hydrogen X can also form an ethylene oxide ring; if a keto group is present in the compound obtained, it is reduced to a hydroxyl group;
b. by condensing a compound of the formula:
CH 1N(O CH-CH.V
l OL CN\ IV.
| n CH;,-NC-N with a compound of the formula:
W-CY V.
where V and W are always different and V is the aldehyde group -CHO or the group CH NH and W is the group C(R )=O or CH(R,)=O or -CH(R- )---NH and Y is an oxygen atom or a hydroxyl group plus a hydrogen atom, with simultaneous or subsequent hydrogenation.
In the above recited processes, it is frequently expedient to protect the phenolic hydroxyl groups as well as the amino groups by a known protective group. Frequently such protective groups are already required for the starting compounds. These protective groups are easily splittable from the end products. It is either a matter of easily solvolytic splittable acyl groups or hydrogenating splittable groups as for example the benzyl group. the solvolytic splittable protective groups are split off for example by saponification with dilute acids at room temperature or by a short boiling. According to the type of protective group, however, the splitting also takes place during the reaction process. For example, the latter is the case if the amino group as well as, in a given case, the phenolic hydroxyl group also are protected by a benzyl group or a carbobenzoxy group and for example a keto group is hydrogenated. if the protective group is not split off during the reaction, a simple after treatment of the reaction product is necessary wherein then the splitting off of the protective groups takes place, for example under the conditions given above.
As protective groups for the amino groups there can be used, for example: the benzyl group, a-phenylethyl group, benzyl groups substituted in the benzene nucleus such as, for example, the p-bromo or pnitrobenzyl group, the carbobenzoxy group, the carbobenzthio group, the trifluoroacetyl group, the phthalyl group, the trityl group, the p-toluenesulfonyl group and similar groups. These same protective groups can be used for the phenolic hydroxyl groups; additionally there can be used simple acyl groups as, for example, the acetyl group.
Process (a) is suitably carried out in a solvent such as alcohols, e.g., methanol, ethanol, propanol, isopropanol, or butanol, alcohol-water mixtures, dimethyl formamide, aromatic hydrocarbons such as benzene, toluene, xylene and other aromatic solvents at elevated temperatures such as for example 50 to 200C. In a given case an acid acceptor is employed such as alkali carbonates, for example, potassium carbonate and sodium carbonate, tertiary amines, e.g., tributylamine or excess amine reactant. On occasion the process also can be carried out without a solvent.
In the case where Y is oxygen, the keto groups in the compound obtained must be reduced to the hydroxyl group. As catalysts, there can be used, for example, the customary finely divided metal catalysts such as noble metal catalysts, for example, platinum and especially palladium. The reduction can be carried out at normal temperature or elevated temperature. Suitably there is used a temperature range of about 40 to C in a solvent such as lower aliphatic alcohols, e.g., methanol, ethanol, isopropanol, propanol and butanol, alcoholwater-mixtures dimethyl formamide, etc. There can be employed the free bases of formula II or the salts. If the phenolic hydroxyl groups as well as the secondary amino groups contain benzyl protective groups then these are split off simultaneously in the catalytic hydrogenation if, for example, a palladium catalyst is used. The reduction of the keto group can also take place with the aid of other known reducing agents which reduce a keto group to the hydroxyl group. These types of reducing agents are, for example, nascent hydrogen, (for example zinc-acid such as zinc-glacial acetic acid or zinchydrochloric acid, aluminum amalgam, metal hydride or complex metal hydrides (such as LiH, LiAlH alkali borohydrides such as sodium borohydride or lithium borohydride, sodiumtriexthoxyaluminum hydride), aluminum alcoholates such as aluminum isopropylate-isopropanol (Meerwein-Ponndorf process), etc.
If R is the hydroxymethyl group under mild conditions, there is obtained the end product of formula I when R is CH OH and by stronger conditions the end product where R is CH If it is desired to maintain the CH OH group it is suitable to work at low or only slightly elevated temperatures as well as at normal pressure and to add the starting compound as the base. Another possibility is to reduce the ketone with a reducing agent which only attacks keto groups, especially complex metal hydrides such as sodium borohydride or lithium aluminum hydride and in a given case to subsequently split off the protective group by catalytic hydrogenation under mild conditions. This type of process is illustrated by example 2 of Klingler application Ser. No. 284,911, filed Aug. 30, 1972, now U.S. Pat. No. 3,855,221 entitled Hydroxyphenyl Hydroxyethylaminoalkyl Theophyllines".
To recover the end product of formula I in which R is CH;, in the case that R is CH OH in the starting material of formula ll hydrogenation is carried out until the amount of hydrogen calculated for the reduction of the keto group and the hydroxymethyl as well as in a given case for the splitting off of the protective group is taken used the customary hydrogenation catalysts such as' platinum, palladium or nickel with or without carriers. lf hydrogenolytically splittable protective groups are present on the nitrogen of the side chain or on the hydroxyl groups of the phenyl radical these are simultaneously split off by using palladium as the hydrogenation catalyst.
The reduction step can take place simultaneously with the condensation or the Schiffs base can be first isolated and this reduced subsequently.
In processes (a) and (b) there can also. be employed starting materials of formulas II and IV in which R, is replaced by an unsaturated radical such as for example an aliphatic alkenyl group having 1 to 6 carbon atoms or a phenyl alkenyl group having at least 8 to 12 carbon atoms. In this case, catalytic hydrogenation must always be employed whereby the unsaturated residue is converted to the corresponding saturated radical.
Those compounds which contain asymmetric carbon atoms and which as a rule are obtained as recemates can be split in known manner, for example, by means of optically active isomers, into optically active acid. However, it is also possible from the outset to employ optically active or disastereometric starting materials whereby there is obtained as the final product a corresponding pure optically active form or a disastereomer configuration. There can also occur stereoisomer racemates since they are present in the compounds produced two or more asymmetrical carbon atoms. Separation is possible in the customary manner, for example, by recrystallization.
As stated previously the compounds of the invention are useful in the production of pharmaceutical compositions. The pharmaceutical compositions or medicaments can contain one or more of the compounds of the invention or mixtures of these with other pharmaceutically active materials. For the production of pharmaceutical preparations there can be used the customary pharmaceutical carriers and assistants. The medicines can be used enterally, parenterally, orally or perlingually. Dispensing can take place in the form of tablets, capsules, pills, dragees, plugs, ointments, powders, liquids or aerosols. As liquids there can be used oily or aqueous solutions or suspensions, emulsions, injectable aqueous and oily solutions or suspensions.
Unless otherwise indicated all parts and percentages are by weight.
Many of the starting theophylline derivatives are known. Those which are not (as well as those which are) can be obtained by the following processes:
PROCESS (a) Compounds of Formula II in which Z is a halogen can be produced by reacting a compound of the following formula:
H oc C-N with a 1,3-dihalopropane, e.g., 1,3-dichloropropane or 1,3-dibromopropane with addition of an alkaline agent such as soda lye for example. The reaction is carried out at 50 to 200C with solvents such as water, alcohols, e.g., methanol, ethanol, isopropanol. propanol or butanol, dimethyl formamide, dioxane or mixtures of these solvents.
The compounds of Formula II where Z is NH or, for example a benzylamino group are prepared from the corresponding halo compounds by reaction with excess ammonia in an autoclave at a temperature between and 150C or by reaction with benzylamine without pressure in the same temperature range. As solvents there can be used water, alcohols, e.g., methanol, ethanol, isopropanol, propanol or butanol, water-alcoholmixtures, dimethyl formamide, hydrocarbons such as toluene and xylene.
Those starting compounds of Formula II in which X with Y form an ethylene oxide ring can be produced from the corresponding halohydrins by reaction with alcoholic KOH at low temperatures. Phenolic hydroxyl groups are likewise preferably protected. This general procedure is disclosed in Houben/Weyl Vol. 6/3/ pages 374 et seq.
PROCESS (b) EXAMPLE 1 7-{ 3-[2-( 3,4-dihydroxyphenyl)-2- hydroxyethylamino]-propyll -8diethylaminotheophylline 40.5 grams of 7-(3-benzylamino-propyl)-8-diethylamino-theophylline were dissolved in ml of 25% ethyl alcohol and there was added by dropping inside two hours with stirring and introduction of nitrogen to the mixture of a solution of 9.5 grams of o-chloroacetyl-pyrocatechol in 48 ml of ethyl alcohol. The mixture was heated for an additional 2 hours, made up to 800 ml with ethyl alcohol, acidified with alcoholic hydrochloric acid and filtered with suction after two days. To purify the product, it was boiled with ethyl alcohol and after cooling filtered with suction. The yield of the dried hydrochloride was 24 grams, M.P. 237239C.
Unreacted starting material was easily recovered from the filtrate,
22.6 grams of the 7-{3-[2-(3,4-dihydroxypheny1)-2- oxoethyl-benzylaminol-propyl}-8-diethylaminotheophylline hydrochloride thus obtained were dis solved in a mixture of 226 ml of distilled water, 300 ml of ethyl alcohol and 200 ml of methanol and hydrogenated at 550C after addition of 2.3 grams of 10% palladium-activated carbon catalyst. The mixture was filtered after the end of the hydrogen take-up and the solvents distilled off. The residue was boiled under reflux with ethyl alcohol with stirring in a nitrogen atmosphere, the crystalline reduction product HCl-salt) filtered off with suction and dried at 50C. Yield: 5.7 grams, M.P. 216217C (with decomposition).
Production of the starting material (1) 7- chloropropyl-B-diethylamino theophylline 57.3 grams of 8-diethylamino-theophylline were boiled with 226 grams of 1-chloro-3-bromopropane in 183 ml of isopropanol and 27 ml of water at reflux. 1nside of 7 hours there were added dropwise with stirring a solution of 23.3 grams of potassium hydroxide in 87 ml of water. The excess chlorobromopropane was distilled off in a vacuum, the residue dissolved by addition of chloroform and dilute caustic potash solution, the two layers separated and the chloroform phase shaken twice with 5% caustic potash and finally with water.
In a given case the process can be carried out as follows:
The mixture was strongly concentrated in a vacuum. After addition of 100 ml of chloroform, it was stirred a short time, filtered, the chloroform phase separated and this phase shaken with 5% caustic potash. The chloroform solution was dried with potassium carbonate, the chloroform distilled off and the residue recrystallized from methanol. There were obtained 47.4 grams of 7-chloropropyl-8-diethylamino-theophylline having a melting point of l2913lC.
2. 7-(3-benzylaminopropyl)-8-diethylaminotheophylline 24 grams of 7-chloropropyl-8-diethylamino- EXAMPLE 2 7-i 3-[ l-methyl-2-hydroxy-2-(4-hydroxyphenyl)- ethylaminol-propyl l-8-morpholino-theophylline 33.3 grams of 7-(3-benzylaminopropyl)-8-morpholinotheophylline together with 12.8 grams of pbenzyloxy-oz-bromopropiophenone in 120 ml of xylene were boiled at reflux with stirring for 8 hours. Suction filtering was then employed and the filtrate evaporated in a vacuum. The residue was dissolved in hot ethanol, filtered and acidified with alcoholic hydrochloric acid. After the reaction mixture had stood for two days in the refrigerator, it was filtered with suction and dried at 80C. There were obtained 23 grams of{7- 3-[1- methy1-2-oxo2-(4-benzyloxyphenyl)-ethylbenzylamino]-propyl -8-morpholino-theophylline hydrochloride having a melting point of 204 to 205C.
10 grams of the thus recovered material were dissolved in 200 ml of ethanol and after the addition of 1.0 gram of 5% palladiumactivated carbon catalyst hydrogenated at C. The product was filtered, evaporated and the residue recrystallized from ethanol. There were obtained 5.8 grams of the hydrochloride having a melting point of 220221C.
EXAMPLE 3 12.8 grams of 7-(3-aminopropyl)-8-morph0linotheophylline were caused to react with 7.5 grams of 2- (3,5-dibenzyloxyphenyl)-2-hydroxyethyl bromide in the molten condition for 5 hours at 135C with stirring. The reaction product was heated with toluene, filtered with suction and stirred with a little water, again filtered with suction and dried at C. By solution in alcohol and acidification with alcoholic hydrochloric acid there were obtained 3.6 grams of 7-{3-[2-(3,5- dibenzyloxyphenyl)-2-hydroxyethyl-amino]-propyl-} 8-morpholino-theophylline hydrochloride, that was purifie'd by recrystallization from aqueous ethanol, MP. l99203C.
15 grams of the intermediate product recovered in this manner were dissolved in 300 ml of ethanol and 60 ml of distilled water and after addition of 1.5 grams of 5% palladiumactivated carbon catalyst hydrogenated at 60C. The product was filtered, evaporated and the residue heated with ethanol whereupon the hydrochloride crystallized out. Yield: 10.4 grams; MP. 25 3256C.
Production of the starting material 8-morpholino theophylline was reacted with l-ch1oro-3- bromopropane in the process described in example 1 and the compound obtained (MP. l51153C, likewise as described in example converted with benzylamine into the 7-(3-benzylaminopropyl)-8-morpholinotheophylline (melting point of the hydrochloride 243-2'45C). From this there were obtained the 7-(3- aminopropyl)-8-morpholinotheophylline (MP. 93C) by catalytic hydrogenation in alcoholic solution at 60C with use of palladiumactivated carbon.
Further examples are given in Table 1 below. The production of compounds 4 to 10 was carried out in a manner analogous to example 1 and the compounds of examples 11-13 were produced in a manner analogous to example 31 In table 2 there are given themelting points of the starting materials forexamples4-8. It may I y be noted that the melting points of'the two starting ma" COMPOUND OF FORMULA l terials which were not given in example 2 are the same 1 EXAMPLE;
TABLE l-Continued as those in example 7. In Table 3 are given the melting 5 1 4 Hydrochloride points of those intermediate compounds for making compounds 9 to 13 which are new: Y 1 on 8 H l88-l89 c 14 (decomposition) 1 l0 CH3 I c Y H 9 H {K {)0 197-198 TABLE 1 CH! 10 H @011 @o 201 204 COMPOUND OF FORMULA l 11 EXAMPLE MP.C. 15
NO. R, R Hydrochloride on C H R I 2 5 o l l H -N 277-278 i on z s H 6 H 6" 210-211 OH OH 13 H Q -Q 208-210 7 H 43 w 195-196 c11 (decomposition) TABLE 2 MELTlNG POINT "C of intermediates N OF R z ii s R7 EXAMPLE 4 I i R; =CH C H 130 132C 179 185C 180 184C f t r v (Hydrochloride) (Hydrochloride) R 4 H; '124 125C 1' 232 234C f 150 lC (from Methanol) (Hydrochloride) (Hydrochloride) A I V i Rt =0 l26-'130C -98C 166 172C R R 3 4 OH 1 v 1 (Hydrochloride) EicXMimE 7 1. R O l5] 153C v 243 245C Methanol 246 247C R R ,3 4 OH I (Hydrochloride) (Hydrochloride) 3:1 t EitAMP E 8 v R 121 123C 113- ll5C from Methanol 2l8220C R R 3 4 08H (free base) (Hydrochloride) TABLE 3 MELTING POINT C. of lntennediates H2%"5 R 11-1r1Riv11a151Ar15s hmm(CH2) NH CHPC" C5: (CH2)=,N-cH,co Q; R :1 FOR COMPOUND or OH m"; I kg mcaus 7 I 'c 4 t EXAMPLE 5 I w I 3 a kng g gtc i no: intermediate of this type 1 R1 a. i I I 1 (Hydrochloride) TQRQ (freebase) 5 v EXAMPLE 1'0 1 w v k nown i 'oiintermediate of this'typ 199-202C C A' N H 1 a Hi i (Hydrochloride) R7 3 "3 (free base) TABLE 3 Continued MELTlNG POINT C. of Intermediates 2 a- 2 (Cl'hh-N-Cl'hCO INTERMEDIATES FOR COMPOUND OF OH CH C H EXAMPLE I l ,g M 4 $2M:
87-89C loo-168C no intermediate of Q i (free base) (Hydrochloride) this type EXAMPLE 12 OH Q 235-237c 193-197C no intermediate of a, (Hydrochloride) (Hydrochloride) this type EXAMPLE I] loo-102C 208-209C no intermediate R, H (free base) (Hydrochloride) of this type 7 The compounds of the invention are suited for the production of pharmaceutical compositions and preparations. The pharmaceutical compositions or drugs contain as the active material one or several of the compounds of the invention, in a given case in admixture with other pharmacologically or pharmaceutically effective materials. The production of the medicine can take place with the use of known and customary pharmaceutical carriers and diluents, as well as other customary assistants.
Such carriers and assistants are set forth for example in Ullmanns Encyklopadie der technischen Chemie, Vol. 4 (I953), pages 1 to 39; Journal of Pharmaceutical Sciences, Vol. 52 (1963), pages 918 et seq; Hiv. Czetsch-Lindenwald, Hilfstoffe fur Pharmazie und angrenzende Gebiete; as well as in Pharm. I Vol. 2 (1961) pages 72 et seq.
Examples of such materials include gelatin, sucrose, pectin, starch, tylose, talc, lycopodium, silica, lactose, cellulose derivatives, micropulverized cellulose, stearates, e.g., methylstearate and glyceryl stearate, emulsifiers, vegetable oils, water, pharmaceutically compatible monoor polyvalent alcohols and polyglycols such as glycerine, mannitol, sorbitol, pentaerythritol, ethyl alcohol, diethylene glycol, triethylene glycol, ethylene glycol, propylene glycol, dipropylene glycol, polyethylene glycol 400, as well as derivatives of such alcohols and polyglycols, dimethyl sulfoxide, esters of saturated and unsaturated fatty acids with monoor polyvalent alcohols such as glycols, glycerine, diethylene glycol, perthaerythritol, sorbitol, mannitol, etc., e.g., glyceryl stearate, glyceryl palmitate, glyceryl oleate, ethylene glycol stearate; such esters of polyvalent alcohols can in a given case also be etherified, benzyl benzoate, dioxolane, glycerine formal, glcyol furfural, dimethyl acetamide, lactamide, lactates, e.g., ethyl lactate, ethyl carbonate, etc.
Furthermore, there can be added preservatives, stabilizers, buffers, taste correctives, antioxidants and complex formers (for example ethylenediaminotetraacetic acid) and the like.
As antioxidants there can be used for example sodium metal bisulfite and ascorbic acid, as preservatives there can be used for example sorbic acid, phydroxybenzoic acid esters, e.g., methyl phydroxybenzoate and ethyl p-hydroxybenzoate and similar materials.
The pharmacological and galenical treatment of the compounds of the invention takes place according to the usual standard methods.
The drugs can be used enterally, parenterally, orally, perlingually or in the form of sprays.
The addition of other medicinally active materials is also possible.
The compounds of the invention have a good bronchospasmolytic activity as exhibited, for example, on the isolated tracheal spiral of the guinea pig.
The bronchospasmolytic activity is comparable to that of the known drug orciprenaline.
The middle of the bronchospasm at 50lOO% expectorant dosage in the above animal experiments expressed as EDSO, for example, at 10 to 10 gram/ml.
The compounds of the invention have utility in treating bronchial asthma, chronic asthmatic bronchitis, emphysema bronchitis with spasmic components and additional respiratory illnesses.
The compounds can be delivered in the form of tablets, capsules, pills, dragees, liquids or aerosols. As liquids there can be used oily or aqueous solutions or suspensions, emulsions, injectable aqueous or oily solutions or suspensions. The preferred forms of use are tablets which contain between 1 and 50 mg. of active material or solutions which contain between 0.1 and 5% of active material.
In individual doses the amount of active component of the invention can be used for example in an amount of 2 mg dispensed orally or 10 strokes of a 0.2% solution dispensed as an aerosol. These doses can be dispensed once or several times a day.
For example there is recommended the use of 1 tablet containing 2 mg of active ingredients 3 times daily or dispensed as an aerosol 1 to 4 times a day up to 10 strokes of the 0.2% solution.
The acute toxicity of the compounds of the invention in the mouse (expressed by the LD 50 mg/kg method of Miller and Tainer, Proc. Soc. Exph. Biol. and Med., Vol. 57 (1944) pages 261 et seq.) in i.v. application is between 80 mg/kg and ISO mg/kg.'
The drugs can be used in human medicine or in veterinary medicine, e.g., to treat cats, dogs, horses, sheep, cattle, goats and pigs.
What is claimed is:
l. A compound having the formula:
wherein R, is hydrogen or methyl, R and R are hydrogen, methyl, hydroxy or hydroxymethyl, R is hydrogen or methyl and R is where R and R individually are hydrogen or alkyl of 1 to 6 carbon atoms or R and R collectively together with the nitrogen atom form a 5 to 7 membered heterocyclic ring with to 1 additional hetero atom and 0 to 2 alkyl substituents, said additional hetero atom being nitrogen, sulfur or oxygen, or a pharmacologically acceptable salt thereof.
2. A compound according to claim 1 wherein R and R are hydrogen or alkyl of 1 to 6 carbon atoms.
3. A compound according to claim 2 wherein R is hydroxyl.
4. A compound according to claim 2 wherein both R and R are alkyl of l to 6 carbon atoms.
5. A compound according to claim 4 wherein R is hydroxyl.
6. A compound according to claim 4 wherein both R and R are ethyl.
7, A compound according to claim 6 wherein R is hydroxyyl.
8. A compound according to claim 1 wherein when R and R are taken collectively with the nitrogen atom the heteroCyclic ring has the formula or is methyl morpholino, where n is l to 3 and X is CH nitrogen or oxygen.
9. A compound according to claim 8 wherein R is hydrogen, methyl or hydroxyl, R is hydroxyl, and R is dialkylamino wherein the alkyl group has 1 to 6 carbon atoms, morpholino, methylmorpholino or piperidino.
10. A compound according to claim 9 wherein R R and R are in the 3, 4 and 5 positions.
11. A compound according to claim 8 wherein R is hydrogen, methyl, hydroxy or hydroxymethyl, R is hydroxy and R R and R are in the 3,4 and 5 positions, and R is morpholino or methylmorpholino.
12. A compound according to claim 8 wherein R is hydrogen, R and R are hydroxyl groups in the 3,4 or 3,5 position and R is a ring of the formula:
\ CH2CH2/ where X is CH N or O or R is methyl morpholino.
13. A compound according to claim 8 wherein R is methyl.
14. A compound according to claim 8 wherein R is hydrogen.
15. A compound according to claim 14 wherein R is hydrogen, methyl or hydroxyl, R is hydroxyl, R, is diethylamino, morpholino, or methyl morpholino.
16. A compound according to claim 1 wherein R cH,cH, N i x where X is CH nitrogen or oxygen, n is l to 3 or heterocyclic ring compounds of said formula wherein up to 2 of the hydrogen atoms are replaced by alkyl.
17. A compound according to claim 16, wherein X is oxygen and n is 2.
18. A compound according to claim 17 wherein is morpholino or alkyl morpholino having 1 to 4 carbon atoms in the alkyl group.
19. A compound according to claim 18 wherein is morpholino or methyl morpholino.

Claims (23)

1. A COMPOUND HAVING THE FORMULA:
2. A compOund according to claim 1 wherein R5 and R6 are hydrogen or alkyl of 1 to 6 carbon atoms.
3. A compound according to claim 2 wherein R3 is hydroxyl.
4. A compound according to claim 2 wherein both R5 and R6 are alkyl of 1 to 6 carbon atoms.
5. A compound according to claim 4 wherein R3 is hydroxyl.
6. A compound according to claim 4 wherein both R5 and R6 are ethyl.
7. A compound according to claim 6 wherein R3 is hydroxyyl.
8. A compound according to claim 1 wherein when R5 and R6 are taken collectively with the nitrogen atom the heteroCyclic ring has the formula
9. A compound according to claim 8 wherein R2 is hydrogen, methyl or hydroxyl, R3 is hydroxyl, and R4 is dialkylamino wherein the alkyl group has 1 to 6 carbon atoms, morpholino, methylmorpholino or piperidino.
10. A compound according to claim 9 wherein R2, R3, and R7 are in the 3, 4 and 5 positions.
11. A compound according to claim 8 wherein R2 is hydrogen, methyl, hydroxy or hydroxymethyl, R3 is hydroxy and R2, R3 and R7 are in the 3,4 and 5 positions, and R4 is morpholino or methylmorpholino.
12. A compound according to claim 8 wherein R1 is hydrogen, R2 and R3 are hydroxyl groups in the 3,4 or 3,5 position and R4 is a ring of the formula:
13. A compound according to claim 8 wherein R7 is methyl.
14. A compound according to claim 8 wherein R7 is hydrogen.
15. A compound according to claim 14 wherein R2 is hydrogen, methyl or hydroxyl, R3 is hydroxyl, R4 is diethylamino, morpholino, or methyl morpholino.
16. A compound according to claim 1 wherein R4
17. A compound according to claim 16, wherein X is oxygen and n is 2.
18. A compound according to claim 17 wherein
19. A compound according to claim 18 wherein
20. A compound according to claim 19 wherein R2 is hydrogen, methyl or hydroxyl and R3 is hydroxyl.
21. A compound according to claim 20 wherein R2, R3 and R7 are in the 3, 4 and 5 positions.
22. A compound according to claim 18, wherein R7 is methyl.
23. A compound according to claim 18, wherein R7 is hydrogen.
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3980646A (en) * 1974-08-14 1976-09-14 Johann A. Wulfing 3-Methylpyrazole-5-carboxylates and medicaments containing these compounds
US4400381A (en) * 1981-07-31 1983-08-23 Laroche-Navarron, S.A. Piperazine derivatives of theophylline
US4592865A (en) * 1976-08-09 1986-06-03 Shionogi & Co., Ltd. Azetidinone intermediates for cephalosporin analogs
US5281605A (en) * 1986-08-28 1994-01-25 Sandoz Ltd. Novel xanthine derivatives
US20040034014A1 (en) * 2000-07-04 2004-02-19 Kanstrup Anders Bendtz Heterocyclic compounds, which are inhibitors of the enzyme DPP-IV
US20040082570A1 (en) * 2002-02-25 2004-04-29 Eisai Co., Ltd. Xanthine derivative and DPPIV inhibitor

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1527543A (en) * 1976-04-15 1978-10-04 Degussa Basically substituted xanthine derivatives

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Kubotz et al., Pharmaceutical Society of Japan, Vol. 89, pp. 441-444, 1969. *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3980646A (en) * 1974-08-14 1976-09-14 Johann A. Wulfing 3-Methylpyrazole-5-carboxylates and medicaments containing these compounds
US4592865A (en) * 1976-08-09 1986-06-03 Shionogi & Co., Ltd. Azetidinone intermediates for cephalosporin analogs
US4400381A (en) * 1981-07-31 1983-08-23 Laroche-Navarron, S.A. Piperazine derivatives of theophylline
US5281605A (en) * 1986-08-28 1994-01-25 Sandoz Ltd. Novel xanthine derivatives
US20040034014A1 (en) * 2000-07-04 2004-02-19 Kanstrup Anders Bendtz Heterocyclic compounds, which are inhibitors of the enzyme DPP-IV
US7235538B2 (en) 2000-07-04 2007-06-26 Novo Nordisk A/S Heterocyclic compounds, which are inhibitors of the enzyme DPP-IV
US20040082570A1 (en) * 2002-02-25 2004-04-29 Eisai Co., Ltd. Xanthine derivative and DPPIV inhibitor
US7074798B2 (en) * 2002-02-25 2006-07-11 Eisai Co., Ltd Xanthine derivative and DPPIV inhibitor

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