GB1561005A - Xanthine compounds and method of treating bronchospastic and allergic diseases - Google Patents

Description

(54) XANTHINE COMPOUNDS AND METHOD OF TREATING BRONCHOSPASTIC AND ALLERGIC DISEASES

(71) We, COOPER LABORATORIES, INC, existing under the laws of the ScarP 'T Route4fi. Pn SPECIFICATION NO 1561005 Act 19 ts application pioceeded in the name of America Bas 7571817 Ameca.

By ORIES venue, Cedar ICnolls, New Jetsey 07927, United States o INC., a Corp a direction Y AMERICA.

United States of Amenca, of 110 East Hanover A Bas 75718/ prnerica.

THE PATENT OFFICE ~~... . u mcli are sensitized. The antigen 15 ."". y or certam chemicals (allergic meW ators) which in r. vuuer tne allergic symptoms. Allergic reactions can also produce effects in organs other than the bronchi, particularly the skin, eyes and nasal mucosa and include such diseases as allergic rhinitis and urticaria.

Acute asthmatic bronchospasm has been treated with drugs which relax bronchial smooth muscle. Sympathomimetic drugs such as epinephrine, isoproterenol, and terbutaline and xanthine drugs such as theophylline and its salts (aminophylline, etc.') have been used for this purpose. Drugs such as cromolyn sodium which inhibit the release of allergic mediators, have been used prophylactically to treat bronchial asthma.

Corticosteriod drugs have also been used to treat bronchial asthma and other allergy diseases.

Many of the drugs used hitherto have shortcomings which make them less than ideal for treatment of asthma and other bronchospastic and allergic diseases. For example, epinephrine and isoproterenol relieve the symptoms of asthma for only a relatively short period of time and are ineffective orally. Theophylline has limited efficacy and produces cardiac and gastrontestinal side effects. Cromolyn sodium is oniv effective by inhalation or injection and is ineffective by oral administration. The corticosteriod drugs have serious side effects which limit their chronic use.

Substituted xanthines have been known for some time as bronchodilators, and theophylline (1,3-dimethylxanthine) has long been used in the treatment of bronchai asthma.

Prior attempts have been made to improve theophylline by substituting the xanthine nucleus with different groups in several positions in the molecule. A number of 1, 3-dialkylxanthines and 1,3,8-trialkylxanthines have been shown to be bronchodilators in animal models. However, none of the substituted xanthine compounds hitherto synthesized have displaced theophylline and its salts as clinicallv useful bronchodilator and antiallergy agents.

A class of substituted xanthine compounds has now been found which are verv (54) XANTHINE COMPOUNDS AND METHOD OF TREATING BRONCHOSPASTIC AND ALLERGIC DISEASES (71) We, COOPER LABORATORIES, INC., a Company organised and existing under the laws of the State of New Jersey, United States of America, of 1259 Route 46, Parsipanny, New Jersey 07054, United States of America, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement :- This invention relates to substituted xanthines which are useful in the treatment of bronchial asthma and other bronchospastic and allergic diseases. The invention also relates to pharmaceutical compositions comprising such a substituted xanthine and a pharmaceutically-acceptable carrier.

Bronchial asthma is characterized by bronchospasm caused by contraction of the bronchial smooth muscle, increased secretion of mucus from the bronchi, and edema of the respiratory mucosa. While the etiology of asthma is not completely known, it is believed to involve an allergic reaction. Allergic reactions occur in sensitized individuals who are exposed to the antigen to which they are sensitized. The antigen provokes the release in the body of certain chemicals (allergic mediators) which in turn produce the allergic symptoms. Allergic reactions can also produce effects in organs other than the bronchi, particularly the skin, eyes and nasal mucosa and include such diseases as allergic rhinitis and urticaria.

Acute asthmatic bronchospasm has been treated with drugs which relax bronchial smooth muscle. Sympathomimetic drugs such as epinephrine, isoproterenol, and terbutaline and xanthine drugs such as theophylline and its salts (aminophylline, etc. ; have been used for this purpose. Drugs such as cromolyn sodium which inhibit the release of allergic mediators, have been used prophylactically to treat bronchial asthma.

Corticosteriod drugs have also been used to treat bronchial asthma and other allergy diseases.

Many of the drugs used hitherto have shortcomings which make them less than ideal for treatment of asthma and other bronchospastic and allergic diseases. For example, epinephrine and isoproterenol relieve the symptoms of asthma for only a relatively short period of time and are ineffective orally. Theophvlline has limited efficacy and produces cardiac and gastrontestinal side effects. Cromolvn sodium is onlv effective bv inhalation or injection and is ineffective by oral administration. The corticosteriod drugs have serious side effects which limit their chronic use.

Substituted xanthines have been known for some time as bronchodilators, and theophylline (1,3-dimethylxanthine) has long been used in the treatment of bronchiai asthma.

Prior attempts have been made to improve theophylline by substituting the xanthine nucleus with different groups in several positions in the molecule. A number of 1,3-dialkylxanthines and 1,3,8-trialkylxanthines have been shown to be bronchodilators in animal models. However, none of the substituted xanthine compounds hitherto synthesized have displaced theophylline and its salts as clinicallv useful bronchodilator and antiallergy agents.

A class of substituted xanthine compounds has now been found which are very effective bronchodilator and antiallergy agents with rapid onset and prolonged duration of action. These compounds are effective, rapid-acting bronchodilators by all routes of administration and accordingly can be used to abort an acute bronchospastic attack.

In addition, they are orally effective, long-acting antiallergy compounds, by suppressing the release of allergic mediators. Hence, these compounds may be used prophylactically to treat bronchial asthma, and other bronchospastic and allergic diseases.

As will be appreciated from the Examples which follow, the compounds of the invention may be used prophylactically as well as in acute bronchospastic and allergic attacks. It will also be appreciated that long-lasting relief of bronchial asthma and other bronchospastic and allergic disease may be achieved using compounds according to the invention.

According to this invention, there are provided novel xanthine compounds with which bronchial asthma and other bronchospastic and allergic diseases can be treated in mammals, the xanthine compounds having the general formula:

Formula I wherein R =C142 alkyi ; R, =-CH2- (C,-C,) alkyl or-CH2- (C,-C" cycloalkyl) ; R, =H or COOR in which R==Ci-C, alkyl, 2-halo C2C3 alkyl or phenyl ; R8=H or C,-, -alkyl ; provided that R, and R8 are not simultaneously H.

"Halo"as used herein means chloro or bromo.

The novel compounds of this invention which are preferred as bronchodilator and antiallergy agents have the following general formula :-

wherein: R, =C1-C2 alkyl, R, =CH2 (C3Cr alkyl), or cycloalkyl), R,= Cl-C, alkyl, R =C,-C, alkyl, 2-halo (C2-C3 alkyl), phenyl.

According to another preferred embodiment of this invention prolonged bronchodilation and prolonged inhibition of allergic mediator release in mammals are produced by administering an effective amount of a substituted xanthine compound having the formula :

wherein : R, = methyl R3=-CH2-(C3-C4 alkyl) ; - CH2-(C3-C4 cycloalkyl) Rg = ClK2 alkyl The compounds of the invention may be administered orally, parenterally, or by inhalation and conveniently will take the form of tablets, capsules, solutions, elixirs, mulsions or aerosols. Typical effective doses in man range from 0.01 to 50 milligrams per kilogram of body weight depending on route of administration and potency of compound selected.

R, may, for example, be n-butyl, iso-butyl, n-pentyl, 2-methyl-1-buryl, 3-methyl- 1-butyl, 2,2-dimethyl-1-propyl, cyclopropylmethyl or cyclobutylmethyl.

Ruz may, for example be methvl, ethvl, n-propyl, isopropyl, n-butyl, isobutyl, 1- merhvtpropy) or t-butvl.

R may, for example be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2chloroethyl, 2-chloropropyl, 2-bromoethyl, 2-bromopropyl or phenyl.

The presence of a carboalkoxy group in the 7-position of the compounds of this invention has been found to give an improvement in efficacy and, as shown for example in Example 5 below, this effect is similar to the effect achieved in the case of prior art compounds (e. g. 7-carbomethoxy-theophylline as compared to theophylline itself). The data show that the xanthine carboxylate ester is more potent, with both faster onset and longer duration of action. These data indicate a greater bioavailability of the xanthine carboxylate ester. The 7-carboalkoxyxanthines are believed to act as latent forms of the alkylxanthine bronchodilators and are biotransformed to the corresponding xanthine-7-carboxylic acids, which then decarboxylate to yield the corresponding alkyl- xanthine. Thus for the case of 1,8-dimethyl-3- (2-methylbutyl)-xanthine-7- carboxylic acid, methyl ester, the major reaction sequence is thought to proceed as follows :

It is preferred to have Re =methyl. The introduction of an alkyl group in the 8-position of the xanthine nucleus has been discovered to produce a compound having a long lasting activity. As shown below in Example 6, all of the 8-alkylxanthine bronchodilators have a longer duration of activity than the corresponding 8-H xanthine. It is believed that the 8-alkyl group prevents the normal enzymic oxidation at the 8-position of xanthines and thereby prevents rapid bioinactivation of the xanthine.

It is preferred to have Rs selected from the following groups mentioned earlier, namely n-butyl, isobutyl, n-pentyl, 2-methyl-l-butyl, 3-methyl-l-butyl, 2,2-dimethyl 1-propyl, cyclopropylmethyl and cyclobutylmethyl. More preferred R, groups of those listed above are isobutyl, 2-methyl-l-butyl, 3-methyl-l-butyl, n-pentyl, 2,2-dimethyl 1-propyl, cyclopropylmethyl and cydobutylmethyl groups. Of these, isobutyl and 2 methyl-1-butyl are especially preferred and 2-methyl-1-butyl is most preferred. This group has to the Applicant's knowledge never been reported as a substituent in a xanthine compound and has a significant advantage over the prior art R, groups. In comparison with the known R groups, as shown below in Example 7, the 2-methyl-1- butyl group surprisingly confers on the xanthine bronchodilators an effectiveness equal to the best Ra group reported in the prior art, the isobutyl group. This is surprising because the next higher homolog, the 2-methyl-1-pentyl group, confers much lower bronchodilation potency. Furthermore, the 2-methyl-1-butyl group surprisingly com bines this great potency with a substantially lower toxicity. Thus the 2-methyl-1-butvl group is uniquely suitable for the R3 group of a xanthine bronchodilator, particularly in combination with a 7-carboalkoxy group which, as previously indicated, increases the eficacy of the compound, and therefore such compounds which contain the 2 methyl-1-butyl group are greately preferred.

Thus the preferred groups for R,, R, and R are methyl. The most preferred group for R, is 2-methyl-1-butyl. The most preferred compound is that which combines all four preferred groups, namely 1,8-dimethyl-3- (2-methyl-I-butyl)-7carbomethoxyxanthine.

A highly preferred compound is 1, 8-dimethyl-3-isobutylxanthine. This compound has great potency and is long-acting. The most preferred compound wherein R. =H is that which combines the preferred groups, namely 1, 8-dimethyl-3-(2-methvl-1- butyl) xanthine. This compound has a unique combination of high potency, relativelv low toxicity, and long-lasting activity.

The 1, 3,8-trialkyl-7-carboalkoxyxanthines of this invention mav be prepared by reacting the sodium salt of the corresponding 1, 3,8-trialkylxanthine with an alkyl chloroformate CICOOR according to the following :

The sodium salt of the 1, 3,8-trialkylxanthine can be prepared by the action of a strong base such as sodium hydride on the 1, 3,8-trialkylxanthine. The reaction can be carried out in a suitable inert solvent such as tetrahydrofuran.

The 1, 3,8-trialkylxanthines can be prepared by the well-known general procedure of Traube, Berichte 33, 1371 and 3055 (1900).

A 1, 3-dialkyl urea having the general formula

is first prepared. This urea can be prepared by reacting one mole of an alkyl isocyanate with one of an amine according to the reaction

It is evident from the symmetry of the product that either RI or R, may be in the isocyanate reagent and either group may be in the amine reagent. The conditions under which this well-known reaction proceeds are known to one skilled in the art.

The isocyanate required for the above reaction may be prepared by reacting the corresponding amine with phosgene according to the equation Rl-NH2 + COCI2 RU-N + 2 HCl The conditions for this reaction are well known to those skilled in the art and are described in the chemical literature, e. g., in British Patent 901,337.

The 1,3-dialkyl urea is next converted into a 1, 3-dialkyl-1-cyanoacetylurea by reaction with cyanoacetic acid according to the following reaction:

The reaction is conveniently carried out in acetic anhydride at 60 to 70 C. The reaction gives preferentially although not exclusively the product containing the smaller alkyl groups as R,. The isomers may be separated by fractional crystallization.

The 1, 3-dialkyl-1-cyanoacetylurea is next cyclized to form a 4-amino-1, 3-dialkyluracil according to the following reaction:

The reaction is carried out by treating the 1,3-dialkyl-1-cyanoacetylurea with a strong base such as sodium hydroxide in an aqueous medium.

The 4-amino-1, 3-dialkyl uracil is then converted into 4-amino-5-nitroso-1, 3 d ; alky ! urac : ! by treating with sodium nitrite in glacial acetic acid at room temperature, according to the following reaction :

The 4-amino-5-nitroso-1, 3-dialkyl-uracil is then reduced to a 4, 5- diamino-1,3-dialkyluracil by reaction with sodium dithionite in ammonium hydroxide tn,-I,--fnllnwina rea (-tion :

The 4,5-diamino-1,3-dialkyluracil is next converted to a 4-amino-5-alkanoylamino- 1,3-dialkyluracil by reacting with a lower aliphatic acid according to the following equation:

wherein R, is a lower alkyl group.

The 4-amino-5-alkanoylamino-1, 3-dialkyluracil is then cyclized to form the 1,3,8 tria] kslxantll ne by heating in lO5/o aqueous sodium hydroxide solution to reSux temperature according to the following equation.

The compounds of this invention wherein R3 contains an asymmetric carbon atom can exist in optically active enantiomeric forms. These forms may exist separately or mixed in any proportions. The racemic, or equimolar mixture of enantiomeric forms is obtained in the synthesis using reagents devoid of optical activity. The optically active forms of the substituted xanthines can be prepared by using the corresponding optically active amines R3NH2 in the synthesis. For example, the optically active dextro-or levo-form of the substituted xanthines having R3=CH2CH (CH3) CH2 CH3 can be obtained by starting with the corresponding optically active form of 2-methylbutyl- amine. Dextro-and levo-2-methylbutylamines can be prepared by from the corresponding commercially available dextro-and levo-2-methylbutanols by the procedure described by Vasi, 1. G., and Desai, R. K., J. Inst. Chemists Calcurta, 45, 66 (1973).

The invention is to be understood as including within its scope processes, as described above, for preparing the novel compounds of the invention and, in its broad sense, this aspect of the invention is to be understood as being defined as follows : (A) A process for preparing a compound of Formula I in which R is COOR which process comprises reacting a sodium salt of a 1,3-dialkyl- or 1,3,8-trialkylxanthine in which the 1-alkyl group is as defined for RI in Formula I, the 3-alkvl group is as defined for Ra in Formula I and the 8-alkyl group is as defined for R. in Formula I, with an alkyl chloroformate of formula CICOOR in which R is as defined in Claim 1.

(B) A process for preparing a compound of Formula I in which R is hydrogen which process comprises cyclizing a 4-amino-5-alkanoylamino-l, 3-dialkv uracil in which the 1-alkyl group is as defined for R, in Formula I, the 3-alkyl group is as defined for R3 in Formula I and the alkanoylamino group is of formula NHCORA in which R, is as defined for Formula I.

The compounds of this invention may be administered in the customary ways such as orally, sublingually, inhalation, rectally, and parenterally. Tablets, capsules, solutions, suspensions and aerosol mist may be used as forms for administration.

The compounds of this invention can be formulated into compressed tablets incorporating the customary inert excipients including diluents, binders, lubricants, disintegrants, colors, flavors, and sweetening agents. Commonlv used pharmaceutical diluents such as calcium sulfate, lactose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar may be used.

Binders for tablets include starch, gelatin, sugars, such as sucrose, glucose, lactose, molasses, natural and synthetic gums such as acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, carboxymethyl cellulose and polvvinylpyrrolidone.

Commonly used lubricants for tablets include talc and hydrogenated vegetable oils, and these may used in compositions according to the invention in tablet form.

A disintegrant may if so desired be incorporated into the tablets. As disintegrants starches, clays, cellulose, algins, and gums may in particular be used as is well known to those skilled in the art.

Conventional coloring agents such as pharmaceutically acceptable dyes and lakes, and flavoring agents such as mannitol, lactose, or artificial sweemers may also be added to the tablet composition.

The compounds of this invention may also be administered orally contained in hard or soft capsules of gelatin or other suitable material. The compound of this invention may be present in the capsule alone or mixed with a suitable diluent such as lactose or starch.

The compounds of this invention may also bc administered sublingually as rapidly disintegrating tablets or as troches or sublingual lozenges or pastilles. These dosage forms are prepared by mixing the active ingredient with flavored, rapidly dissolving or rapidly disintegrating excipients. For example a suitable base would comprise starch, lactose, sodium saccharin and talc.

Parenteral means can also be used for administering the compounds of this invention. They may be incorporated into implantable, slow-dissolving pellets or into aqueous injectable suspensions or solutions, or oily injectable media such as fixed oils.

In general, the parenteral forms should be prepared just prior to use.

The compounds of this invention may also be administered by inhalation of a mist. The active compound may be dissolved or suspended in an aerosol propellant or suitable carrier liquid and loaded into a standard aerosol container with suf cient propellant to provide the proper pressure for dispensing the compound. These pro Pellants are usually fluorinated or fluorochlorinated lower saturated aliphatic hydro carbons. The active ingredient is then dispensed through a special valve in the form of a fine mist which is inhaled.

The great potency of 1,8-dimethyl-3- (2-methyl-1-butyl)-7-carbo OMthoxyxanthine and 1,8-dimethyl-3- (2-methyl-I-butyl) xanthine makes them preferred compounds for aerosol administration, like epinephrine and iso Proterenol, to abort acute attacks. Aerosols of theophylline and its salts have been tried in the art, but the high doses required for these drugs to be efficacious and the rtSUltlng toxic reactions make this mode of administration impractical.

As is well-known in the pharmaceutical art, it is necessary in compounding dosage forms to avoid incompatibilities between ingredients. In formulating dosage forms containing the compounds of this invention, it is necessary to avoid combinations of ingredients which will result in the instability of the active compound if the dosage forms are to be stored for long periods of time. The particular incompatibilities to be avoided to attain this goal will be evident to one skilled in the art for each particular dosage form. Thus, for example, aqueous dosage forms of some of these compounds cannoi be stored for long periods of time; however, they are perfectlv satisfactory forms forms if prepared immediately before administration.

It is preferred to administer the bronchodilator and antiallergy compounds of this invention orally in the form of tablets or capsules. Preferred dosage ranges in humans Ire from 2 to 50 mg. The following examples illustrate the practice of this invention but art not intended to limit its scope.

Example 1.

Synthesis of 1, 8-dimethyl-3- (2-methyl-l-butyl) xanthine Step 1 1-methyl-3- (2-methyl-l-butyl) urea (1)

1.03 kg (11.8 mole) of 2-methyl-l-butylamine was added to 4.5 L of chloroform and the solution cooled to 0-5 C.

Then 674.0 g (11.8 mole) of methyl isocyanate was added slowly while maintaining the temperature at 0.5 C.

After the addition was complete the reaction was allowed to reach room temperature. Stirring was continued for 18 hours.

The chloroform was removed under vacuum to yield ~1. 7 kg of 1-methyl-3 (2-methyl-l-butyl) urea (I)-an oil. Yield 100% Step 2 1-methyl-1-cyanoacetyl-3- (2-methyl-1-butyl) urea (2)

To #1. 7 kg (11.8 mole) of 1-methyl-3-(2-methyl-1-butyl) urea (1) were ~ 4.3 L of acetic anhydride and 1.18 kg (13.9 mole) of cyanoacetic acid. This was heated for 2 hr. @ 60-70 C.

The acetic anhydride was removed under vacuum to yield ~2. 9 kg of an oil.

This material is a mixture of cyano acetic acid and 1-methyl-1-cyanoacetyl-3-(2 methyl-1-butyl) urea (2). No attempt was made at purification ; (2) was used immediately in the next step.

Step 3 4-amino-l-methyl-3- (2-methyl-l-butyl) uracil (3)

10.3 L of 10 /, NaOH solution was slowly added to 2.9 kg (11.8 mole) of crude l-methyl-l-cyanoacetyl-3- (2-methyl-1-butyl) urea (2) with stirring.

The oil dissolved and shortly another oil precipitated. The temperature rose to -60 C and then dropped.

After stirring for a while at room temperature the oil crystallized.

After cooling the product was filtered. The crude product was slurried in water and dried @ 50 C in vacuo to yield ~2. 1 kg of 4-amino-1-methyi-3-(2-methyl-1butyl) uracil (3) (m. p. 121-124 C). Yield 85 ó from fl).

Step 4 4-amino-5-nitroso-1-methyl-3-2-methyl-1-butyl) uracil 4)

21 kg (9.9 mole) of 4-amino-1-methyl-3-(2-methyl-1-butyl)uracil (3) was suspended in 22.0 L of water. A solution of 745. 5 g (10.8 mole) of sodium nitrite in 5. 7 L of water was added to the suspension. Then 1.2 L of glacial acetic acid was added dropwise and the suspension was stirred for 18 hr. at room temperature.

After cooling the precipitate was filtered. The crude product was slurried in water and dried @ 80 C in vacuo to yeld #1. 9 kg of 4-amino-5-nitroso-1-methyl-3 (2-methyl-1-butyl) uracil (4) (m. p. 202-204 C). Yield 80%.

Step 5 4, 5 4, 5-diamino-1-methyl-3- (2-methyl-1-butyl) uracil f S)

8.65 L of conc. ammonium hydroxide (58 /) was added to 1. 9 kg (7.9 mole) of 4-amino-5-nitroso-l-methyl-3- (2-methyl-l-butyl) uracil (4). An orange salt formed.

The suspension was placed in an oil bath at 80-90 C and a solution resulted.

5.6 kg (32.3 mole) of sodium dithionite was added in portions over about 30 min.

When the addition was complete stirring was continued for 30 min.

The reaction was allowed to cool to room temperature and stirred overnight.

After cooling the precipitate was filtered, slurried with water and dried @ 80 C in vacuo to yield #1.25 kg of 4n5-diamino-l-methyl-3-(2-methyl-l-butyl) uracil (5) (m. p. 161-163 C). Yield 70%.

Step 6 4-amino-5-acetylamino-1-methyl-3- (2-methyl-l-butyl) uracil (6)

1.25 kg (5. 5 mole) of 4a5-diamino-l-methyl-3-(2-methyl-l-butyl) uracil (5) was added to 4.5 L of glacial acetic acid and heated to reflux for 2 hrs.

The acetic acid was evaporated and the residue triturated with ether. The solid was filtered and dried @ 60 C in vacuo to yieid-1. 26 kg. of 4-amino-5-acetylamino 1-methyl-3- (2-methyl-l-butyl) uracil (6) (m. p. 178-182 C). Yield 85C/.

Step 7 Step 8-dimethyl-3- (2-methyl-I-h utyl) xan th ine (7)

1.26 kg (4.7 mole) of 4-amino-5-acetylamino-l-methyl-3-(2-methvl-l-butvl)- uracil (6) was added to 3. 9 L of 10% sodium hydroxide solution and heated at reflux for 30 min.

The solution was filtered and the filtrate cooled to room temperature.

The pH of the filtrate was adjusted to 5.0 with glacial acetic acid.

After cooling the precipitate was filtered. The crude product was slurried twice with water and dried @ 80 C in vacuo to yield about 1.0 kg of 1, 8-dimethyl-3- (2 methyl-1-butyl) xanthine (7) (m. p. 189-191 C). Yield 85%.

Example 2.

1, 3-dialkylxanthines and 1,3,8-trialkylxanthines By the procedure of Example 1 a number of 1,3-dialkylxanthines and 1,3,8 trialkylxanthines are synthesized. By proper choice of the reagents containing the precursors of the Rl, R, and R, groups the particular compounds are synthesized. R, and R, are determined by the reagents reacted in Step 1, R, is determined by the carboxylic acid reagent used in Step 5. Table 1 shows the reagents used in Steps 1 and 5 to introduce R1, R,, and R8, and produce the listed compound.

TABLE 1

STEP 1 STEP 5 No. Compound isocyanate amine acid 4315 1 methyl 3 methyl isocyanate n-butylamine formic acid (n-butyl)- xanthine 4258 1-methyl-3-methyl isocyanate isobutylamine formic acid (isobutyi) xanthine 6806 1-methyl-3-methyl isocyanate pentylamine formic acid (n-pentyl) xanthine 4280 DL-1-methyl-methyl siocyanate 2-methylbutyl-formic acid 3-(2-methyl-1-amine butyl)-xanthine 4340 1-methyl-3-methyl isocyanate 2,2-dimethyl- formic acid (2, 2-dimethyl- propylamine 1-propyl) xanthine 6840 1, 8-dimethyl-3- methyl isocyanate n-butylamine acetic acid (n-butyl) xanthine 4506 1,8-dimethyl- methyl isocyanate pentylamine acetic acid 3-n-pentyl- xanthine 4500 1,8-dimethyl- methyl isocyanate isopentylamine acetic acid 3-isopentyl xanthine 6738 1, 8-dimethyl-3- methyl isocyanate neopentylamine acetic acid (2,2-dimethyl propyl)-xanthin 6796 D-1, 8-dimethyl- methyl isocyanate D-2-methyl-l-acetic acid 3- (2-methyl-l- butylamine butyl) xanthine 6807 L-1, 8-dimethyl- methyl isocyanate L-2-methyl-1- acetic acid 3-(2-methyl-1- butylamine butyl) xanthine 4490 DL-1-methyl-3- methyl isocyanate 2-methyl-1- propionic acid (2-methyl-l-butylamine butyl)-8-ethyl xanthine 4489 DL-1-ethyl-3-ethyl isocyanate 2-methyl-1- acctic acid (2-methyl-butyU-butylamme 8-methyl xanthine TABLE 1 (Continued)

STEP 1 STEP 5 No. Compound isocyanate amine acid 4495 DL-1, S-diethyl- ethyl isocyanate 2-methyl-1-propionic acid 3-(7-methyl-1-butylamine butyl)xanthine 4388 1 8-dimethyl-methyl isocyanate isobutylamine acetic acid 3-i sobuty l xanthine Example 3.

1, 8-dimethyl-3-(2-methyl-1-butyl) xanthine-7-carboxylic acid, methyl ester

1.0 kg (4.0 mole) of 1, 8-dimethyl-3-(2-methyl-1-butyl) xanthine was suspended in 19.0 L of dry tetrahydrofuran.

288.0 g of sodium hydride (50% in oil) (6.0 mole) was washed with anhydrous ether and was then carefully added to the suspension.

The suspension was stirred for 1 hr. (a solution resulted).

567.0 g (4.0 mole) of methyl chloroformate was slowly added.

After addition was complete the reaction was heated to reflux for 18 hrs.

Then the reaction was filtered hot. The filtrate was evaporated and the residue triturated with hexane. The resultant solid was washed with a little ether, filtered and dried @ 40 C in vacuo to yield-1. 0 kg of 1, 8-dimethyl-3-(2-methyl-1-butyl) xanthine-7-carboxylic acid, methyl ester (m. p. 110-112 C). Yield 82%.

Example 4.

1,3-dialkylxanthine- and 1,3,8-trialkylxanthine-7-carboxylic acid esters By the procedure of Example 3 using the corresponding 1,3,8-trialkylxanthine and ester of chloroformic acid listed in Table 2, the 1,3-dialkylxanthine- and 1,3,8-trialkyl xanthine-7-carboxylic acid esters listed in Table 2 are prepared.

TABLE 2

Reagents No. Product Xanthine Chloroformic Ester 6896 1-methyl-3- (n-butyl)- 1-methyl-3- (n-butyl)- methylchloroformate xanthine-7-carboxylic xanthine acid, methyl ester 4274 1-methyl-3- (isobutyl) 1-methyl-3- (isobutyl)- methylchloroformate xanthine-7-carboxylic xanthine acid, methyl ester 6865 1-methyl-3- (n-pentyl) 1-methyl-3- (n-pentyl)- methylchloroformate xanthine-7-carboxylic xanthine acid, methyl ester 4380 1-methyl-3-(2-methyl-1-methyl-3-(2-methyl-methylchloroformate 1-butyl) xanthine-7- 1-butyl) xanthine carboxylic acid, methyl ester 6854 1-methyl-3- (2, 2- 1-methyl-3- (2, 2- methylchloroformate dimethyl-1-propyl) dimethyl-1-propyl) xanthine-7-carboxylic xanthine acid, methyl ester 6892 1, 8-dimethyl-3-(n- 1,8-dimethyl-3- methylchloroformate butyl)-xanthine-7- (n-butyl) xanthine carboxylic acid, methyl ester 4507 1,8-dimethyl-3-n 1,8-dimethyl-3-n- methylchloroformate pentylxanthine-7-pentylxanthine carboxylic acid, methyl ester 4505 1, 8-dimethyl-3-iso- 1, 8-dimethyl-3- methylchloroformate pentyl-xanthine-7-isopentylxanthine carboxylic acid, methyl ester 6897 1.8-dimethyl-3- (2, 2- 1, 8-dimethyl-3- methylchloroformate dimethylpropyl) xanthine (2,2-dimethyl propyl) 7-carboxylic acid, xanthine methyl ester 4390 1, 8-dimethyl-3-iso- 1,8-dimethyl-3- methylchloroformate butylxanthine-7-isobutylxanthine carboxylic acid, methyl ester 6919 D-1. 8-dimethyl-3-(2- D-1,8-dimethyl-3-(2- methylchloroformate methyl-1-butyl) xanthine methyl-1-butyl)- 7-carboxylic acid, xanthine methyl ester TABLE 2 (Continued)

Reagents No. Product Xanthine Chloroformic Ester 6938 L-1, 8-dimethyl-3- (2-L-1, 8-dimethyl-3-(2-methylchloroformate methyl-1-butyl) xanthine- methyl-1-butyl)- 7-carboxylic acid, xanthine methyl ester 4491 DL-1-methyl-3-(2-DL-1-methyl-3-(2-methylchloroformate methyl-1-butyl)-8-ethyl-methyl-1-butyl)-8- xanthine-7-carboxylic ethylxanthine acid, methyl ester 4494 DL-l-ethyl-3- (2-methyl- DL-l-ethyl-3- (2- methylchloroformate 1-butyl)-8-methyl-methyl-butyl)-8 xanthine-7-carboxylic methylxanthine acid, methyl ester 4498 DL-1, 8-diethyl-3-(2-DL-1, 8-diethyl-3-(2-methylchloroformate methyl-1-butyl) xanthine- methyl-1-butyl)- 7-carboxylic acid, xanthine methyl ester 4477 DL-1, 8-dimethyl-3- (2- DL-1, 8-dimethyl-3- (2- ethyl chloroformate methyl-1-butyl) xanthine methyl-1-butyl) ethyl ester xanthine 4488 DL-1, 8-dimethyl-3- (2- DL-l, 8-dimethyl-3- (2- n-propyl chloroformate methyl-l-butyl) xanthine- methyl-l-butyl) 7-carboxylic acid, xanthine n-propyl ester 6852 DL-1, 8-dimethyl-3- (2- DL-1, 8-dimethyl-3- (2- 2-chloroethylchloro- methyl-1-butyl) xanthine-methyl-1-butyl)-formate 7-carboxylic acid, xanthine 2-chloroethyl ester 6860 DL-1, 8-dimethyl-3- (2- DL-1, 8-dimethyl-3- (2- phenylchloroformate methyl-1-butyl) : canthine- methyl-1-butyl)- 7-carboxylic acid, xanthine phenyl ester In the following comparative examples results of pharmacological tests with a number of the compounds of this invention and of the prior art are presented. The pharmacological properties were evaluated by standard tests which are defined, together with the symbols used as follows: BD Bronchodilator activity evaluated against histamine-induced bronchocon striction in the guinea pig, and expressed as /O protection at the stated time interval (in minutes and hours) post-drug against histamine agonist. Doses are expressed in milligrams per kilogram or body weight (mpk) per os (po) or intraperitoneally (ip).

A modification of the method of Siegmund. O. H., et. al., J. Pharmacol. and Exp.

Therap. 90 : 254-9, 1947, is used. Healthy guinea pigs weighing from 250 to 300 grams are placed four at a time and separated by wiring screening in an 11 liter plastic @@ the time of @eek activity following drug administration. The challenge consists of histamine diphosphate (1% solution) aerosolized in a de Vilbiss #40 nebulizer at 200 mg Hg. ("de Vilbiss"is a Registered Trade Mark). Times for prostration are recorded. All animals exposed to the aerosols for 10 minutes or longer without prostration, are arbitrarily considered fully protected.

Per cent protection is calculated as follows : 100 (Test prostration time-control prostration time) % Protection = 600-control prostration time wherein the times are measured in seconds.

CP Cardiopulmonary activity evaluated against histamine-induced bronchocon striction in the dog and expressed as % increase (T) or decrease () in the following parameters: BP blood pressure HR heart rate PR pulmonary resistance PC pulmonary compliance RMV respiratory minute volume The method used is that of Giles, R. E., Finkel, N. P., and Mazurowski, J., Arch. Int. Pharmacodyn. Therap. 194, 213 (1971). A simulated asthmatic state is induced in anesthetized spontaneously breathing dogs by graded intravenous doses of histamine. The degree of induced bronchoconstriction is reflected by proportionate increases in pulmonary resistance. Pretreatment with bronchodialtor drugs aims to block the bronchospastic response to histamine. Each dog serves as its own control.

Mean values 2 hours post drug are given.

SP Spasmolytic activity evaluated in vitro using guinea pig tracheal chain prepartion, and expressed as the molar (M) concentration required to produce maximum relaxation.

The method used is that of Castillo and de Beer, J. Pharmac. Expt. Therap. 90, 104,1947.

AA Antiallergy (anti-anaphylactic) activity evaluated against antigen-induced bronchoconstriction in rats sensitized with N. brasliensis, and expressed as % protection (R).

The method used is that of Church, N. K., Collier, H. O. J., and James, G. W. L., Brit. J. Pharmacot. 46, 5965 (1972).

Rats sensitized with antigen from Nippostrongylus brasiliensis exhibit anaphylactic shock when re-exposed to this antigen 28 days later. The animals are subdivided into control and test groups.

Test animals receive a drug either orally, intraperitoneally or intravenously and are challenged with intravenous antigen at fixed time intervals after dosing. Antigeninduced increases in tracheal pressure are monitored and reflect the extent of bronchoconstriction.

PCA Antinaphthylactic activity against passive cutaneous anaphylaxis in the rat, expressed as % protection against antigen-induced wheal formation.

The method used is that of Ogilvie, B. M., Immunology 12, 113-131 (1967).

Reaginic AgE antibodies develope in the rat following subcutaneous injection of Nippostrongylus brasiliensis larvae. Antisera, collected 28 days later are injected subcutaneously into new rats. These new rats when challenged with antigen 24 hours later exhibit an immediate type I reaction characterized by local swelling and edema (wheal) at the site of antisera injection.

LDso Dose required to cause death of 50% of test animals.

The LD50 was determined in three species, the mouse (male 18-25 g), the albino rat (female, 15 v 200 g) and the albino guinea pig (male, 180-280 g) by oral administration and in the albino rat by intraperitoneal administration. The animals are fasted overnight prior to testing. Six groups of ten animals are used; five groups are dosed with the test substance, the sixth group serves as a control and receives the drug vehicle at the highest test concentration. The compounds were administered in a 0.5% gum tragacanth solution in distilled water using a constant logarithmic increment dose. Dose volume ranged from 5 to 40 mg/kg.

The animals were housed five per cage (rat and guinea pig) or ten per cage (mouse) with free access to food and water. The number of dead animals was recorded daily for five consecutive days. The total mortality per group of ten for each dose level was recorded and LD,, with Confidence Limits calculated according to the method described by Weil, C. S., Biometrics 8 (3): 249-263, 1952.

Example 5.

This Example illustrates the superiority of 7-carboalkoxyxanthines over the corresponding 7-H xanthines. Several pairs of compounds were tested in a number of assays as described above.

The results may be seen in Table 4 wherein corresponding xanthines with and without the 7-carbomethoxy group are compared, it being noted that some of the compounds appearing in the Table are known and included for comparison only. The effect can be seen most clearly by comparing the potency of the compounds in the bronchodilation assay in the guinea pig (BD [guinea pig] In interpreting the BD data it should be noted that a dose giving less than 40 30% protection is not considered useful. Differences in percent protection of less than 10% are probably not significant. 4378 gives 96% protection at 1 hour at a dose of 60 mpK while the corresponding compound devoid of the 7-carbomethoxy groups, 4296, gives only 53% protection at the larger dose of 100 mpK. Clearly, the 7carbomethoxy derivative is superior. 4274 gives greater protection than 4258 at equal doses. In comparing 4387 and 4383 at equal doses (10 mpK) it can be seen that the 7-carbomethoxy compound 4387 shows greater activity. Although both of these compounds are already very potent, the benefit of the 7-carbomethoxy group is particularly evident in the dog at 1 mpK. Another comparison shows that 4260 is clearly superior to theophylline at the same dose (80 mpK).

TABLE 3 EFFECT OF 7-CARBOMETHIOXY GROUP ON POTENCY

BD (guinea pig) AA (rat SP (in vitro) LD50 CPD. R1 R3 R8 R7 mpK 30' 1h 2h 4h 6h 10h mpK 1h C mpK spec 4296 CH3 CH3 CH3 H 100po 53 45 43 23 150po 68 80 71 79 86 85 75ip 49 M/14 4378 CH3 CH3 CH3 COOCH3 60po 96 95 89 75ip 54 M/10 * 4258 CH3 CH2CHMe2 H H 15po 45 75 39 1.5ip 79 M/1000 * 25po lethal 2/4 2.0ip tox 4274 CH3 CH4CHMe2 H COOCH3 150po 92 87 64 18 5ip 74 M/2000 40po lethal 1/6 4383 CH3 CH2CHMeEt CH3 H 10po 35 63 66 2.5po 58 M/1000 21.7po g.pig 20po 92 100 97 24.6ip rat 88.7 po rat 60.6po mouse 4387 CH3 CH2CHMeEt CH3 COOCH3 10po 44 87 59 37 M/1000 37.4po g.pig 20po 94 92 2.5po 72 54.9po mouse 5po 68 10po 57 5ip 55 18.3ip rat 60.0po rat 75ip 70 Theo- CH3 CH3 H H 80po 32 69 42 17 25po 50 M/10 183po g.pig phyline 100po 45 58 36 25 14 100po 73 225po rat 150ip rat 4260 CH3 CH3 H COOCH3 80po 99 100 86 95 0 75ip 82 M/20 * * for comparison.

Example 6.

This Example illustrates the prolonged activity of the 8-alkylxanthines over that of the corresponding 8-H compounds. The increased and prolonged activity of the 1, 3,8-trialkyl-7-carboalkoxyxanthines relative to that of the 1, 3-dialkyl-7-carboalkoxyxanthines may be seen in Table 4 which compares the activity of corresponding pairs of substituted xanthines with and without 8-alkyl groups, it again being noted that known xanthine compounds appear in the Table for comparative purposes.

The data on bronchodilator activity in the guinea pig (BD [guinea pig]) show the prolonged activity of the compounds having an 8-alkyl group. In each pair the protection at 4 hours or 6 hours produced by the 8-methyl compound is greater than the protection by the corresponding compound devoid of the 8-methyl group. For pairs 4387 vs. 4380,4390 vs. 4274,4378 vs. 4260, pairs 4383 vs. 4280,4388 vs. 4258 and 4296 vs. theophylline the 8-methyl derivatives are shown to be effective at lower doses and for longer duration than the 8-H compounds. This phenomenon is attri buted to the 8-alkyl substituted interfering with the normal bioinactivation of 1,3 dialkylxanthines by enzymatic oxidation at the 8-position, and was not anticipated by the teachings of the prior art on xanthine compounds.

TABLE 4 PROLONGED ACTIVITY OF 8-ALKYLXANTHINES

BD (guinea pig) AA rat) SP in vitro LD50 Cpd. R1 R3 R5 R7 mpK 30' 1h 2h 4h 6h 10h mpK 1h C mpK spec.

4274 CH3 CH2CHMe2 H COOCH3 15po 92 87 64 18 5ip 74 M/2000 40 po lethal 1/6 4390 CH3 CH2CHMe2 CH3 COOCH3 10po 49 86 79 48 2ip 60 M/1000 25.2po g.pig 4ip 52 27.6po mouse 2.5po 77 9.1ip rat 33.5po rat 4260 CH3 CH3 H COOCH3 80po 99 100 86 95 0 75ip 82 M/20 * 4378 CH3 CH3 CH3 COOCH3 60po 96 95 89 75ip 54 M/10 * 4380 CH3 CH2CHMeEt H COOcH3 40po 99 57 12 5po 66 M/700 20po 64 4387 CH3 H2CHMeEt CH3 COOCH3 10po 44 87 59 37 M/1000 27.4po g.pig 20po 94 92 2.5po 72 54.9po mouse 5po 68 10po 57 18.3po rat 60.0po rat TABLE 4 PROLONGED ACTIVITY OF 8-ALKYLXANTHINES

BD (guinea pig) AA (rat) SP in vitro LD50 Cpd. R1 R3 R8 R7 mpK 30' 1h 2h 4h 6h 8h mpK 1h C mpK spec.

4280 CH3 CH2CHMeet H H 20po 86 86 80 13 15ip 56 M 1000 * 80po lethal 3/8 4383 CH3 CH2CHMeEt Ch3 H 10po 35 63 66 21/2po 58 M 1000 21.7po g.pig 20po 92 100 97 4ip 57 24.6ip rat 88.7po rat 66.6po mouse 4258 CH3 CH2CHMe2 H H 15po 45 75 39 1.5ip 79 M 1000 * 25po lethal 2/4 2.0ip tox 4388 CH3 CH2CHMe2 CH3 H 10po 76 73 80 2.5po 50 M 1000 20po lethal 1/4 Theo- CH3 CH3 H H 80po 32 69 42 17 75ip 70 M 10 183po g p@g phylline 100po 45 58 36 25 14 225po 50 225po rat 100po 73 150ip rat 4296 CH3 CH3 CH3 H 100po 53 45 43 23 * 150po 68 80 71 79 86 85 75ip 49 M 14 * for comparison.

Example 7.

This Example illustrates, in some instances by reference to known compounds for ^omparison, the decreased toxicity of substituted xanthines having R=2-methyl-1- butyl over those having R3=isobutyl while the potency of the compounds remains approximately equal.

The unexpected improvement in activity of 1-alkyl-3-(2-methyl-1-butyl)-7- carbomethoxy xanthines, without a corresponding increase in toxicity with reference to the corresponding 3-isobutyl homologs can be seen in Table 5 where the data for corresponding pairs of compounds is presented. This effect is seen most clearly in the pair 4387 vs. 4390. The effectiveness of the 7-carbomethoxy compounds can be compared in the bronchodilation assay in the guinea pig and the antiallergy assay in the rat. The effectiveness data show that the 1-methyl-3-(2-methyl-1-butyl)-8-methyl- 7-carbomethoxyxanthines (4387) is about as effective as the corresponding 3-isobutyl compound (4390) in the guinea pig, rat and dog assays. Yet 4387 is only about one-half as lethal as 4390 in the rat and mouse. Likewise, in the guinea pig toxic effects can be seen in the case of the xanthines having the 3-isobutyl group, while at the same dose the corresponding compound having the 3-(2-methyl-1-butyl) group is effective and non-toxic.

Among the 1,3,8-trialkylxanthines, 4383 has about the same bronchodilation potency as 4388 in the BD (guinea pig) assay at a dose of 10 mpK per os ; yet at a dose of 20 mpK po 4383 shows no toxic effects while 4388 shows pronounced toxicity and was even lethal to one animal.

4280 and 4258 show about equal potency as shown by the results for doses of 20 mpK po and 15 mpK po respectively; however 4258 shows lethal effects at only 25 mpK po while 4280 must be given at a dose of 80 mpK po to show similar lethal effects.

Clearly, the xanthines having a 2-methyl-1-butyl group in the 3-position are less toxic than those having a 3-isobutyl group.

TABLE 5 EQUAL ACTIVITY WITHOUT INCREASED TOXICITY 3-(2-METHYLBUTYL) VS. 3-ISOBUTYL

BD (guinea pig) AA (rat) SP in vitro LD50 Cpd. R1 R3 R5 R7 mpK 30' 1h 2h 4h 6h 10h mpK 1h C mpK spec.

4390 CH3 CH2CHMe2 CH3 COOCH3 2ip 60 M/1000 25.2po g.pig 10po 49 86 79 48 4ip 52 27.6po mouse 20po lethal 1/2 91ip rat 2.5po 77 33.5po rat 4387 CH3 CH2CHMeEt CH3 COOCH3 10po 44 87 59 37 M/1000 27.4po g.pig 20po 94 92 2.5po 72 54.9po mouse 5po 68 10po 57 5ip 55 18.3 ip rat 60.0po rat 4274 CH3 CH2CHMe2 H COOCH3 15po 92 87 64 18 5ip 74 M/2000 40po lethal 1/6 4380 CH3 CH3CHMeEt H COOCH3 40po 99 57 12 5po 66 M/700 20po 64 TABLE 5 EQUAL ACTIVITY WITHOUT INCREASED TOXICITY 3-(2-METHYLBUTYL VS. 3-ISOBUTYL)

BD (guinea pig) AA (rat) SP in vitro LD50 R1 R3 R5 R7 mpK 30' 1h 2h 4h 6h 8h mpK 11h C mpK spec.

4388 CH3 CH2CHMe2 CH3 H 10po 76 73 80 20po lethal 1/4 2.5po 50 M/1000 4383 CH3 CH2CHMeEt CH3 H 10po 35 63 66 2.5po 58 M/1000 21.7po g.pig 20po 92 100 97 24.6ip rat 88.7po rat 66.6po mouse 4258 CH3 CH2CHMe2 H H 15po 45 75 39 1.5ip 79 M/1000 25po lethal 2/4 2.0ip tox 4280 CH3 CH2 CHMeEt H H 20po 86 86 80 13 15ip 56 M/1000 * 80po lethal 3/8 * for comparison.

Example 8.

This Example illustrates (again with reference to known xanthines) the activity of substituted xanthines according to this invention and the variation in pharmacological effects produced by introducing different R, substituents.

Table 6 shows the results of the bronchodilation assay described above in the guinea pig for a series of 1,3-dialkyl and 1, 3,8-trialkylxanthine-7-carboxylates in which the R, group was varied. The most effective compounds are those in which the lowest dose produces an acceptable bronchodilation (-40%). Data is also included showing effectiveness in the antiallergy assay in the rat, and the in vitro bronchodilation activity.

The data for the effectiveness of the compounds shown in the Table 6 teaches that the activity of xanthine bronchodilators depends not only upon the total number of carbon atoms comprising R,, R3, and R, but also upon the distribution of these carbon atoms among R"R3, Rs and R, and especially upon the branching within the structure of the R, group.

Maximum activity is obtained when R, =R8=R=methyl and R3 is a C, or Cs alkyl group. Peak activity is obtained when the alkyl group of R,, is branched at the number 2 carbon

as in 2-methyl-1-butyl.

Optimal activity, i. e., maximum activity with relatively lowest toxicity is obtained when R, is a 2-methyl-l-butyl group. Of all the possible C, and C : alky ! groups, only the 2-methyl-1-butyl group is both primary and asymmetric, i. e., capable of existing as dextro and levo forms.

TABLE 6 BRONCHODILATION ACTIVITY OF 1,3,8-TRIALKYL7-CARBOMETHOXYXANTHINES

BD (guinea pig) AA (rat) SP in vitro CK R1 R3 R5 R7 mpK 30' 1h 2h 4h 6h 10h mpK 1h C 4274 CH3 CH2CHME2 H COOCH3 15po 92 87 64 18 5ip 74 M/2000 40po lethal 1/6 4380 CH3 CH2CHMeEt H COOCH3 40po 99 57 12 5po 66 M/700 20po 64 4377* CH3 CH2CHMePr H COOCH3 80po 72 0 20po 64 4378* CH3 CH3 CH3 COOCH3 60po 96 95 89 75ip 54 M/10 4390 CH3 CH2CHMe2 CH3 COOCh3 2ip 60 M/1000 10po 49 86 79 48 4ip 52 2.5po 77 4387 CH3 CH2CHMeEt CH3 COOCH3 10po 44 87 59 37 M/1000 20po 94 92 2.5po 72 5po 68 10po 57 5ip 55 4477 CH3 CH2CHMeEt CH3 COOC2H5 10po 47 87 50 4488 CH3 CH3CHMeEt CH3 COOC3H7(n) 10po 24 44 20o 78 68 40po 100 89 80po lethal 1/4 TABLE 6 (Continued)

BD (guinea pig) AA (rat) SP in vitro CK R1 R3 R5 R7 mpK 30' 1h 2h 4h 6h 8h mpK 1h C 4491 CH3 CH2CHEt C2H2 COOCH3 10po 25 21 40po 52 Mc 4494 C2H5 CH2CHEt CH3 COOCH3 10po 0 49 40po 9 80 Mc 80po lethal 2/2 4498 C2H5 CH2CHEt C2H5 COOCH3 40po 15 38 80po 63 79 Mc 4507 CH3 CH2(CH2)3Me CH3 COOCH3 10po 26 20po 52 40po 100 63 80po lethal 2/2 4505 CH3 CH2CH2CHMe CH3 COOCH3 10po 15 40po - Me 80po lethal 3/5 4515* CH3 CH2CHCH2Et CH3 COOCH3 20po 7 40po 100 Mc 4373* CH3 CH2CHMePr CH3 H 40po 71 87 96 20ip 54 M 20 80po 81 100 * for comparison.

Example 9.

This Example illustrates the antiallergy properties of the compounds of this invention.

1,8 - dimethyl - 3 - (2 - methyl - 1 - buty) - 7 - carbomethoxyxanthine, 1,8dimethyl - 3 - isobutyl - 7 - carbomethoxyxanthine and 1,8 - dimethyl - 3 - (2methyl - 1 - butyl)xanthine were tested in the rat passive cutaneous anaphylaxis screen describ3ed above, The date in Table 6 shows that these compounds are effective antiallergy agents.

TABLE 7 PERCENT PROTECTION IN THE RAT PASSIVE CUTANEOUS ANAPHLAXIS SCREEN

Dose Wheel Diameter (cm)# Mean ~ S.E.M. Wheal Intensity : Mean ~ S.E.M.

(mg/kg) No. Compound & Route Control Response % # Control Response % # 4387 1,8-dimethyl-3-(2-methyl-1-butul)- 10po 2.39 ~ 0.10 1.41 ~ 0.17 41 2.46 ~ 0.13 1.65 ~ 0.20 33 7-carbome thoxyxanthine 20po 1.90 ~ 0.15 0.81 ~ 0.13 57 1.91 + 0.21 1.18 ~ 0.21 38 4380 1,8-dimethyl-3-isobutyl-7- 20po 1.86 ~ 0.15 0.74 ~ 0.21 60 2.35 ~ 0.21 1.10 ~ 0.23 53 carbomethoxyxanthine 4383 1,8-dimethyl-3-(2-methyl-1-butyl) 20po 1.50 ~ 0.16 0.74 ~ 0.16 50 2.17 ~ 0.21 1.13 ~ 0.27 48 xanthine Example 10.

This Example illustrates the effectiveness of the compounds of this invention in the dog.

The results of studies at cardiopulmonary activity in the dog by the above described procedures are shown in Table 8. The data show that compounds 4390, 4387, and 4383 significantly reduce the decrease in pulmonary compliance and increase in pulmonary resistance due to histamine administration. The corresponding values for theophylline, a clinically used xanthine bronchodilator, are shown for comparison. It can be seen that the three compounds of this invention are more potent bronchodilators than theophylline in the dog.

TABLE 8 : CARDIOPULMONARY ACTIVITY IN THE DOG

CP (dog) (mean value at 2h) mpK BP HR PC PR RMV 4387 1po #17 #40 #40 #61 #39 2po0316608510 3po #08 #8 #74 #100 #68 4po #25 #17 #42 #77 #76 4390 3po #07 #13 #70 #85 #41 Theophylline 40po #08 #06 #25 #36 #38 4383 1po #12 #21 #18 #36 #33 Example 11.

Tablets 19.5 grams of starch are dried to a moisture content of 10%. 0.5 grams of 1,8 dimethyl-3- (2-methyl-l-butyl)-7-carbomethoxyxanthine in finely powdered form are thoroughly mixed with the starch. The mixture is compressed into slugs. The slugs are reground into powder of 14-16 mesh size. This powder is recompressed into tablets weighing 200 mg. each. Each tablet thus has the composition: 1,8-dimethyl-3- (2-methyl-1-butyl)-7 carbomethoxyxanthine 5 mg Starch 195 mg Examples 12.

Capsules A dry mixture of 19.5 grams of starch and 0.5 grams of 1, 8-dimethyl-3-(2-merhyl- 1-butyl)-7-carbomethoxyxanthine is prepared as described in Example 11. The powder is loaded into hard gelatin capsules that each capsule contains 200 mg of the powder.

Example 13.

Sublingual Tablets Tablets for sublingual administration were prepared by standard procedure, each tablet containing 5 mg of 1, 8-dimethyl-3- (2-methyl-l-butyl)-7-carbomethoxyxanthine in a rapidly disintegrating base comprising starch, lactose, sodium saccharin and talcum.

Example 14.

Aerosol Five grams of 1, 8-dimethyl-3-(2-methyl-1-butyl)-7-carbomethoxyxanthine were dissolved in 1000 grams of a mixture of 20 parts by weight of dichlorodifluoromethane and 80 parts by weight of 1, 2-dichloro-1, 1, 2,2-tetrafluoroethane and loaded into a conventional aerosol medication dispenser to provide a means of administering the active ingredient by inhalation.

Claims (57)

WHAT WE CLAIM IS :-

1. A compound having the formula :-

wherein; R, = C,-C, alkyl ; R, =--CH,-- (C,-C,) alkyl or-CH,- (C,-C, cycloalkyl) ; R7=H or COOR in which R=C1-C4 alkyl, 2-halo C2-c3 alkykl or phenyl; and R,=H or Cl-C, alkyl, provided that R and R8 are not H simultaneously

2. A compound according to Claim 1 and having the general formula :-

wherein: R, =C,-C2 alkyl, R, =CH2-(C3-C4 alkyl), CH,- (C3-C4)-cycloalkyl, R8 = H, C1-C2 alkyl, R =ClVs alkyl, 2-halo- (Cz--3 alkyl), or phenyl.

3. A compound according to Claim 2 wherein R, =methyl.

4. A compound according to Claim 2 wherein Ra is n-butyl.

5. A compound according to Claim 2 wherein R3 is isobutyl.

6. A compound according to Claim 2 wherein R, is n-pentyl.

7. A compound according to Claim 2 wherein R3 is isopentyl.

8. A compound according to Claim 2 wherein R3 is 2-methyl-1-butyl.

9. A compound according to Claim 2 wherein R3 is cyclopropylmethyl.

10. A compound according to Claim 2 wherein R3 is cyclobutylmethyl.

11. A compound according to Claim 2 wherein R, is ethyl.

12. A compound according to Claim 2 wherein Rs is methyl.

13. A compound according to Claim wherein R is ethyl.

14. A compound according to Claim 2 wherein R is methyl.

15. 1, 8-Dimethyl-3-(3-methyl-1-butyl)-7-carbomethyoxyxanthine.

16. dextro-1, 8-dimethyl-3- (2-methyl-1-butyl)-7-carbomethoxyxanthine.

17. levo-1, 8-dimethyl-3-(2-methyl-1-butyl)-7-carbomethoxyxanthine.

18.1,8-Dimethyl-3-(2-methyl-1-butyl)-7-carboethoxyxanthine.

19. dextro-1, 8-dimethyl-3-(2-methyl-1-butyl)-7-carboethoxyxanthine.

20. levo-1, 8-dimethyl-3- (2-methvl-1-butyl)-7-carboethoxyxanthine.

21.1,8-Dimethyl-3- (2-methyl-1-butyl)-7-carbopropoxyxanthine.

22. 1-Methyl-3-(2-methyl-1-butyl)-7-carbomethoxyxanthine.

23. dextro-1-Methyl-3- (2-methyl-1-butyl)-7-carbomethoxyxanthine.

24. levo-1-Methyl-3- (2-methyl-1-butyl)-7-carbomethoxyxanth ine.

25. 1, 8-Dimethyl-3-isoburyl-7-carbomethoxyxanthine.

26.1,8-Dimethyl-3-isobutyl-7-carboethoxyxanthine.

27. A compound according to Claim 1 and having the general formula :

wherein: R, =methyl, R3=CH2-(C3-c1 alkyl), -CH2-(C3-C4)-cycloalkyl, and R, =C1-C2 alkyl.

28. A compound according to Claim 27 wherein Ra is isobutyl or 2-methyl-1butyl.

29. A compound according to Claim 27 wherein Ra is n-butyl.

30. A compound according to Claim 27 wherein R, is isobutyl.

31. A compound according to Claim 27 wherein R, is n-pentyl.

32. A compound according to Claim 27 wherein Ra is isopentyl.

33. A compound according to Claim 27 wherein R, is 2-methyl-1-butyl.

34. A compound according to Claim 27 wherein R3 is cyclopropylmethyl.

35. A compound according to Claim 27 wherein R, is cyclobutylmethyl.

36. A compound according to Claim 27 wherein Re is ethyl.

37. A compound according to Claim 27 wherein R, is methyl.

38. 1, 8-Dimethyl-3- (2-methyl-1-butyl) xanthine.

39. dextro-1, 8-dimethyl-3- (2-methyl-l-butyl) xanthine.

40. levo-1, 8-dimethyl-3-(2-methyl-1-butyl) xanthine.

41.1,8-Dimethyl-3-isobutylxanthine.

42. A process for preparing a compound as claimed in Claim 1 in which R, is COOR, which process comprises reacting a sodium salt of a 1, 3-dialkvl-or 1,3,8trialkylxanthine in which the 1-alkyl group is as defined for R, in Claim 1, the 3-alkyl group is as defined for R3 in Claim 1 and the 8-alkyl group is as defined for R, in Claim 1, with an alkyl chloroformate of formula CICOOR in which R is as defined in Claim 1.

43. A process as claimed in Claim 42 and substantially as hereinbefore described in Example 3 or Example 4.

44. A process for preparing a compound as claimed in Claim 1 in which R, is hydrogen which process comprises cyclizing a 4-amino-5-alkanoylamino-1, 3 dialkyluracil in which the 1-alkyl group is as defined for Ri in Claim 1, the 3-alkyl group is as defined for R3 in Claim 1 and the alkanoylamino group is of formula NHCOR8 in which Ra is as defined in Claim 1.

45. A process as claimed in Claim 44 and substantially as hereinbefore described in Example 2.

46. A compound as claimed in Claim 1 and obtained by a process as claimed in any one of Claims 42 to 45.

47. A pharmaceutical composition comprising an amount of a compound according to Claim 1 effective for bronchodilation in combination with a pharmaceutically acceptable carrier.

48. A composition according to Claim 47 in the form of a tablet.

49. A composition according to Claim 47 which is in the form of a capsule containing a compound as claimed in Claim 1 optionally in the form of a mixture thereof with a pharmaceutical carrier material.

50. A composition according to Claim 47 in the form of a sublingual tablet.

51. A composition according to Claim 47 wherein said diluent is an aerosol propellent.

52. A composition according to Claim 47 comprising 1,8-dimethyl-3- (2 methyl-1-butyl)-7-carbomethoxyxanthine dissolved in a pharmaceutically acceptable aerosol propellant.

53. A composition according to Claim 47 comprising 1,8-dimethyl-3- (2 methyl-1-butyl) xanthine dissolved in a pharmaceutically acceptable aerosol propellant.

54. A pharmaceutical composition in the form of a tablet comprising between 2 mg and 50 mg of a compound according to Claim 2 in combination with non-toxic pharmaceutically acceptable excipients.

55. A pharmaceutical composition in the form of a tablet comprising between 1 mg and 100 mg of a compound according to Claim 27 in combination with non-toxic pharmaceutically acceptable excipibents.

56. A compound according to Claim 1 and specifically identified herein.

57. A pharmaceutical composition substantially as described in any one of Examples 11 to 14.