Claims
- 1. A compound which is characterized by physiological activity, pharmaceutical acceptability, xanthineoxidase-inhibitory utility and a structure which has a (1H)-pyrimidine nucleus that is (organic-acid-acyl)amino substituted in the 1-position, unsubstituted in the 2- and 6-positions, oxo substituted in the 4-position and cyano substituted in the 5-position; the organic acid of the organic-acid acyl being a diazinoheterocyclic-free carbonic or carboxylic acid, a carbon atom of which is directly bound to the amino nitrogen.
- 2. A compound according to claim 1 which is further characterized by low toxicity and freedom from substitution in the 3-position.
- 3. A physiologically-active and pharmaceutically-acceptable 1-acylamino-5-cyano-4(1H)-pyrimidinone of the formula ##STR19## wherein R.sup.3 is --C(O)--R.sup.4, --C(O)--O--R.sup.4 or --C(O)--N(R.sup.5)R.sup.6;
- R.sup.4 is --H, alkyl having from 1 to 14 carbon atoms, alkenyl having up to 14 carbon atoms, alkynyl having up to 14 carbon atoms, substituted or unsubstituted alkoxyalkyl having from 2 to 13 carbon atoms, substituted or unsubstituted alkenyloxyalkyl having up to 13 carbon atoms, substituted or unsubstituted cycloalkyl having from 3 to 6 ring carbon atoms, substituted or unsubstituted phenyl, nuclearly-substituted or unsubstituted phen(lower)alkyl; any substituent of, substituted alkoxyalkyl, substituted alkenyloxyalkyl or substituted cycloalkyl being methyl; and any substituent of substituted phenyl or substituted phenalkyl being lower alkyl, lower alkoxy, alkoxycarbonyl with from 2 to 5 carbon atoms, halo, trifluoromethyl, nitro or cyano;
- R.sup.5 is --H, lower alkyl, lower alkoxyalkyl, cycloalkyl with from 3 to 6 ring carbon atoms or, together with R.sup.6, alkylene having from 2 to 5 carbon atoms or a divalent aliphatic chain having three to five chain members, each of at least two of which is methylene or another lower alkylidene and at least one remaining chain member is, independently, --O-- or --S-- or --N(R.sup.7)--;
- R.sup.6 is --H, lower alkyl, lower alkoxyalkyl, cycloalkyl with from 3 to 6 ring carbon atoms or, together with R.sup.5, alkylene having from 2 to 5 carbon atoms or a divalent aliphatic chain having from three to five chain members, each of at least two of which is methylene or another lower alkylidene and at least one remaining chain member is, independently, --O-- or --S--.
- 4. A pharmacologically-active and therapeutically-acceptable compound according to claim 3 wherein:
- R.sup.4 is --H, alkyl having from 1 to 14 carbon atoms, alkoxyalkyl having from 2 to 13 carbon atoms, substituted or unsubstituted cycloalkyl having from 3 to 6 ring carbon atoms, phenyl, substituted phenyl, phenalkyl wherein the alkyl has 1 or 2 carbon atoms, nuclearly-substituted phenalkyl wherein the alkyl has 1 or 2 carbon atoms; any substituent of substituted cycloalkyl being methyl; and any nuclear substituent of substituted phenyl or of substituted phenalkyl being alkyl having from 1 to 4 carbon atoms, alkoxy having from 1 to 4 carbon atoms, alkoxycarbonyl having from 2 to 5 carbon atoms, trifluoromethyl, nitro or cyano;
- R.sup.5 is --H, alkyl having from 1 to 4 carbon atoms, alkoxyalkyl having 2 or 3 carbon atoms, cycloalkyl having from 3 to 6 ring carbon atoms or, together with R.sup.6, pentamethylene, 3-oxapentamethylene or 3-thiapentamethylene; and
- R.sup.6 is --H, alkyl having from 1 to 4 carbon atoms, alkoxyalkyl having 2 or 3 carbon atoms, cycloalkyl having from 3 to 6 ring carbon atoms or, together with R.sup.5, pentamethylene, 3-oxapentamethylene or 3-thiapentamethylene.
- 5. A pharmacologically-active and physiologically-compatible compound according to claim 3 which is of the formula ##STR20## wherein R.sup.3* is --CO--R.sup.4*, --CO--OR.sup.4* or --CO--N(R.sup.5*)R.sup.6* ;
- R.sup.4* is alkyl having from 1 to 14 carbon atoms, alkoxyalkyl having from 2 to 13 carbon atoms, alkenyloxyalkyl having up to 13 carbon atoms, substituted or unsubstituted phenyl, nuclearly-substituted or unsubstituted benzyl or substituted or unsubstituted cycloalkyl having from 3 to 6 ring carbon atoms; any substituent of substituted cycloalkyl being methyl; and any substituent of substituted phenyl or substituted benzyl being lower alkyl, lower alkoxy, alkoxycarbonyl with from 2 to 5 carbon atoms, halo, trifluoromethyl, nitro or cyano; and each of R.sup.5* and R.sup.6* is, independently, --H or alkyl having from 1 to 4 carbon atoms.
- 6. A therapeutically-active and pharmaceutically-acceptable compound according to claim 5 wherein R.sup.4* is alkyl having from 1 to 7 carbon atoms, alkoxyalkyl having from 2 to 6 carbon atoms, substituted or unsubstituted cyclohexyl, phenyl or benzyl; and any substituent of substituted cyclohexyl being methyl; and each of R.sup.5* and R.sup.6* is, independently, --H or methyl.
- 7. A pharmaceutically-active and physiologically-acceptable compound according to claim 5 wherein R.sup.3* is --CO--R.sup.4* or --CO--OR.sup.4*.
- 8. The compound according to claim 1 which is N-[5-cyano-4(1H)-oxo-1-pyrimidine]acetamide.
- 9. The compound according to claim 1 which is (2-methoxyethyl)-N-[5-cyano-4(1H)-oxo-1-pyrimidine]aminoformate.
- 10. The compound according to claim 1 which is methyl-N-[5-cyano-4(1H)-oxo-1-pyrimidine]aminoformate.
- 11. The compound according to claim 1 which is ethyl-N-[5-cyano-4(1H)-oxo-1-pyrimidine]aminoformate.
- 12. The compound according to claim 1 which is phenyl-N-[5-cyano-4(1H)-oxo-1-pyrimidine]aminoformate.
- 13. A compound according to claim 3 wherein R.sup.3 is --C(O)--R.sup.4.
- 14. A compound according to claim 3 wherein R.sup.3 is --C(O)--O--R.sup.4.
- 15. A compound according to claim 3 wherein R.sup.3 is --C(O)--N(R.sup.5)R.sup.6.
- 16. A medicament composition in dosage form which contains, as a pharmacologically-active component thereof, an effective amount of at least one compound according to claim 1 and pharmaceutical vehicle or diluent therefor.
- 17. A pharmaceutically-acceptable composition which contains a total of from about 0.1 percent to about 75 percent by weight of at least one pharmacologically-active compound according to claim 1 and pharmaceutical vehicle for diluent therefor.
- 18. A composition according to claim 17 which contains a total of from 1 to 50 percent by weight of the pharmacologically-active compound.
- 19. A method which comprises administering an effective amount of a medicament composition according to claim 17 to a subject afflicted with gout.
- 20. The compound according to claim 3, wherein R.sup.3 is --CHO.
- 21. A medicament composition according to claim 16 for treating gout and having an effective concentration and amount of the pharmacologically-active component.
- 22. A medicament composition according to claim 16 for treating cardiac insufficiency and having an effective concentration and amount of the pharmacologically-active component.
- 23. A medicament composition according to claim 16 for treating arrhythmia and having an effective concentration and amount of the pharmacologically-active component.
Priority Claims (3)
| Number |
Date |
Country |
Kind |
| 66036 |
Sep 1972 |
LU |
|
| 66037 |
Sep 1972 |
LU |
|
| 66038 |
Sep 1972 |
LU |
|
RELATED APPLICATIONS
This application is related to three concurrently-filed applications of the subject inventors. These applications are entitled FORMYLAZAPENTADIENENITRILES (U.S. Pat. No. 3,944,667); 3-CHLORO-2-HYDRAZONOMETHYL-4-AZA-2,4-PENTADIENENITRILES (Ser. No. 393,812, now abandoned) and 2-HYDRAZONOMETHYL-3-HYDROXY-4-AZA-2,4-PENTADIENENITRILES (U.S. Pat. No. 3,923,817). The disclosure of each of these related applications is incorporated herein, in its entirety, by reference.
Derivatives of pyrazolo-(3,4-d)-pyrimidine which have enzyme inhibiting properties have been known for a considerable time. 4-hydroxy-1H-pyrazolo-(3,4-d)-pyrimidine, known as "allopurinol", inhibits the enzyme, xanthineoxidase. This enzyme catalyses the oxidation of purine derivatives to uric acid in vivo. In a similar manner allopurinol suppresses the oxidation of 6-mercaptopurine to 6-thiouric acid (German Offenlegungsschrift No. 1,904,894). Since allopurinol considerably reduces the amount of uric acid formed in purine metabolism, it is used therapeutically for treating gout. A disadvantage of so using allopurinol is, however, that it has relatively high toxicity and, in comparison with its toxicity, is used in relatively high doses, i.e. at the rate of 100 to 800 mg per person per day. It has thus been desirable to find products which, while having a substantially lesser degree of toxicity, also inhibit xanthineoxidase and are useful for treating gout.
1-(organic-acid-acyl)amino-5-cyano-4-(1H)-pyrimidinones, an acid addition salt thereof (preferably one which is pharmacologically acceptable) or an acid amide or other functional derivative thereof, particularly a compound of the formula ##STR1## wherein R.sup.3 is an organic acid acyl, e.g. --C(X)--R.sup.4, --C(X)--Y--R.sup.4 and --C(X)--N(R.sup.5)R.sup.6 ;
R.sup.8 is hydrogen atom (--H), lower alkyl, lower alkoxyalkyl, cycloalkyl or methyl-substituted cycloalkyl with from 3 to 6 ring carbon atoms or, together with R.sup.9, alkylene having from 2 to 5 carbon atoms, preferably pentamethylene, or a divalent aliphatic chain having from 3 to 5 chain members, each of at least two of which is methylene or another lower alkylidene and at least one remaining chain member is, independently, --O--, --S-- or --N(R.sup.7)--, such as 3-thia, 3-aza- or, preferably, 3-oxapentamethylene;
A further method of preparation of compounds of formula I comprises reacting cyanoacetamide with a trialkyl orthoformate or a dialkoxymethyl ester of an organic carboxylic acid in the presence of an acid anhydride and reacting the resulting reaction product with a hydrazine derivative R.sup.3 --NH--NH.sub.2, in which R.sup.3 has the same meaning as given in the general formula I.
Any obtained free compound with a salt-forming group is, optionally, converted by conventional means into one of its acid addition salts, more particularly a pharmacologically-acceptable acid addition salt, or any resultant acid addition salt is conventionally converted, if desired, into another acid addition salt, e.g., a therapeutically-compatible salt, or into the corresponding free base.
The starting materials of formula II are described in the concurrently-filed and previously-noted application Ser. No. 393,812; those of formula III are described in U.S. Pat. No. 3,923,817.
3-Chloro-2-(organic-acid-acyl-substituted)hydrazonomethyl-5-(tertiary)amino or cycloimino-4-aza-2,4-pentadienenitriles of formula II and acid addition salts thereof are prepared by reacting a corresponding 4-aza-3-chloro-2-formyl-5-(tertiary)amino or cycloimino-2,4-pentadienenitrile or an acid addition salt thereof with an acyl hydrazine, R.sup.3 --NH--NH.sub.2, wherein R.sup.3 has its previously-ascribed meaning. The reaction is preferably carried out in an inert organic solvent, e.g. benzene, toluene, xylene, dioxane, ethyl acetate, chloroform, dimethylformamide or an alcohol, such as ethanol or isopropanol, or solvent mixture while cooling or at an elevated temperature, preferably at temperatures between 0.degree. and 100.degree. C. or at the boiling temperature of the solvent, more particularly between 20.degree. and 60.degree. C.
2-(organic-acid-acyl-substituted)hydrazonomethyl-3-hydroxy-5-[hydroxy, (lower)alkoxy, amino, amido, cycloimino or cycloimido]-4-aza-2,4-pentadienenitrile of formula III, tautomers and acid addition salts thereof are prepared, e.g., by reacting a corresponding 5-hydroxy, amino, amido, cycloimino or cycloimido-4-aza-2-formyl-3-hydroxy-2,4-pentadienenitrile with an acyl hydrazine, R.sup.3 --NH--NH.sub.2, wherein R.sup.3 has its previously-ascribed meaning. This reaction is preferably carried out in an inert organic solvent, e.g. chloroform, benzene, toluene, xylene, dioxane, dimethylformamide or acetyl acetate, with cooling or at an elevated temperature, for example at the boiling point of the solvent, preferably at room temperature.
Starting materials of formula IV are obtained by reacting a compound of the formula ##STR5## in which R.sup.1 and R.sup.2 have the meanings given for formula IV, with an trialkyl orthoformate, for example triethyl orthoformate, or a dialkoxymethyl acetate, for example diethoxymethyl acetate, in the presence of an acid anhydride, for example acetate anhydride; the resulting reaction product is reacted with a hydrazine derivative of the formula H.sub.2 N--NH--R.sup.3, in which R.sup.3 has its previously-ascribed meaning. The reaction of V with trialkyl orthoformate or dialkoxymethyl acetate is carried out in the presence, preferably in the absence, of inert organic solvents, and preferably at temperatures between 50.degree. to 150.degree. C. The reaction of V with a trialkyl orthoformate is preferably carried out in the presence of at least equimolar quantities of acid anhydride; the reaction of V with a dialkoxymethyl acetate is preferably carried out in the presence of at least catalytic quantities of acid anhydride, and the orthoester or dialkoxymethyl acetate is preferably used in an excess, and more particularly in a twofold to fourfold molar amount relative to the amount of V.
Compounds of formula V are prepared according to the method disclosed in the Belgian Pat. No. 727,754 or by heating of cyanacetamide with formamide acetals of the formula R.sup.1 (R.sup.2)NCH(OR).sub.2, wherein R.sup.1 and R.sup.2 have the above mentioned meanings and R represents and alkyl group having from 1 to 7, preferably 1 to 4 carbon atoms, at about 50.degree. C. in a molar ratio of formamide acetal: cyanacetamide of about 1:1.
Throughout this disclosure and that for the previously-identified related applications a number of terms reappear. The following retain the same meanings throughout the four applications unless expressly further limited:
Compounds of this invention which have particularly noteworthy properties are therapeutically-active and pharmacologically-compatible compounds of the formula ##STR6## wherein R.sup.3* is --CO--R.sup.4*, --CO--OR.sup.4* or, moreover, --CO--N(R.sup.5*)R.sup.6* or --C(NH)--N(R.sup.5*)R.sup.6* ; R.sup.4* is alkyl having from 1 to 14, preferably from 1 to 7, carbon atoms; substituted or unsubstituted alkoxyalkyl having from 2 to 13, preferably from 2 to 6, carbon atoms; substituted or unsubstituted alkenyloxyalkyl having up to 13, preferably from 5 to 7, carbon atoms; substituted or unsubstituted phenyl; nuclearly-substituted or unsubstituted benzyl; substituted or unsubstituted cycloalkyl with from 3 to 6 ring carbon atoms, preferably a cyclohexyl radical; any substituent on a substituted alkyl, substituted alkoxyalkyl, substituted cycloalkyl (other than a methyl group) being a salt-forming basic group, particularly an --N(R.sup.5*)R.sup.6* group; any substituent on a substituted phenyl or on a substituted benzyl being lower alkyl, lower alkoxy, lower alkylmercapto, alkoxycarbonyl with from 2 to 5 carbon atoms, halo, trifluoromethyl, nitro or cyano; and
from 1 to 4 carbon atoms, preferably --H or methyl. Especially valuable compounds are N-[5-cyano-4(1H)-oxo-1-pyrimidin]acetamide, (2-methoxyethyl)-N-[5-cyano-4(1H)-oxo-1pyrimidin]aminoformate, methyl-N-[5-cyano-4-(1H)-oxo-1-pyrimidin]aminoformate, ethyl-N-[5-cyano-4(1H)-oxo-1-pyrimidin]aminoformate and phenyl-N-[5 -cyano-4(1H)-oxo-1- pyrimidin]aminoformate which, when administered per os to rats at a rate of 10 to 100 mg/kg, produce a pronounced lowering of the uric acid level in the blood.
Synthesis of compounds of formula I from compounds of formula II is effected without, but preferably in, an organic solvent, for example benzene, toluene, xylene, dioxane, dimethylformamide, ethyl acetate or chloroform, but preferably, an alcohol, more particularly methanol, or a solvent mixture while cooling or at an elevated temperature, preferably between 0.degree. C. and 60.degree. C. and, more particularly, at 20.degree. C.
Alternatively, compounds of formula I are synthesized by heating a compound of formula III or a compound of the formula ##STR7## wherein R.sup.3 has its previously-ascribed meaning;
For acid treatment of either a compound of formula II, one of the formula III or one of formula IV (or an acid addition salt or tautomer thereof) suitable acids are hydrogen halides, preferably hydrogen chloride, p-toluenesulfonic acid, formic acid, acetic acid, sulfuric acid or perchloric acid. Acetic acid is preferred for the acid treatment of compounds III and IV. The acid used should be present in at least catalytic quantities for effecting ring closure with compounds of formula II. When ring closure is effected on compounds of formula III or those of formula IV with acid treatment, the acid should also be employed in at least catalytic quantities.
According to a still further method for preparing compounds of formula I, cyanacetamide is reacted with a trialkyl, preferably tri(lower)alkyl, orthoformate [HC(OR).sub.3 ] or a dialkoxymethyl, preferably di(lower)alkoxymethyl, ester of an organic carboxylic acid [R'COOCH(0R).sub.2 ] in the presence of an acid anhydride, and the resulting reaction product is reacted with a hydrazine derivative of the formula C., C.,
In the last-noted synthesis cyanacetamide is reacted with an trialkyl orthoformate or a dialkoxymethyl ester of an organic carboxylic acid in the presence or preferably in the absence of inert organic solvents, such as benzene, toluene, xylene or o-dichlorobenzene, and the reaction is carried out at room temperature or, preferably, at temperatures between 50.degree. and 150.degree. C., more particularly between 80.degree. and 120.degree. C., or at the boiling temperature of the solvent. The reaction of cyanacetamide with trialkyl orthoformate is preferably carried out in the presence of at least equimolar quantities of acid anhydride. The reaction of cyanacetamide with a dialkoxymethyl ester is preferably carried out in the presence of at least catalytic quantities of acid anhydride, and the orthoester or dialkoxymethyl ester is preferably used in an excess, and more particularly in a twofold to fourfold molar amount relative to the amount of cyanacetamide.
The reaction of the reaction product, obtained from cyanacetamide and trialkyl orthoformate or dialkoxymethyl ester of an carboxylic acid, with the hydrazine derivative H.sub.2 N--NH--R.sup.3 is preferably carried out in the presence of an inert organic solvent, for example chloroform, benzene, toluene, xylene, dioxane, dimethyl formamide and especially ethyl acetate, while cooling, at room temperature or particularly at an elevated temperature, more particularly between 50.degree. and 150.degree. C., or at the boiling temperature of the solvent.
In a trialkyl orthoformate of the formula HC(OR).sub.3 R denotes an alkyl group with 1 to 7, preferably 1 to 4 carbon atoms, and a trialkyl orthoformate denotes particularly trimethyl- or triethyl orthoformate.
In a dialkoxymethyl ester of organic carboxylic acids of the formula R'COOCH(OR).sub.2 R' denotes an organic residue, for example aryl, e.g. phenyl, aralkyl, e.g. benzyl, or cycloalkyl, e.g. cyclohexyl, and particularly a hydrogen atom (--H) or an alkyl group with 1 to 7, preferably 1 to 4, carbon atoms; R denotes alkyl with from 1 to 7, preferably 1 to 4, carbon atoms; and a dialkoxymethyl ester of organic carboxylic acids denotes, particularly, dimetho xymethylacetate or diethoxymethylacetate.
Acid anhydrides are anhydrides or mixed anhydrides of organic carboxylic acids, preferably containing from 1 to 4 carbon atoms, for example propionic anhydride or butyric anhydride, and especially acetic anhydride or formic-acetic anhydride. At least when an anhydride, which is different from a mixed anhydride containing the formic residue, is used, it is convenient to use, in addition to the anhydride, an at least catalytic quantity of formic acid to reduce the reaction time.
Based on NMR analysis, the reaction product obtained from the reaction of cyanacetamide with trialkyl orthoformiate or dialkoxymethyl ester of an organic carboxylic acid is a mixture of compounds of the formula ##STR8## and compounds of the formula ##STR9## or their tautomers, in which R has the previously-ascribed meaning.
The conditions for the described reactions are selected with due consideration of all substituents of the reactants. 1 LU 09081972 66039
The invention also relates to those embodiments wherein (a) a compound (which can be obtained as an intermediate in any particular stage of the method) is used as starting material and additional method steps are carried out, (b) the method is interrupted at some particular stage or (c) a compound used as a starting material is formed under reaction conditions or is used in the form of a reactive derivative, a tautomeric form or a salt.
The new compounds with salt-forming basic groups, such as NR.sup.5 R.sup.6 groups, are obtained in free-base form or in the form of their salts, depending upon reaction conditions, and these forms are interconverted in a conventional manner.
Salts of the compounds of formula I may be readily or sparingly soluble in water, and the sparingly soluble salts are particularly useful for producing retard forms of such compounds.
The starting materials are preferably materials which lead to the compounds which are indicated to be particularly valuable.
Compounds of formula I and their pharmacologically-compatible salts with organic or inorganic acids possess valuable pharmacological properties and are useful as medicaments. They possess an inhibiting action, novel for such a group of substances, on the enzyme, xanthineoxidase, and concurrently possess extremely low toxicity. These compounds produce a pronounced lowering of the uric acid blood level when administered per se to rats.
Compounds of formula I and their pharmacologically-compatible salts with inorganic and organic acids are therefore valuable therapeutic chemicals, preferably for the treatment of gout, but also for treating coronary insufficiency and with an anti-arrhythmic action. They are also valuable intermediates, for example, for the production of compounds IV, including tautomers thereof. Synthesis of the latter compounds is effected by reacting a compound of formula I with a secondary amine or a cycloimine, such as piperidine, according to the reaction scheme: ##STR10## wherein R.sup.1, R.sup.2 and R.sup.3 have the meanings previously ascribed to them under formula IV.
Compounds of formula IV possess an inhibiting action on the enzyme, xanthineoxidase. They, their tautomers and their pharmacologically-accepatable acid addition salts are useful for treating gout by, e.g. administering them orally in unit dosage from to those afflicted with gout.
Medicaments or pharmaceutical compositions which contain one or more compounds of formula I (in a free form or in the form of a pharmacologically-compatible acid addition salt) as active substance can, but need not, contain other pharmacologically-active substance. Such medicaments are produced in a conventional manner by combining the active substance with a pharmaceutical vehicle, such as a filler, a diluent, a correcting agent and/or components conventional for medicaments. The medicaments are produced in a solid dosage form as, e.g., tablets or capsules, or in a liquid form as, e.g., solutions or suspensions. The pharmaceutical vehicle can also contain conventional diluent and tablet-forming additions, such as cellulose powder, maize starch, lactose and talcum, as conventional for such purposes.
The production of a pharmaceutical preparation is carried out in a conventional manner, for example by means of conventional mixing, granulating and coating methods. The pharamaceutical preparations contain from approximately 0.1% to 75%, preferably from 1% to approximately 50%, by weight of the active substance. Administration is enteral, for example oral, or parenteral; individual doses of active substance are between 0.1 and 10, preferably from 0.5 to 5, mg/kg of body weight. For application in human medicine these doses correspond to an individual dose of approximately 10 to 1000, preferably 50 to 500, mg of active substance.
The indicated doses are administered 1 to 4 times daily, for example at mealtimes and/or in the evening. The individual dose, the frequency of administration and the duration of treatment are determined by the nature and severity of the illness.
The invention thus relates to medicaments, particularly for treating gout but also for cardiac insufficiency and arrhythmia. The medicaments are characterized by a content of one or more compounds of formula I in a free form or in the form of pharmacologically-compatible salts.
US Referenced Citations (1)
| Number |
Name |
Date |
Kind |
| 2831833 |
Aycock et al. |
Apr 1958 |
|
Non-Patent Literature Citations (1)
| Entry |
| Kloetzer et al., "Chemical Abstracts," vol. 66, 1967, Col. 46390t, (Abstract of Montash. Chem., vol. 96(6), 1965, pp. 1731-1738). |
Patent Grant
4034093
