CA1271597A - Biologically-active xanthine derivatives - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

Certain functionalized congeners of 1,3-dialkylxanthine exhibit high potency and selectivity as antagonists for A1- and A2-adenosine receptors and are suitable for attachment to probes, drug carriers, or solid supports. These derivatives are characterized by the presence of a phenyl at the 8 position para-substitued with a functionalized chain to provide high water solubility and high receptor affinity. Some of these analogs, containing a distal amino- or carboxylic-functionalized chain, are suitable for synthesis of amino acid conjugates. The compounds of this invention are suitable for use as antiallergenic, antiasthmatic, or cardiotonic drugs, central nervous system stimulants, and diuretics.

Description

~L~7~5~7 BIOLOGICALLY-ACTIVE XANTHINE DERIVATIVES

Background Certain functionalized congeners of 1,3-dial-kylxanthine exhibit high potency and selectivity as an-tagonists for Al- and A2-adenosine receptors and are suitable for attachment to probes, drug carriers, or solid supports. These derivatives are characterized by the presence of a phenyl or a phenyl substituent at the 8 position para-substituted with a functionalized chain to provide high water solubility and h~igh receptor affini~y to such an extent that these compounds are suitable for use as antiallergenic, antiasthmatic, or cardiotonic drugs, central nervous system stimulants3 and diuretics.
Alkylxanthines, of which theophylline is the most well known, represent a major class of antagonists for adenosine receptors. Although theophylline anà other xanthines such as caffeine are relatively weak adenosine antagonists, with affinity constants in the 10-50 micro-molar range, they owe many of their pharmacological ef-fects to blockage of adenosine mediated functions at theAl an~ A2 receptor sites noted above. The Al-adenosine receptor is inhibitory to adenylate cyclase and appears involved in antilipolytic, cardiac, and central depres-sant effects of adenosine. The A2-adenosine receptor is stimulatory to adenylate cyclase and is involved in hypo-tensive, antithrombotic, and endocrine effects of adeno-sine. Some xanthines, such as 3-isobutyl-1-methylxan-thine, not only block adenosine receptors but also have potent inhibitory effects on phosphodiesterases. In an effort to identify highly potent and specific analogs of adenosine receptor antagonists (xanthines) the "functi~n-alized congener approach~ was applied, as described in Jacobson et al, J._Med. Chem., 1983, Vol. 26, p. 492.
Analogs of adenosine receptor ligands bearing function-alized chains are synthesized and covalently attached to . ~

i~7~ 9~

various organic moieties7 such RS amines and peptides.The binding affinities (competitive CHA binding on rat cerebral cortex) and the specificity are modulated by changes in the attached moiety. The present invention discloses that the presence of a functionalized chain linked to the 8-phenyl group through a -0-CH2C0- linkage greatly enhances the potency of 1,3-dialkyl-xanthines as adenosine antagonists. Potent antagonists are produced by replacing the 1,3-methyl groups of 8-phenyltheophyl-line with n-propyl groups ancl by situating uncharged electron-donating p~ra-substituents on the 8-phenyl ring. Amino acid conjugates are syrnthesized in which an amino- acid "carrier" is linked through an amide bond to a functionalized xanthine congener. In addition to high potency, some of these 1,3-dipropyl-8-phenylxanthine derivatives exhibit selectivity toward either the Al- or A2-subclass of adenosine receptors. The amino congeners, in particular, exhibit improved water solubility and partition characteristics, permitting in vivo use of these congeners.
Many of the xanthines (such as theophylline) exhibit undesirable side-effects, such as cardiac stimu-lation. The present invention avoids or reduces these side-effects by developing compounds that are more potent or selective adenosine receptor blockers.
Furthermore, the Al-specific antagonists, such as compound 6d, are useful therapeutically in combination with a non-specific adenosine agonist. The net effect of such a combination is decreasing blood pressure (an Aa effect of the agonist) without a concomitant effect on the heart rate (since the Al-agonist effect of slowing the heart rate would be cancelled by the specific anta-gonist).
In the design of active covalent conjugates of drugs, the goals of the congener approach are several, including targeting, increasing the potency, prolonging the duratiorl of action, and/or changing the specificity, ~7 and prodrugs. As noted above, they are useful therapeu-tically as antiasthmatic and antiallergenic drugs. Non-therapeutic applications of these active functionalized drugs include receptor probes, immobilized ligands for affinity chromatography, and radiolabeled analogs.
A further benefit of applying the congener approach to xanthines is the opportunity to increase water solubility. The series of super-active 8-phenyl~
xanthines [PNAS, Vol. 80, p. 2077 (1983)] is highly non-polar with aqueous solubility vlry often falling below lUmicromolar, see Acta Physiol. Scand., ~ol. 122, pp 191-198 (1984). By increasing water solubility through the attachment of highly polar charged or uncharged groups at positions which are also favorable to potency as adeno-sine antagonists, it is possible to overcome undesirablebinding to plasma proteins and partition into lipidso This leads to improve pharmacokinetics of the drugs.
Some similar known compounds, such as the 8-arylxanthines, contain up to four substituents on the ~0 phenyl ring. These substituents usually contribute to the compound's insolubility in water. The present inven-tion not only discloses a single substituent on the phenyl ring, it also discloses a variety of charged and uncharged hydrophilic substituents attached to xanthine through a functionalized chain. The combination of nano-molar potency and water solubility (concentrations approximately 10,000-fold greater than the receptor affinity constants) in the compounds of the present invention indicate high potency~ plus increased absorp-tion.
General Description of the Invention The present invention discloses the synthesisof a series of highly potent congeners of theophylline and l,3-dipropylxanthine. ~ome of these congeners con-tain groups designed for radiolabeling through introduc-tion of radioisotopes of elements such as iodine, carbon, fluorine, or through metal complexes. The radioisotope 1~'715 is attached by linking the drug to a "radioisotope accep-tor" or prosthetic group, which is specially designed for the facile introduction of a particular isotope. These radiolabeled compounds have high adenosine receptor af-finities. Those that contain short-lived positron emit-ters, such as l3F, are potentially useful for the de-velopmental diagnostic technique of positron emission tomography. Other functionalized congeners of this in-vention are suitable for the preparation of affinity columns. The amino congeners of l,3-dipropylxanthine (including those bearing attachled chains derived from ethylene diamine) produce affinity constants in the l0 9 to l0 molar range, favoring high potency as well as im~oved solubility characteristics.
As noted above, the compounds of the invention are characterized by the presence of lower alkyl groups such as n-propyl groups at the l and 3 position on the theophylline ring and by R variety of para-substituents on the 8-phenyl ring. It should be noted, however, that some of the compounds of this invention retain the dim-ethyl groups of theophylline. The compounds of this invention are of the general formula:
Formula l: H ~ ~R

R3-C-G~-o ~ I~ O

wherein Rl and R2 = a carbon chain of 1-6 carbons;
R3 = hydroxy, , alkoxy, aryloxy, ~-oxyimide; or wherein R3 = R4RSN
wherein R5 is hydrogen, alkyl, aryl~ or alkylaryl groups; and wherein R4 = R5 or X (CH2)n wherein X = primary, secondary, or tertiary amino group; or secondary or tertiary amino i27~.5~7 group wher~ein one of the amine substituents is a p-hydroxbenzyl group; or hydroxy or carboxy; or acyl-amino group of the form R~CO-;
wherein R6 is such that R5CoOH =
lower carobxylic acid having from two to six carbon atoms, optionally sub-stituted wi~h at least one halogen; or Hlpha-amino acid of the L or D
configuration; or N-benzyloxycarbonyl alpha-amino acid cf the L or D configur-ation; or biotin, optionally bonded through an amide linkage to a straight chain ornega-amino acid having between l and 6 methylene groups; or

2-thiopheneacetic acid;
n = l-lD
and pharmaceutically acceptable salts.
The compounds of this invention are produced by processes described in the examples.

Utility Statement Selected com~ounds of this invention have shown significant activity as antiallergenic and antiasthmatic drugs by standard phamacological tests. Theophylline and other xanthine derivatives are used clinically in the treatment of asthma, cardiac or renal failure, high blood pressure, and depression; i.e., conditions involving the inhibition or blocking of adenosine receptors. The pre-sent compounds are adenosine antagonists and, as such, are useful in the same manner as theophylline and other xanthine derivatives. Furthermore, the present compounds .

~7~597 are more water-soluble and more potent than most known xanthine derivatives. Moderate selectivity depending on the nature of the group attached to the functionalized congener has been demonstrated, thus reducing the side effects associated with the administation of known aden-osine receptor antagonists. ~urthermore, the Al-specific antagonists such as compound 6d are useful therapeuti-cally in combination with a non-specific adenosine agonist. The net effect of such a combination is de-creasing blood pressure (an A2 effect of the agonist) without a comcomitant effect on the heart rate (since the Al-agonist effect of slowing the ~heart rate would be cancelled by the specific ant~gonistj. ln short, some of the compounds of this invention, used in conjunction with adenosine analogs, are useful as hypotensives/vasodila-tors, antithrombotics, and selective central nervous system stimulants. Table 2 shows the solubility values of these compounds.

S ecific Disclosure:
. P
The compounds of the present invention are of the general formula:
Formula 1:

R3~ CH2-o ~ ~2 wherein Rl and R2 = Cl - C6 and R3 is any one of the 8-phenyl substituents illustrated in Table 1.
The general formula for the amino acid conju-gates and oligopeptide conjugates (compounds 11-31) is:

127~,59t7 Pormula 2:
A - B
where A and B are linked together in ~n amide linkage, and where A (the primary pharmacophore is:

~ o~ ~ O

O
or I ~ ~/
-NH-(CH2)n-NHCOCHa-o ~ N ~ ~ ~ O

where Rl and R2 are carbon chains of 1-6 carbons and n = 2-6 and B (the carrier) is an amino acid or the L- or D-configuration or an oligopeptide consisting of 1-5 amino acids of the L- or D- configuration.
When A=Al, the point of the A-B amide bond is at the terminal w-amino group of the carrier ~B). The ~_ carboxylic acid group of the carrier (BJ may be present as a free carboxylate or blocked by a conventionAl pep-tide protecting group (including, but not exclusively, the t butyl ester groupj.
When A-A2, the point Ofthe A-B amide bond is at the terminal ~-carboxyl group of carrier (BJ. The w-amino group of carrier (B) may be presen.t as a free amine (or a phsrmaceutically acc.eptable salt thereof), or blocked by a conventional peptide protecting group (in-cluding, but not exclusively, the t-butyloxcarbonyl or benæyloxycarbonyl gtOUpS).
The preferred compounds of this invention ~For-muls 1) are:
i~

1.~7~S97 Rl = R2 = (cH2j2cH3 and R3 = H2~ NH 2-- (6g), H2N-(CH2)2NHCOCH2-O- (6d), H2N-(CH2)8NHCOCH2-O- (6e~, HO- ~ -CH2 ~ (CH2)2NHOOCH2 O (8 ), HO2C-CH2 ~lb), o ~ N-O-C-CH2-O- (5), and The preferred amino compounds corresponding to Pormula 2 are:
HBr H-(Gly)2-Y- (lSbj TFA-H-L-Met-Y- (19b) (HBr)2 H-L-Lys(H)-Y- (20b) HBr-H-D-Lys(H)-Y- (21d) TFA H-D-Lys-Y- ~ (23b) CO(CH2)2 ~ ~ OH
TFA-H-L-Cit-Y- (24b) HBr-H-L-Tyr-Y- (26bl (HBr)2 H-D-Tyr-D-Lys(H)-Y- (29bJ
TFA-H-L Tha-Y- (31bJ
o where Y = -NH(CH)2)2-NH-~-~H2 O

Gly = glycyl TFA = CF3COOH
Lys = lysyl Cit = citru11ine, H2NOONH(CH2J3CH
(NH2)COO~
Tyr = tyrosyl Tha = 3(2'-thi~nyl)alanyl, S CH2CH ( NH2 ) COOH

1~715~7 All of these compounds combine high potency with high solubility. The solubility value is partly due to the covalent attachment of polar groups (i.e., para substituents on the 8-phenyl ring) noted above and is therefore not intended to be limited by the polar groups specifically designated. Examples of the compounds of this invention, as well as their activity and solubility are set out in Table 1.
Biological activity at the A2-receptor is mea-sured by inhibition of ~-chloroadenosine-stimulated cy-clic-AMP formation in guinea plg brain slices. The re-sults for selected analogs are surrmarized in Table lA.
Many of the free amino conjugates show a high degree of selectivity for Al-receptors. Among the most selective are conjugates of methionine, phenylalanine, thienyl-slanine, tyrosine.
Many of the highly potent Al-antagonists also exhibit greatly enhanced water solubility. Upon attach-ment of citrulline to the amino congener the aqueous solubility (pH 7.2, 0.1 M sodium phosphate) rose from90 micromolar to 250 micromolar. The neutral, polar side chain of citrulline improves water solubility in oligo-peptides. The lysine conjugates, with an additional ammonium group on the carrier, displayed an aqueous solu-bility of 350 micromolar. This is in contrast to 3.2 micromolar solubility measured for 1,3-dipropyl-8-p-hydroxyphenylxanthine. The favorable water solubility made possible effective HPLC for analytical and semi~
preparative purposes using a C-18 bonded silica column with 50-65% methanol in aqueous buffers (easing labora-tory purification of these compounds). Octanol/water partition coefficients which demonstrate further the improved polarity characteristics of the amino acid con-jugates are given in Table 4.
Polar groups that promote water solubility and are uncharged at physiological pH include carboxamide, ureido, alcohol, amide, ether, carbamate, nitrogen ~ ~27:~lS~

heterocycle, hydrazide, and sulfonamide. Charged polar groups include alkylamino, carboxyl, sulfonate, guani-dine, phosphate, metal salts and their complexes. See particularly Table 1 for xanthine anslogs containing amino acids (compounds 12-31).
IC50 values for Al-receptors were obtained from antagonism of binding of 1 nM 13H] cyclohexyladenosine to rat cerebral cortical membranes. IC50 values for A~-receptors were obtained from antagonism of [3H]cyclic-AMP
accumulation elicited by 15 uM 2-chloroadenosine in [3H]adenine-labeled guinea pig cerebral cortical slices. Ki = IC50/(1 + conc. of adenosine analog/Ka for adenosine analog).
The ratio of Aa to Al indicates the degree of specificity of the particular compound (low values repre-sent high A2-specificity)~ The compounds with A2-speci-ficity are expected to be more useful as anti-allergenic or anti-asthmatic agents. Compounds with high Al speci-ficity in general block the cardiac depressant effects of adenosine without diminishing blobd flow to the heart, thus they may be more useful therapeutically in treating cardiac insufficiency and angina. Some analogs are ex-pected to hQve activity as inhibitors of phosphodiest-erase, as do theophylline and caffeine, thus contributing anti-allergenic and anti-asthmatic activity. The solu-bility of these compounds is also shown and should be noted as an index to a compound's medicinal value--a D compound that does not dissolve in water cannot be used therapeutically. If the ratio ~of A2 to Al is low, the compound is A2-selective and is anti-allergenic or snti-asthmatic (without cardiovascular effects). The ideal ratio is about 0.1 or less, but this has never been achieved. The most selective A2 antagonists known prior to this invention is about 0.6. Note that preferred compounds lb and 6g are more selective.
If the ratio of A2 to Al is high, the compound is Al-selective and exhibits lipolytic, central stimu-, lant, and cardiac stimulant properties. Most known com-pounds of interest are no lower than l0. Note that many o~ the compounds of this invention are significantly higher than l0.
Compounds bearing multiple charged groups (such as 20b and 2ldj or permanently charged groups do not penetrate cells and thus are not active as inhibitors of phosphodiesterase. Moreover, they do not pass the blood-brain barrier. This adds an additional degree of selec-tivity to the action of Al-selective compounds, which means fewer side effects in vivo. The effect of non-penetration is similar to that observed previously for p-sulfophenylxanthines, which are not Al-selective.
One class of congeners, the analogs bearing a distal amino group and capable of introducing a wide range of substituents on an amin-functionalized chain, exhibit wa~er solubility and partition characteristics which allow these compounds to be absorbed into a human or animal circulatory system after intraperitoneal injec-tion. These analogs comprise an amino acid carrier lin-ked through an amide bond to a functionalized xanthine congener. This distal amino group may be as many as 14 bond lengths from the phenyl ring. As shown in Tables 3 and 4, these analogs may be either free amino conjugates or amino-protected intermediates. In general, the attached carrier (amino acid group or oligopeptide) sub-stantially affects the overall solubility of the analog, increasing solubility by approximately l0,000 fold.
The attachment of free~amino acids to the chain not only favors high potency in these adenosine conju-gates but has led to improved solubility characteristics due to the presence of the amino group, which is pre-dominantly charged at physiological pH. It has been observed that frequently the 8-phenylxanthine analogs noted for high potency, such as 8-phenyltheophylline, are too hydrophobic to be absorbed into circulation after intraperitoneal injection. This is not a limitation in the compounds of this invention, which combine nanomolar potency with greatly increased water solubility (ki at Al-receptors and maximum aqueous concentration differ by a factor of approximately 104). As expected, the attached carrier in general may have a substantial effe~t on the overall solubility of the analog even in organic solvents. For example, compound 13a, containing two bulky hydrophobic groups on a lysine residue, is freely soluble in ethyl acetate, in contrast to smaller analogs.
10The wide range of incorporated amino acid side chains that lead to high potency suggests considerable - versatility in this approach for constructing receptor probes and labels. The conjugates of tyrosine (26b and 28b), trytophan (30b), and the unnatural amino acid thienylalanine (31b~ may be iodinated by virtue of elec-tron rich aromatic rings (see also Example 14).
The fact that high potency was observed for a simple dipeptide conjugate 115b) and the corresponding protected intermediate (15aj indicates that monodisperse oligopeptides are suitable covalent carriers for the xanthines as adenosine receptor antagonists. Previously, oligopeptide conjugates of isoproterenol were noted to have increased potency and prolonged duration of action in vivo. Linkage of a functionalized drug congener to amino acids or peptides as carriers has advantages in the design of new analogs. The variety of side chains avail-able allows great flexibility in the charge, steric char-acteristics, hydrophobicity, and functionality of the carrier. These side chains are well known to the prac-titioner and may be incorporated in the compounds of thisinvention as specific carriers which favorably alter the physical and/or pharmacological properties of a drug.

Synthetic Methods The carboxylic acid congener of theophylline (la), its dipropyl analog (lbj, and the other 1,3-dialykyl analogs are synthesized by a standard approach ~ 7~
. ..

to xanthines, as described in US Patent 4,452,788.
Briefly, 5,6-diamino-1,3-dimethyluracil (leading to com-pounds in which Rl=R2-CH3) is commercially available, but other 1,3-dialkyl compounds are prepared with appropriate dialkyl urea and cyanoacetic acid. These reactions are described in J Org. ~hem., Vol. 16, p. 1879 (1951) and Can. J. Chem., Vol~ 46, p. 3413 (1968J. The imidazole ring is formed by oxidative closure of the benzylidene adduct derived from the appropriate diaminouracil and a substituted benzaldehyde (Example 1). 4-(Carboxymethyl-oxy) benzaldehyde (Compound A) is the product of alkyla-tion of p-hydroxybenzaldehyde by iodoacetate.
Ring closure of the benzylidene adduct occurs by heating with substoichiometric amounts of anhydrous ferric chloride. In the case of the carboxylic acid derivatives, considerable ethyl ester (3) is formed using ethanol as a solvent. To avoid separating the mixture of acid and ethyl ester, the esterification is brought to completion by prolonged heating of the reaction mixture in the presence of one equivalent of ferric chloride.
Use of trifluoroethanol as the solvent during ring clo-sure produces 1 exclusively. Compound 1 may alterna-tively be prepared by basic hydrolysis of the ester (3).
Coupling of the carboxylic acid congeners to amines using carbodiimides presents problems due to limi-ted solubility. Attempts to couple 8b to various polar amines using carbodiimides in dimethylformamide often results in isolation of the N-acylurea (4) derived from the acid and the coupling reagent. Compound la is coupled in low yield to p-toluidine. In an alternate approach to amide formation, the N-hydroxysuccinimide ester (5) of the carboxylic acid congener is prepared and is readily separable from the N-acylisourea by crystallization. The N-hydroxysuccinimide esters and the water-soluble esters of N-hydroxy-2-sulfosuccinimide of the carboxylic acid congeners are activated forms of the drug for coupling to amines, including biopolymers such as proteins, to serve ~7~g7 :.

as drug carriers. These drug derivatives may also be attached to directed carriers such as monoclonal anti-bodies.
Alternatively, an amide bond may be introduced on the substituted benzaldehyde (as in Example 1) prior to formation of the imidazole ring.
The ethyl ester (3) may be aminolyzed by excess unhindered amines in dimethylformamide to form amides (6). Aminolysis by alkyl diamines produces the function-alized amino cogeners (6d, 6e), which are the basis foradditional derivatives including amides ~7 and 8J and secondary and tertiary amines (9), made via reductive amination. See the camples for additional descriptioh of .
these synthesis procedures.
The amino cogeners of 1,3-dialkylxanthine der-ived from ethylene diamine, e.g., 6d, are coupled to various urethane protected amino acids by the active ester method. Protected amino acid conjugates 13 through 31 were synthesized by the coupling methods specified in Table 3, following the general procedures noted above.
Active ester derivatives of glutamine, leucine, and phen-lalanine were obtained from Sigma. Protected amino acid derivatives of citrulline and methionine were from Bachem, and deriYates of asparagine, glycine, and glycyl-glycine were from U.S. Biochemical Corporation.
Some protected amino acid derivatives wereprepared. Representative examples are as follows:
t-Butyloxycarbonyl-D-tyrosine N-hydroxy-suc-cinimide ester (32) is prepared~ from the Boc-D-tyrosine (Chemical Dynamics), N-hydroxysuccinimide, and dicyclo-hexylcarbodiimide (DccJ in dimethylformamide (DM~) ;n 95%
yield.
t-Butyloxycarbonyl-L-3-(2'-thienyl)alanine (33) is prepared from L-3-(2'-thienyl)alanine (Chemical Dyna-mics) and di-t-butyl-dicarbonate by standard methods.
The product is isolated as a clear oil (yield 95%).
t~-Butyloxcarbonyl-L-3-(2'-thienyl)alanine N-~,~

- ~ ~.27~
- l5 hydroxysuccinimide ester (34) is prepared from compound 34 by the DCC method in 84% yield. These compounds are intermediates of the formula set out below:
Rl _ R2 R3 Some protected amino acids and active ester intermediates used in the synthesis of conjugates.
Deblocking of acid-labile protecting groups is carried out for one hour ~t room temperature in anhydrous 48~ B r in acetic acid for carbobenzoxy- (Cbz-) deriva-tives and in neat trifluoroacetic acid for t-butyloxy-carbonyl- (Boc-) derivatives. Compounds l9a and 30a were deprotected in the presence of thiophenol. After evapor-ation, the residue is triturated with ether, and the solid product is collected, washed with ether, and dried under vacuum. The purity of the xanthine analogs is checked by thin layer chromatography in chloroform/-meth-anol/acetic acid (85/lO/5 or 50/50/5), and, if necessary, the product is recrystallized from dimethylformamide/-ether or methanol/ether. Since N-hydroxy-succinimide esters and p-nitrophenyl esters of the protected amino acid are used, minimal side chain protection is required (e.g., in the cases of tyrosine and asparagine). During ~71~

the reaction in dimethylformamide, the amino congener dissolves gradually as the acylation proceeds, thus excess base which might lead to racemization of the amino acid is minimized. The urethane protecting groups are subsequently cleaved in acid without serious side reac-tions on the xanthine portion of the molecule.
Biolo~ical Activity The 1,3-dialkyl-8-(p-hydroxphenyl)xanthine, from which the functionalized congeners are formalistic-10 811y derived, have been shown in earlier studies to bepotent antagonists of Al- and A2~adenosine receptors [P _ , Vol. 77, p. 5547 (1980)]. 8 p-Hydroxyphenyl-theophylline is 280-fold more potent than theophylline in displacing [3H]cyclohexyladenosine from Al-adenosine receptors in rat cerebral cortical membranes and is 107-fold more potent than theophylline in antagonizing A2-adenosine receptor mediated activation of cyclic A~-generation by 2-chloroadenosine in guinea pig cerebral cortical slices. ~eplacement of the 1,3-dimethyl groups with n-propyl groups yields 1,3-dipro~yl -8-(p-hydroxy-phenyl)xanthine (2b)~. This analog is an 3xtremely potent Al-adenosine antagonist with a Ki vaIue versus [3~]cyclo-hexyl-adenosine binding in rat cerebral cortical slices of 2.9 nM. The change in the alkyl residues, thus, has increased potency at Al-receptors by about 17 fold. The change in alkyl residues also increases potency at A2-receptors but to a much lesser extent (2.6-fold), yield-ing a somewhat selective Al antagonist.
Functionalization of these two xanthines is based on the presence of a p-carboxymethyloxy residue on the 8-phenyl ring. This functionalization permitted facile syntheses of Q wide variety of amides. In the case of the 8-phenyltheophyllines, the p-carboxymethyloxy compound (la) has a ten fold lower activity than the p-hydroxy compound at Al-receptors and a 3.3-fold lower activity at A2-receptors (Table 1). It appears likely that the presence of the anionic carboxyl group is not favorable to high sffinity binding to either receptor.
With an anionic p-carboxyl group directly on the 8-phenyl ring, even lower activity pertained with Ki values of 3000 nM at Al-receptors and 2500 nM at A2-receptors. A
p-toluide function (2a) was well tolerated by both Al and A2-receptors, and this neutral derivative of a function-alized congener was about 2-fold more potent than 8-(p-hydroxyphenyl)theophylline at Al-receptors and about-6-fold more potent at A2-receptors (Table 1).
Further syntheses of functionali~ed congeners were based on the higher potency and selectivity of 1,3 dipropyl -8-(p-hydroxyphenyljxanthine relative to the 1,3-dimethyl homolog which enhances the activity of the p-carboxymethyloxy congeners and derivatives even fur-ther. In this serves the p-carboxymethyloxy compound is 20-fold less potent than the p-hydroxy compound at Al-receptors. At A2-receptors the p-carboxymethyloxy com-pound is nearly equipotent with the p-hydroxy compound.
Again, it appears likely that the presence of the anionic carboxy group mitigates against high activity at the Al-receptors. Similarly, 8-p-carboxyl-1,3-dipropylxanthine is about 60-fold less active than the p-hydroxy compound at Al receptors, while being only 2-fold less active at A2-receptors nearly identical to that of the anionic carboxylic acid. ~he carboxamide (6a) is very active at Al-receptors and moderately selective, being 8-fold more active at Al receptors than at A2-receptors. Remarkably, the p-toluide (2b) is no more potent than the acid at Al receptors, while being 22-fold less potent than the acid at A2-receptors. This finding stands in direct contrast to results obtained with the analogous compounds in the theophylline (1,3~dimethyl) series, in which series the p-toluide was about 20-fold more active than the acid both at Al-receptors and at A2 receptors. It is believed that contributions to affinity afforded by the 1,3-dialkyl substituents and by para-substituents on the 8-phenyl ring are not independent and can ~reatly influence ., . . _, .

~L~7~ 5~:7 each other in either a positive or a negative manner.
For example, the p-hydroxyanilide (2c) is nearly 10-fold more potent than the p-toluide at both Al- and A2 recep-tors, thus illustrating the potential importance of minor structural modifications distant from the primary pharma-cophore (in this case the 8-phenylxanthine) on biological activity. The o-hydroxy-m-sulfoanilide (6f) is synthe-sized as a water~soluable xanthine suitable for radioio-dination. It is not selective, and its potency was a least three-fold less than the parent acid.
The aminoethylamide (6dj is synthesized with a view of increasing water solubility and also of providing a key intermediate for preparation of affinity columns, fluorescent probes and a biotin-containing xanthine. The aminoethylamide is very potent at Al-adenosine receptors with a Ki value of 1.2 nM. It was some forty-fold less potent at A2-adenosine receptors. The presence of a p-hydroxybenzyl and ethyl substituents (9b) (phenol suit-able for radioiodination) on the terminal amino group exhibits little effect on the potency at Al-receptors, while reducing potency at A2-receptors by over four-fold. This compound is among the most selective Al-antagonist (145-fold) in the present series.
A number of compounds were prepared in which the terminal amino group was acylated. The acetyl com-pound (7a) is 20-fold less potent than the parent amine at Al-receptors while the biotinyl compound (7d) is 45-fold less potent. Potency at the A2-receptor is not significantly affected in the case of the acetyl com-pound, while potency for the biotinyl compound is reducedat A2-receptors by only three-fold. Both acyl compounds are, thus, relatively nonselective antagonists for Al-and A2-adenosine receptors in contrast to the parent amine that exhibits a 40-fold selectivity for Al-receptors.
The potency of the acetyl compound suggests th~t affinity columns prepared through acyl coupling to the amino com-pound could be effective in isolation of solubilized Al-1 ! ~ ~ 7 ~L ~ 97 and A2-receptors andtor xanthine-binding sites.
The use of longer spacer chains appears fea-sible for preparation of affinity columns if the amino-ethylamide proves unsatisfactory. The aminooctylamine (6C) was only 5-fold less potent than the aminoethylamide (6d) at Al-receptors and about 2-fold less potent at A2-receptors.
A bulky ureide (4) was found to have relatively low activity at both Al- and A2-receptors.
The compounds of the invention form pharmaceu-tically acceptable salts with both organic and inorganic acids and bases. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, suc-cinic, ascorbic, maleic, methansulfonic, and the like.
The salts are preared by contacting the free base form with an equivalent amount of the desired acid in the conventional manner. Examples of suitable bases for salt formation are sodium hydroxide, sodiurn carbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, potassium hydroxide, calcium hyroxide, ammonia, organic amines, and the like. The salts are prepared by contacting the free acid form with an equivalent amount of the desired base in the conventional manner.
In sumnary, the functionalized congener approach to xanthine antagonists for adenosine receptors has yielded a series of potent compounds which in some cases are moderately selective for Al- or A2-receptors The effects on biological activities caused by modifica-tions or functions distal from the primary pharmacophore in some cases are quite impressi~e. Dramatically high potency at the Al-receptor is associated with the pre-sence of an alkyl amino group on the chain attached to the 8-phenyl ring.
Affinities of congeners and derivatives for the Al-reeeptors seems somewhat more sensitive to distal modifications th~n affinities for the A2-receptor. As .

yet no completely selective A2-receptor antagonists have been discovered and as yet no completely specific Al-receptor antagonists are available. The present set of functionalized xanthines are improved analogs of theo-phylline and caffeine and will thus have more selectiveantiasthmatic, diuretic, respiratory stimulant, central stimulant, cardiac stimulant, analgesic adjuvant, and anti-inflammatory applications.

EXAMPLES
In all of the following examples, thin layer chromatography (T~C) was carried out using Analtech silica gel GF plates using mixtures of chloroform/meth-anol/acetic acid (v/v; A: 50/50/5; B: 94/4/2J. Reagent grade dimethylformamide (DM~, Aldrich gold label) was stored over 3A molecular sieves. Proton NMR specta were taken on a Varian ~20 MHz instrument in the Fourier transform mode. Dicyclohexylcarbodiimide (DCC) was pur-chased from Sigma. 5,6-Diaminouracil hydrate in Example

3 was purchased from Aldrich.

Example l

4-(Carboxymethyloxy)benzaldehyde (A). To a solution of p-hydroxybenzaldehyde (49 g, 0.40 molJ were added iodoacetic acid (75 g, 0.40 mol) and potassium carbonate (anhydrous, 120 gj, and the magnetically stir-red mixtured was warmed at 60C for three days. The resulting solid was dispersed mechanically in a mixture neutralized cautiously with phosphoric acid. After the dissolution of the solid mass, the neutral aqueous layer was withdrawn~ The organic layer was extracted repeat-edly with a concentrated solution of dibasic sodium phos-phate, to remove additional acidic organic material. The aqueous extracts were combined, filtered through glass wool, and acidified to pH l using 6N HCl. This solution was placed in the refrigerator overnight, and a product of tan crystals (2l.85 g) was collected. Unreacted p-3L~7'1S~

hydroxybenzaldehyde was recovered upon evaporation of the organic layer. Yield based on recovery of starting material was 60%. Mp 191-193C. Analysis (CgH804):
calc. 60.00% C, 4.48% H; found 59.66% C, 4.37% H.
4-(Carboxymethyloxy)benzaldehyde p-toluide.
Dicyclohexylcarbodiimide (DCC~ 1.32 g, 6.4 mmol) was added to a solution of compound A (1.15 g, 6.4 mmolJ in tetrahydrofuran (50 ml). After stirring for ten minutes p-toluidine (0.7 g, 6.5 mmolj was added. After one hour, the precipitate was removed by filtration, and the fil-trate was reduced in volume by evaporation. A crystal-line product (l.Q9 g, 63% yield) was obtained by tritura-tion of the filtrate with petroleum ether. An analytical sample was obtained by thin layer purification (solvent B) which was necessary for the removal of a faster moving impurity, later shown ~y C,H,N analysis to be the imine adduct of the product with p-toluidine.
4-(Carboxymethyloxy)benzaldehyde p-hydroxy-anilide. Compound A (1.80 g, 10 mmol) was dissolved in 25 ml of tetrahydrofuran containing 20% ~. To this solution were added DCC (2.06 g, 10 mmol) and after ten minutes a solution of p-aminophenol hydrochloride (1.46 g, 10 mmol) and triethylamine (0.78 g, 10 mmol) in DME
(10 ml). After 2 hours the precipitate was removed by filtration and washed with tetrahydrofuran. The combined filtrates were evaporated and triturated with water. A
yellow oil separated and crystallized, providing 2.40 g (89%) of product. The product~was recrystallized from ethanol/petroleum ether to give a white solid which melted at 185-186~C. Analysis (C15H13NO4): calc. 66.41%
C, 4.83~ H, 5.16% N; found 66.11% C, 5.07% H, 5.36% N.
Example 2 -Amino-1,3-diprop~1-5-(4'-carboxymethyloxy-benzylideneaminojuracil. A representative synthesis of benzylidene adduct is given. Compound A (1.51 g, 8.37 mmol) was dissolved in a mixture of methanol (35 ml) and acetic acid (5 mlj in a 50 ml boiling flask on a steam bath. To this was added a methanolic solution (60 ml) of freshly synthesized 5,6-diamino-1,3-dipropyluracil.
After heating 15 minutes, the volume was reduced by evaporation until crystallization occurred. Ether (40 ml) was added and the nearly white solid was collected.
Yield 2.80 g (86%), mp 179-180C. Analysis (ClgH24N4O5):
calc. 58.60~ C, 6.21~ H, 14.39% N; found 58.72% C, 6.16%
H, 14.43~ N.
Example 3 8-(4'-Carbox Qmethyloxyphenyl)-1,3-dimethyl-xanthine (la). The benzylidene adduct prepared. as described in Example 2 from compound A (0.609 g, 3.38 mmol) and 5,6-diamino-1,3-dimethyluracil hydrate (0.58 g, 3.4 mmol). Tan crystals (0.963 g, 85.7%) were obtained upon cooling the reaction mixture overnight in the refrigerator. The benzylidene adduct (98 mg), used with-out further purification, was dissolved in warm DME (7 ml), treated with ferric oxide (20 mg) and heated on the steam bath for four hours. After adding an equal volume of ethanol, the precipitate was collected and dried.
Yield 76 mg (67% overall yield), not melting up to 310C.

Example 4 8-(4~-carboxymethylo~ypheny~ 3-dipr xanthine (lb).
Method A: The benzylidene adduct (191 mg, 0.49 mmol) was suspended in trifl~orethanol (15 ml) and dissolved by refluxing on a steam bath. Anhydrous ferric chloride (20 mgj was added and heating was continued for two hours. Ether was added to complete the precipitation of product, which was collected and dried in vacuo. The crude product, 0.17 g (89%j, was recrystallized from DMF/methanol/ether to give analytically pure material, mp 283-285C. Analysis (ClgH22N405j: CQlC. 59.06% C, 5.74%
H, 14.50% N; found 59.03~ C, S.33~ H, 14.24~ N.

5~37 Method B: The ethyl ester (114 mg, o.a8 mmol) was dissolved in DME (5 ml) and treated with sodium car-bonate (5 ml, O.lN). The mixture was heated on the steam bath for one-half hour. The solvent was evaporated, leaving a white film, which was triturated with dilute HCl. The resulting white precipitate was collected and washed with water and dried in vacuo. This material was homogeneous by TLC (solvent B; Rf 0.24) and identical to the product prepared by method A. Yield lD5 mg ~99%J.
Example 5 8-(4'CarboxymethyloxyphenylJ-1,3-dipropy~xan-thine 4-methy anilide (2b). The p-toluide of the car.box-ylic acid congener (lb) was prepared by the method described below for compound 2c, except that the reaction was continued overnight.
8-(4'-Carboxymethyloxyphenyl)-1,3-dipropyl-xanthine 4-hydroxyanilide (2cj. The benzylidene adduct formed from freshly prepared 5,6-diamino-1,3-dipropylura-cil (see Example 2) (0.385 mmol) and the substituted benzaldehyde (88 mg, 0.325 mmol) was formed according to the method described for the compound in Example 2. The solid adduct (0.14 g, 90% yield) was dissolved in hot absolute ethanol (10 ml), treated with ferric chloride (20 mg) and heated on the steam bath unti1 the product precipitated (30 min). Ether was added and the product (93 mg, 60% overall yield from 5,6 diamino-1,3-dipropyl-uracil and 4-~carboxymethyloxy)benzaldehyde) was isolated. r Example 6 8-(4'-Carboxymethylox~henyl)-1,3-dipropylxan-thine ethyl ester (3j. The compound from Example 2 (1.69 g, 4.3 mmol) was suspended in 100 ml absolute ethanol.
Anhydrous ferric chloride (0.70 g, 4.3 mmol) was added, and the mixture was refluxed on a steam bath for one day. The slow conversion of the free acid (identical to compound lb, Rf 0-35) to the ethyl ester (Rf 0.78) was 5~7 followed by TLC on silica gel using solvent B. The reaction mixture was evaporated in vacuo to a small volume, and dry ether was added. The bulky crystalline mass was collected by filtration, washed with ether, and dried in vacuo. Yield 1.21 g (70.8%), mp 243-244C.
lysis (C21H26N4~5): calc- 60.8% C, 6.23% H9 13.51% N;
found 60.42% C, 5.80% H, 13.50~ N.
Example 7 8-(41-Carboxymethyloxyphenyl)-1,3-dipropyl-xanthine N-hydroxysuccinimide ester (S). The carboxylic acid congener (compound lb, 18.4 mg, 0.048 mmolJ was dissolved in DM~ (5ml), cooled in an ice bath, and treated with N-hydroxysuccinimide (6 mg) and DCC (11 mg). After stirring for one aay at room temperature, the urea was removed by filtration. Upon addition of water, a white solid precipitated and was collected. Recrystal-lization from DMP/water provided 11.1 rng of the pure product (48% yield). A side product removed by crystal-lization was identical to the N-acyl urea.
Example 8 8-(4'-Carboxymethyloxyphenyl)-1,3-dipropyl-xanthine 2-aminoethylamide (6d). Compound 3 (57.5 mg, 0.14 mmol) was dissolved in warm dimethylformamide (1.0 ml). Upon reaching room temperature ethylene diamine (1.0 ml) was added. After stirring overnight most of the solvent was evaporated under a stream of nitrogen. The resulting oil WQS triturated with methanol. After crys-tallization began, ether w~s added and the product was collected and dried. Yield 59 mg (99%), melting at 214-216C with decomposition, homogeneous by TLC (solventsystem A).
Exam~le 9 8-(4'-Carboxymethyloxyphenyl)-1,3-dipropyl-xanthine 2-(biotinylamino)ethylamide ~7d). Compound 6d , , .

~7~5~7 (24.1 mg, 0.056 mmol) was suspended in 1 ml DM~. N-Hydroxysuccinimido-d-biotin (Sigma, 23.6 mg, 0.069 mmol) was added with stirring. A solution formed after several minutes, and a precipitate appeared soon thereafter.
After one day methanol (1 ml) and ether were added. The precipitate was collected and dried (yield 26.6 mg, 73~).

Example 10 (A) 8-(4'-Carboxymethyloxphenyl)-1,3-diprop~
xanthine 2-(N-4'hydroxybenz:yl-N-ethylamino)ethylamide acetate (8b). Compound 6c (56 mg, 0.13 mmol) and 4-hydroxybenzaldehyde (19 mg, 0.16 mmol) were dissoived in warm acetic acid (5%) in ethanol (2 ml) and heated on a steam bath for two hours. The solvent was evaporated and the residue triturated with ether to give 9b, a tan solid (75% yieldj. NMR (ppm, DMSO, d6): 8.15 (s,lH,CH=N), 8.05 and 7.04 (each d,2H,8-phenyl,J=8.9HzJ, J=8.5Hz), 4.56 (s,2H,CH20), 3.59 (CH2N), 1.91 (s,3H,acetate), and signals from propyl groups. AnalySis (C30H36N6O7~
calc: 60.80% C, 6.12% H, 14.18% N; found: 60.93% C, 5.95% H, 14.12% N.
(B) 8-(4'-Carboxymethyloxyphenyl)-1,3-dipropyl-xanthine 2-(N-4'-hydroxybenzyl-N-ethylamino)ethylamide acetate (8b). Compound 8b (8.7 mg, 0.015 mmol) was sus-pended in methanol (1 ml) and treated with excess sodium cyanoborohydride (20 mg, 0.32 mmol). The mixture was warmed at 60C to form a solution and treated with acetaldehyde (0.03 ml). After two hours the solvent was evaporated and the residue was chromatographed on LH-20 eluting with methanol. Evaporation of the solvent left a clear film of 16 (5.9 mg, 61%j. The product was chroma-tographically pure ~Rf 0.45, Analtech RPS-F, 75% MeOH/5 HOAc/H20, positive Pauley reaction, unreactive towards ninhydrin). An average molecular weight of 563 was determined by californium plasma desorption mass spectro-scopy.

Example ll Biochemical ass~ys. Inhibition of binding of 1 nM [3H]N6-cyclohexyladenosine to Al-adenosine receptors in rat cerebral cortical membranes was assayed as described in Daly et el, Cell. Mol. Neurobiol., Vol. 3, p.6 (l983). Inhibition of binding by range of concentra-tions of each xanthine was assessed in triplicate for at least two separate experiments. Inhibition of 2-chloro-adenosine-stiumulated cyclic AMP accumulation in [3H]adenine-labeled guinea pig cerebral cortical slices W8S assayed essentially as described in Daly et al article, supra. In the present experiments l0 ugjml of adenosine deaminase was present in incubations with slices to prevent effects of endogenous adenosine, and 30 uM 4-(3-cyclopentyloxy-4-methoxyphenyl~-2-pyrrolidone (rolipram, ZK 627ll) was present to inhibit phospho-diesterases. Under these conditions 2-chloroadenosine elicited a miximal l0-20 fold increase in levels of radioactive cyclie AMP in guinea pig cortical slices with an ECSo of about 8 uM. Inhibition of the response to l5 uM 2-chloroadenosine by a range of concentrations of each xanthine was assessed in triplicate in at least two separate experiments.
Example 12 The following are also representative of the claimed invention and m~y be synthesized in generally the same manner as shown in the preceeding examples.
Histamine derivative ~-\ (cH2J2-NH-x (can be iodinated) HN\5~N

Quaternary amine Cl~ ~3 (always positively ~H3- ~ (cH2)2-NH-x charged) ~3 Glucosamine derivativeH ~ OH
(charged and water ~ /Off soluble) HO ~ ~
] [ ~H-(CH2j2 NH X

Aminopyridine (charged, /==\
H2O soluble and can N ~ - NH-(CH2j~-NH-X
be iodinated~
x= -~-CH2-O~ ,R~

Il R~
Example 13 The free amino conjugates and the amino pro-tected intermediates were screened for the ability to compete against [3H]-cyclohexyladenosine (~HAj in rat cerebral cortex homogenates. The binding affinity con-stants are shown in Table 4. A pattern appeared in which analogs with a free amino group on the chain exhibited high potency. In this series the amino group was located at between 8 and 14 bond lengths from the phenyl ring, and the receptor binding affinity was in the 10 9 to 10 8 molar range. In most cases the activity of the blocked intermediate was less than that of the free amino analog. The carbobenzoxy- (Cbz-j protected coniugates tended to be of moderate potency and t-butyloxycarbonyl-(Boc-) protected conjugates (of different amino acids) fell into a less potent range (Ka greater than 20 nM).
The protected dipeptide conjugate (of Cbz-glycylglycinej was of exceptionally high potency (Ka=0~95 nM) relative to other amino-protected conjugates.
.

Example 14 A radioiodinated analog of theophylline was needed for studies on the adenosine receptor in tissues where it occurs in low levels. By attachment of the functionalized congener to a inolecule which is subject to facile iodination, such as a phenol, this may be achieved. A substituted phenol was attached to an amino congener of 1,3-dipropyl xanthine resulting in binding affinity for the Al adenosine receptor in the nanomolar range.

The preliminary success towards the radioiodi-nation of xanthines provides a general approach to the design of radiolab~led drug analogs (specifically, radio-labeled ligands for receptors for transmitters and hor-mones) based on the functionalized congener approach. Afunctionalized drug congener may be attached to a molecule specifically designed to accept a particular radioisotope. By treating separtely the receptor recog-nition moiety contained in the congener and the chemistry of the radioisotope acceptor unit, one has more freedom to design schemes for efficient reactions with radio-isotopes. A preferred compound for radiolabeling is compound 26b.

Example 15 The melting point of some of the compounds of this invention were determined as follows:
CompoundMeltin~ Point (C) la > 310 lb 283-285 2a 287-290 2b 300 2c > 320 3 243-2~4 4 > 190 6a 301-303 6c 227-331 6d 218-220 6e ~ 300 6g > 310 7a 309-312 7d 262-264 7e 218-221 15bdecomp. 260-295 . ~

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Compound 8-Phenyl Substituent~* Solubility*
-- HO- 3.2 micromolar lb HO2C-cH2 1.2 millimolar 6a H2NcOCH2-0- 26 micromolar 6d H2N-(CH2)2NH 2-- 90 micromolar (primary amine with 2 methylenes~
6g HaN-NHOOCH2-0- 36 micromolar 7a CH CONH-(CH2)2- 8.6 micromolar NH~ OCH2 --c~3 9 HOOC-(CH ) CH-NH- 110 micromolar ( CH2 j 2NH~H2 21d HBr-H-D-Lys(H)-Y- 340 micromolar 24b TFA-H-Cit-Y- 250 micromolar 26b H2N CIH CONH ( NHc ~H2-0- 36 micromolar OH

pH 7.21, 0.1 M sodium phosphate All compounds are 1,3-dipropyl derivatives A value of 20 micromolar for solubility is deemed superior with reference to this table.

CompoundSynthetic Method Yield (%) 12a A 56 12b E 78 13a A 85 13b D 100 14a B 36 14b D 93 15a B 69 15b D 55 15c C 85 16a B 92 16b D 76 17a C 48 17b E
18a C 82 18b E 98 18a C 47 l9b E 73 20a C 39 20b D 100 21a 2 lb F 54 21c E 100 21d D 100 22a A 82 22b E r 62 ~.3a C 17 23b E 93 24a B 71 24b E 68 25a C 63 25b E 100 26a B 89 26b D 81 27a C 41 :~.

~ -,: :

3 ~7~37 TABLE 3 (continued) Compound Synthetic Method Yield (%
27b E 100 28a C 70 28b E 88 30a C 70 30b E 93 31a C 71 3lb E 98 _ A = c.arbodiimide coupling B = p-nitrophenyl ester eoupling to compound 2d C = N-hydroxysuccinimide ester coupling D = HBr/HOAc E = TFA
F = H2/Pd .

` 3L~7~L5~3~7 Partition Coefficients of Xanthanine Amino Acid Conjugates (free ~-amino con jugates unless specified) Conc. in octanol phase Cbmpound ~mino Acid log Conc. in aqueous phase , 28b D-Tyr 2.0 32b Tha 2.0 13b Lys* 0.29 18b Leu 1.9 14b Gly 1.4 15b Gly-Gly 1.0 24b Cit 0.81 * Free ~carboxylate ~ .,,

Claims (39)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. Compounds having the structural formula:

wherein R1 and R2 = a hydrocarbon chain of 1-6 carbons R3 = hydroxy, alkoxy, aryloxy N-oxyimide; or wherein R3 = R4R5N
wherein R5 is hydrogen, alkyl, aryl, or alkylaryl groups; and wherein R4 = R5 or X (CH2)n wherein X = primary, secondary, or tertiary amino group; or secondary or tertiary amino group wherein one of the amine substituents is a p-hydroxybenzyl group, or hydroxy or carboxy: or a group of the form R6CO-;
wherein R6 is such that R6COOH=
lower carboxylic acid, having from two to six carbon atoms, optionally substituted with at least one halogen; or alpha-amino acid of the L or D
configuration; or N-benzyloxycarbonyl alpha-amino acid of the L or D configuration; or biotin, optionally bonded through an amide linkage to a straight chain omega-amino acid having between 1 and 6 methylene groups; or 2-thiopheneacetic acid;
n = 1-10 and pharmaceutically acceptable salts.

2. The compound of Claim 1 having the name 8-(4'carboxymethyloxyphenyl)-1,3-dipropylxanthine hydrazide.

3. The compound of claim 1 having the name 8-(4'-carboxymethyloxyphenyl)-1,3-dipropylxanthine-2-aminoethylamide.

4. The compound of claim 1 having the name 8-(4'-carboxymethyloxyphenyl)-1,3-dipropylxanthine 2-(4'-hydroxybenzylethylamino) ethylamide acetate.

5. The compound of claim 1 having the name 8-(4'-carboxymethyloxyphenyl)-1,3-dipropylxanthine n-hydroxysuccinimide ester.

6. The compound of claim 1 having the name 8-(4'-carboxymethyloxyphenyl)-1,3-dipropylxanthine 2-(L-tyrosylamino) -ethylamide.

7. The compound of claim 1 having the name 8-(4'-carboxymethyloxyphenyl)-1,3-dipropylxanthine-8-aminooctylamide.

8. A pharmaceutical composition useful as anti-allergy and anti-asthma reagents comprising a compound as defined in claim 1 and the pharmaceutically acceptable salts therof in combination with the pharmaceutically acceptable carrier.

9. Compounds having the general formula:
A - B

where A And B are linked together in an amide linkage, and where A (the primary pharmacophore) is:

(A1) or (A2) where R1 and R2 are hydrocarbons of 1-6 carbons and n = 2-6 and B (the carrier) is an amino acid of the L- or D-configuration or an oligopeptide consisting of 2-5 amino acids of the L- or D- configuration.

10. The compound of claim 9 having the name 8-(4'-carboxymethyloxyphenyl)-1,3-dipropyl xanthine 2-(glycyl-glycyl-aminoi-ethylamide.

11. The compound of claim 9 having the name 8-(4'-carboxymethyloxyphenyl)-1,3-dipropyl xanthine 2-(L-methionyl-amino)-ethylamide.

12. The compound of claim 9 having the name 8-(4'-carboxymethyloxyphenyl)-1,3-dipropyl xanthine 2-(L-lysyl-amino)-ethylamide.

13. The compound of claim 9 having the name 8'(4'-carboxymethyloxphenyl)-1,3-dipropyl xanthine 2-(D-lysyl-amino)-ethylamide.

14. The compound of claim 9 having the name 8-(4'-carboxymethyloxyphenyl)-1,3-dipropyl xanthine 2-(.epsilon.-4-hydroxyphenylpropionyl-D-lysyl-amino)-ethylamide.

15. The compound of claim 9 having the name 8-(4'-carboxymethyloxyphenyl)-1,3-dipropyl xanthine 2-(L-tyrosyl-amino)-ethylamide.

16. The compound of claim 9 having the name 8-(4'-carboxymethyloxyphenyl)-1,3-dipropyl xanthine 2-(D-tyrosyl-D-lysyl-amino)-ethylamide.

17. The compound of claim 9 having the name 8-(4'-carboxymethyloxyphenyl)-1,3-dipropyl xanthine 2-(3(2'-thienyl)-L-alanyl-amino)-ethylamide.

18. The compound of claim 9 having the name 8-(4'-carboxymethyloxyphenyl)-1,3-dipropylxanthine-2-(L-leucyl-amino)-ethylamide.

19. The compound of claim 9 having the name 8-(4'-carboxymethyloxyphenyl)-1,3-diptopylxanthine-2-(L-phenylalanyl-amino)-ethylamide.

20. A pharmaceutical composition useful as hypotensive/vasodilator and antithrombotic reagents comprising a compound as defined in claim 9 and the pharmaceutically acceptable salts thereof in combination with a pharmaceutically acceptable carrier.

21. A process of producing a compound having the struc-tural formula:

and pharmaceutically acceptable salts of said compound wherein R1 and R2 each constitute a hydrocarbon chain of 1-6 carbons R3 constitutes hydroxy, alkoxy, aryloxy, N-oxyimide or R4R5N, wherein R5 is hydrogen, alkyl, aryl, or alkylaryl groups; and wherein R4 is the same as R5 or constitutes X(CH2)n, wherein X constitutes:
a primary, secondary, or tertiary amino group; or a secondary or tertiary amino group wherein one of the amine substituents is a p-hydroxybenzyl group; or

Claim 21 (continued) a hydroxy or carboxy; or a group of the form R6CO-;
wherein R6 is such that R6COOH is a lower carboxylic acid having from 2 to 6 carbons, optionally substituted with at least one halogen; or an alpha-amino acid of the L or D
configuration; or an N-benzyloxycarbonyl alpha-amino acid of the L or D configuration;
or biotin, optionally bonded through an amide linkage to a straight chain omega-amino acid having between 1 and 6 methylene groups;
or 2-thiopheneacetic acid; and n = 1-10 comprising treating compound A possessing the group wherem R1 and R2 have the meanings defined abcve with a compound B
possessing the group R3 wherein R3 has the meaning defined above.

22. The process of Claim 21, wherein 8'-(4'-carboxy-methyloxyphenyl)-1,3-dipropyl xanthine is condensed with a source of H2NNH2 and 8'-(4'-carboxymethyloxyphenyl)-1,3-dipropyl xanthine hydrazide is isolated.

23. The process of Claim 21, wherein 8'-(4'-carboxy-methyloxyphenyl)-1,3-dipropyl xanthine is condensed with a source of H2N(CH2)2NH2 and 8'-(4'-carboxymethyloxyphenyl)-1,3-dipropyl xanthine-2-aminoethylamide is isolated.

24. The process of Claim 21, wherein 8'-(4'-carboxy-methyloxyphenyl)-1,3-dipropyl xanthine is condensed with a source of and 8'-(4'-carboxymethyloxyphenyl)-1,3-dipropyl xanthine N-hydroxysuccinimide ester is isolated.

25. The process of Claim 21, wherein A is 8'-(4'-carboxymethyloxyphenyl)-1,3-dipropyl xanthine, B is an L-tyrosine derivative of the formula and A-B is 8'-(4'-carboxymethyloxyphenyl)-1,3-dipropyl xanthine 2-(L-tyrosylamino)-ethylamide.

26. The process of Claim 21, wherein 8'-(4'-carboxy-methyloxyphenyl)-1,3-dipropyl xanthine is condenssd with a source of H2N-(CH2)8NH2 and 8'-(4'-carboxymethyloxyphenyl)-1,3-dipropyl xanthine-8-amino-octylamide is isolated.

27. A process for producing a pharmaceutical composi-tion useful as anti-allergy, anti-asthma, diuretic, central nervous system stimulant and cardiac stimulant reagents, comprising combining a compound or a pharmaceutically acceptable salt thereof produced according to the process of Claim 22 with a pharmaceutically acceptable carrier.

28. A process of producing a compound having the struc-tural formula:

and pharmaceutically acceptable salts of said compound wherein R1 and R2 each constitute a hydrocarbon chain of 1-6 carbons;
R3 constitutes R4R5N, wherein R5 is hydrogen, alkyl, aryl, or alkylaryl groups; and wherein R4 is the same as R5 or constitutes X(CH2)n, wherein X constitutes:

a primary or secondary amino group; and n = 1-10 comprising treating a compound A possessing the group wherein R1 and R2 have the meanings defined above, with a compound B
possessing the group R3, wherein R3 has the meaning defined above, to form a first product and treating said first product with an aldehyde or ketone by reductive amination to convert the primary amino group to a secondary or tertiary amino group or to convert a secondary amino group to a tertiary amino group.

29. The process of Claim 28, wherein 8'-(4'-carboxy-methyloxyphenyl)-1,3-dipropyl xanthine -2-aminoethylamide is treated with an aldehyde or a ketone and 8'-(4'-carboxymethyloxy-phenyl)-1,3-dipropyl xanthine 2-(4'-hydroxybenzylethylamino) ethylamide acetate is isolated.

30. A process of producing compounds having the general formula A-B comprising:
treating a compound possessing group A with a compound possessing group B to form an amide linkage, wherein group A is a primary pharmacophore having the structure:

and wherein R1 and R2 comprise hydrocarbons of 1-6 carbon atoms and n = 2-6; and group B is an amino acid of the L- or D- configuration or an oligopeptide consisting of 2-5 amino acids of the L- or D- configuration.

31. The process of Claim 30, wherein A is 8'-(4'-car-boxymethyloxyphenyl)-1,3-dipropyl xanthine, B is H2NCH2CONHCH2CO
and the compound A-B is 8'-(4'-carboxymethyloxyphenyl)-1,3-dipropyl xanthine-2-(glycyl-glycylamino)-ethylamide.

32. The process of Claim 30, wherein A is 8'-(4'-car-boxymethyloxyphenyl)-1,3-dipropyl xanthine, B is CH3S(CH2)2CH(NH2)CONH(CH2)2NH- and the compound A-B is 8'-(4' carboxymethyloxyphenyl)-1,3-dipropyl xanthine-2-(L-methionyl-amino)-ethylamide.

33. The process of Claim 30, wherein A is 8'-(4'-car-boxymethyloxyphenyl)-1,3-dipropyl xanthine, B is an L-lysine derivative of the formula H2N(CH2)4CH(NH2)CONH(CH2)2NH- and the compound A-B is 8'-(4'-carboxymethyloxyphenyl)-1,3-dipropyl xanthine-2-(L-lysyl-amino)-ethylamide.

34. The process of Claim 30, wherein A is 8'-(4'-car-boxymethyloxyphenyl)-1,3-dipropyl xanthine, B is a D-lysine derivative of the formula H2N(CH2)4CH(NH2)CONH(CH2)2NH- and the compound A-B is 8'-(4'-carboxymethyloxyphenyl)-1,3-dipropyl xanthine-2-(D-lysyl-amino)-ethylamide.

35. The process of Claim 30, wherein A is 8'-(4'-car-boxymethyloxyphenyl)-1,3-dipropyl xanthine, B is a D-lysine derivative of the formula CH2CH2CONH(CH2)4CH(NH2)CONH(CH2)2NH- and the compound A-B is 8'-(4'-carboxymethyloxyphenyl)-1,3-dipropyl xanthine-a-(E-4-hydroxy-phenylpropionyl-D-lysyl-amino)-ethylamide.

36. The process of claim 30, wherein A is 8'-(4'car-boxymethyloxyphenyl)-1,3-dipropyl xanthine, B is a D-tyrosine and D-lysine derivative of the formula and the compound A-B is 8'-(4'-carboxymethyloxyphenyl)-1,3-dipropyl xanthine-2-(D-tyrosyl-D-lysyl-amino)-ethylamide.

37. The process of Claim 30, wherein A is 8'-(4'-car-boxymethyloxyphenyl)-1,3-dipropyl xanthine, B is -CH2CH(NH2CONH(CH2)2NH- nnd the compound A-B is 8'-(4'-carboxy-methyloxyphenyl)-1,3-dipropyl xanthine-2-(3(2'-thienyl)-L-alanyl-amino)-ethylamide.

38. The process of Claim 30, wherein A is 8'-(4'-car-boxymethyloxyphenyl)-1,3-dipropyl xanthine, B is an L-leucine derivative of the formula (CH3)2CHCH2CH(NH2)COHN(CH2)2NH- and the copound A-B is 8'-(4'-carboxymethyloxyphenyl)-1,3-dipropyl xanthine-2-(L-leucyl-amino)-ethylamide.

39. The process of Claim 30, wherein A is 8'-(4'-car-boxymethyloxyphenyl)-1,3-dipropyl xanthine, B is an L-phenyla-lanine derivative of the formula and the compound A-B is 8'-(4'-carboxymethyloxyphenyl)-1,3-dipropyl xanthine-2-(L-phenylalanyl-amino)-ethylamide.