US3207758A - Certain 2-(benzenesulfonamido)-5-alkoxypyrimidines - Google Patents

Certain 2-(benzenesulfonamido)-5-alkoxypyrimidines Download PDF

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US3207758A
US3207758A US118534A US11853461A US3207758A US 3207758 A US3207758 A US 3207758A US 118534 A US118534 A US 118534A US 11853461 A US11853461 A US 11853461A US 3207758 A US3207758 A US 3207758A
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sulfonamido
pyrimidine
benzene
methylbenzene
ethoxy
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Worffel Udo
Horstmann Harald
Wirtz Sophie
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Bayer AG
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Bayer AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/69—Benzenesulfonamido-pyrimidines

Definitions

  • the present invention relates to sulfonamides and more particularly to 2 benzene sulfonamido S-alkoxypyrimidines.
  • sulfonamides are obtained with an intensive and long lasting blood sugar depressant activity, when 2-amino-S-aIkoXy-pyrimidines, in which the alkyl residue has a straight or branched chain and possesses 2 to 5 carbon atoms, are reacted in the presence of acid binding agents with benzene sulfochloride or with benzene sulfochlorides which are substituted in the benzene nucleus by lower alkyl and/or alkoxy residues and/or halogen atoms, or when the reaction products of the Vilsmeier reaction between alkoxyacetaldehyde acetals or between 1,2-dialkoxyethylenes, in which the alkyl residue has a straight or branched chain and possesses 2 to 5 carbon atoms, and N,N-disubstituted formamides and inorganic acid chlorides, are condensed in the presence of basic condensation agents, with benzene sulfonyl
  • the 2-amino-5-alkoxy-pyrimidines employed as starting materials for the first mentioned method of execution can be prepared by the process described in the copending application Serial No. 54,836, filed September 9, 1960, and now abandoned.
  • Tertiary organic bases such as pyridine or triethylamine, are the preferred suitable acid-binding agents.
  • Dimethyl formamide is the preferred suitable N,N- disubstituted formamide in the sense of the second method of execution, and phosgene is the preferred suitable inorganic acid chloride.
  • the condensation is carried out within a temperature range of 50-200 C., preferably in an aliphatic alcohol; alkali metal alcoholates or alkali metal hydroxides are particularly suitable as condensation agents.
  • the 2 benzene-sulfonamido-5-alkoxy-pyrimidines obtained according to the process lead to a distinctly exhibited and long lasting depression of the blood sugar level upon administration to experimental animals (rabbit, dog).
  • a single oral administration of 250 mg./ kg. of 2 (4 methylbenzene sulfonamido) 5 npropoxy-pyrimidine to a rabbit with normal metabolism 3,207,758 Patented Sept. 21, 1965 can achieve a 54% depression in the blood sugar level within the first 6 hours.
  • the depression in the blood sugar level is still maintained to the same extent 24 hours after the start of the experiment.
  • a maximum depression in the blood sugar level of 45% can be obtained in 5 hours under the same experimental conditions with 250 mg./kg. of N-(4-aminobenzenesulfonyl -N-n-butyl-urea.
  • the Z-benzene-sulfonamido-5-alkoxy-pyrimidines have a superior effect compared with the Z-sulfanilamido-S- alkoxy-pyrimidines with 2 to 4 carbon atoms in the alkyl residue, as known from the copending application Serial No. 54,853, filed September 9, 1960, and now abandoned. Moreover, they are also distinguished by their lack of undesirable bacteriostatic properties.
  • Example 1 14 g. (0.1 mole) of 2-amino-S-ethQXy-pyrimidine are dissolved in ml. of pyridine. 17.5 g. (0.1 mole) of benzene sulfochloride are added dropwise with stirring and on cooling by ice/common salt. The temperature is allowed to rise gradually, and it is stirred oveinight at room temperature. After heating to 100 C. bath temperature for one hour, the pyridine is distilled oil in vacuo, the residue is digested with dilute hydrochloric acid on the Water bath, and after cooling with ice, it is filtered off with suction.
  • 2-(4-methyl'benzene-sul fonamido) 5 isopnopoxy-pyrimidine of M .P. 186187 C. from Z amino-Sdsopropoxypyrimidine and p-toluene sulfochloride;
  • Example 2 80 g. (0.25 mole) of ethoxy-acetaldehyde diethylacetal are brought to reaction in 300 ml. of methylene chloride with 73 g. of dimethyl formamide and g. of phosgene in analogy to the directions stated by Z. Arnold and F. Srm (Coll. Czechoslovak Chem. Commun. 23 (1958), 452). After neutralization with a methanol solution of sodium methylate and evaporation of the solvent in vacuo there are obtained 82.5 g. of an oily reaction product, which is added dropwise to a suspension of 96 g.
  • 2-benzenesulfonamido-5-n-propoXy-pyrimidine of MI. 181182 C. starting from n-propoXy-acetaldehyde di-npropyl-acetal, by Vilsmeier-Haak reaction with dimethyl formamide and phosgene, and by condensation of the reaction product With benzene-sulfonylguanidine.
  • X is a member selected from the group consisting of hydrogen, chlorine, methyl and methoxy; and R is a member selected from the group consisting of ethyl, propyl, isopropyl and butyl.

Description

United States Patent 3,207,758 CERTAIN 2-(BENZENESULFONAMIDO)-5- ALKOXYPYRFNES Udo Wiirtfel, Wuppertal-Elberfeld, Harald Horstmann,
Wuppertal-Vohwinkel, and Sophie Wirtz, Wuppertal- Eiberfeld, Germany, assignors to Farbenfabriken Bayer Aktiengesellschatt, Leverkusen, Germany, a corporation of Germany N0 Drawing. Filed June 21, 1961, Ser. No. 118,534
Claims priority, application Germany, July 6, 1960,
F 31,592; Aug. 26, 1960, F 31,983 9 Claims. (Cl. 260-256.5)
The present invention relates to sulfonamides and more particularly to 2 benzene sulfonamido S-alkoxypyrimidines.
It is known that, in addition to sulfaureas, certain heterocyclic substituted sulfonamides, e.g. S-sulfa-Z-alkyl- 1,3,4 thiadiazoles and sulfa-Z-alkyl-l,3,4-oxadiazoles, also exhibit a blood sugar depressant activity (cf., e.g., Medizin und Chemie, vol. VI (1958), p. 61 ii).
In spite of a large number of experiments, no further heterocyclic substituted sulfonamides other than the specified compounds have been reported with an antidiabetic etfect which can be utilized in practice.
It is therefore an object of the present invention, to provide heterocyclic substituted sulfonamides useful in the therapy of diabetes. A further object is the provision of sulfonamides having an anti-diabetic effect, but no undesirable bacteriostatic properties. Further objects will become apparent as the present specification proceeds.
We have found that sulfonamides are obtained with an intensive and long lasting blood sugar depressant activity, when 2-amino-S-aIkoXy-pyrimidines, in which the alkyl residue has a straight or branched chain and possesses 2 to 5 carbon atoms, are reacted in the presence of acid binding agents with benzene sulfochloride or with benzene sulfochlorides which are substituted in the benzene nucleus by lower alkyl and/or alkoxy residues and/or halogen atoms, or when the reaction products of the Vilsmeier reaction between alkoxyacetaldehyde acetals or between 1,2-dialkoxyethylenes, in which the alkyl residue has a straight or branched chain and possesses 2 to 5 carbon atoms, and N,N-disubstituted formamides and inorganic acid chlorides, are condensed in the presence of basic condensation agents, with benzene sulfonylguanidine or benzene sulfonylguanidines which are substituted in the benzene nucleus by lower alkyl and/ or alkoxy groups and/or halogen atoms.
The 2-amino-5-alkoxy-pyrimidines employed as starting materials for the first mentioned method of execution can be prepared by the process described in the copending application Serial No. 54,836, filed September 9, 1960, and now abandoned.
Tertiary organic bases, such as pyridine or triethylamine, are the preferred suitable acid-binding agents.
Dimethyl formamide is the preferred suitable N,N- disubstituted formamide in the sense of the second method of execution, and phosgene is the preferred suitable inorganic acid chloride.
During this form of execution, the condensation is carried out within a temperature range of 50-200 C., preferably in an aliphatic alcohol; alkali metal alcoholates or alkali metal hydroxides are particularly suitable as condensation agents.
The 2 benzene-sulfonamido-5-alkoxy-pyrimidines obtained according to the process lead to a distinctly exhibited and long lasting depression of the blood sugar level upon administration to experimental animals (rabbit, dog). Thus, a single oral administration of 250 mg./ kg. of 2 (4 methylbenzene sulfonamido) 5 npropoxy-pyrimidine to a rabbit with normal metabolism 3,207,758 Patented Sept. 21, 1965 can achieve a 54% depression in the blood sugar level within the first 6 hours. The depression in the blood sugar level is still maintained to the same extent 24 hours after the start of the experiment. By comparison, a maximum depression in the blood sugar level of 45% can be obtained in 5 hours under the same experimental conditions with 250 mg./kg. of N-(4-aminobenzenesulfonyl -N-n-butyl-urea.
The Z-benzene-sulfonamido-5-alkoxy-pyrimidines have a superior effect compared with the Z-sulfanilamido-S- alkoxy-pyrimidines with 2 to 4 carbon atoms in the alkyl residue, as known from the copending application Serial No. 54,853, filed September 9, 1960, and now abandoned. Moreover, they are also distinguished by their lack of undesirable bacteriostatic properties.
Example 1 14 g. (0.1 mole) of 2-amino-S-ethQXy-pyrimidine are dissolved in ml. of pyridine. 17.5 g. (0.1 mole) of benzene sulfochloride are added dropwise with stirring and on cooling by ice/common salt. The temperature is allowed to rise gradually, and it is stirred oveinight at room temperature. After heating to 100 C. bath temperature for one hour, the pyridine is distilled oil in vacuo, the residue is digested with dilute hydrochloric acid on the Water bath, and after cooling with ice, it is filtered off with suction. After reprecipitation from aqueous ammonia/acetic acid, the Z-benzene-sulfonamido-5-ethoxypyridine is obtained in the form of colourless crystals of M.P. 174175 C. at a yield of 17.5 g.=62.5% of the theoretical.
By analogy, 2 (4' methylbenzene sulfonamido) 5- ethoxy-pyridine of M.P. 197 C. is obtained from 2- amino-5-ethoxy-pyridine and p-toluene sulfochloride;
2 (2' methylbenzene-sulfonamido)-5-ethoXy-pyrimidine of M.P. 181 C. from 2-amino-5-ethoxy-pyrimidine and o-toluene sulfochloride;
2 (4' methoxybenzene sulfonamido) 5 ethoxypyrimidine of M.P. 196 C. from 2 amino 5 ethoxypyrimidine and p-methoxybenzene sulfochloride;
2- 4'- chlorobenzen e-sulfona-mido -5-ethoxy-py1 imidine of M.P. 183-184 C. from Z-amino-5eth oxy-pyrimidine and p-chlorobenzene sulfochloride;
2- 4'- methylb enzene-sulfonamido) -5-n-propoxy-pyrirnidine of M.P. 196-197 C. from 2amino-5-n-pnopoxypyrimidine and p-toluene sulfochloride;
2-(4-methyl'benzene-sul fonamido) 5 isopnopoxy-pyrimidine of M .P. 186187 C. from Z amino-Sdsopropoxypyrimidine and p-toluene sulfochloride;
2 (4' methylbenzene sulfonamido)-5-n-butoxy-pyrimidine of M.P. 179-180 C. from 2-amino-5-n-butoxy pyrimidine (M.P. 72-74 C.) and p-toluene sulfochloride.
Example 2 80 g. (0.25 mole) of ethoxy-acetaldehyde diethylacetal are brought to reaction in 300 ml. of methylene chloride with 73 g. of dimethyl formamide and g. of phosgene in analogy to the directions stated by Z. Arnold and F. Srm (Coll. Czechoslovak Chem. Commun. 23 (1958), 452). After neutralization with a methanol solution of sodium methylate and evaporation of the solvent in vacuo there are obtained 82.5 g. of an oily reaction product, which is added dropwise to a suspension of 96 g. (0.45 mole) of p-rnethylbenzene-sulfonylguanidine in 1000 ml. of ethanol containing 46 g. of dissolved sodium. After boiling under reflux for 8 hours, the ethanol is distilled oil in vacuo. The residue is digested with cold water, non-reacted p-methylbenzene-sulfonylguanidine is filtered oil with suction, and the filtrate is acidified with acetic acid. 2 (4' methylbenzene sulfonamido)-5-ethoxypyrimidine, which on reprecipitation from aqueous am- G monia/acetic acid melts at 197 C., is obtained in good yield.
By analogy, 2 (2' methylbenzene sulfonamido)-5- ethoxy-pyrimidine of MP. 184 C. is obtained, starting from ethoxy-acetaldehyde diethyl-acetal, by Vilsmeier reaction With dimethyl formamide and phosgene, and by condensation of the reaction product with 2-methylbenzene-sulfonylguanidine;
2-benzenesulfonamido-5-n-propoXy-pyrimidine of MI. 181182 C., starting from n-propoXy-acetaldehyde di-npropyl-acetal, by Vilsmeier-Haak reaction with dimethyl formamide and phosgene, and by condensation of the reaction product With benzene-sulfonylguanidine.
We claim:
1. A 2-benzene sulfonamido S-aIkQXy-pyrimidine of the formula:
wherein X is a member selected from the group consisting of hydrogen, chlorine, methyl and methoxy; and R is a member selected from the group consisting of ethyl, propyl, isopropyl and butyl.
2. 2-benzene-sulfonamido-5-ethoXy-pyrimidine.
3. 2 (4' methylbenzene sulfonamido)-5-ethoXy-pyrimidine.
4. 2 (2 methylbenzene sulfonamido)-5-ethoXy-pyrimidine.
5. 2 (4' methoxybenzene-sulfonamido)-5-ethoxy-pyrimidine.
6. 2 (4 chlorobenzene -sulfonamido)-5-ethoXy-pyrimidine.
7. 2 (4' methylbenzene-sulfonamido)-5-n-propoxypyrimidine.
8. 2 (4-methylbenzene-sulfonamido)-5-isopropoxypyrimidine.
9. 2 (4 methylbenzene sulfonamido)-5-n-butoxypyrimidine.
References Cited by the Examiner UNITED STATES PATENTS 12/50 Hultquist et al. 260256.5 8/51 Hultquist et a1 260-256.5
OTHER REFERENCES NICHOLAS S. RIZZO, Primary Examiner.
IRVING MARCUS, Examiner

Claims (1)

1. A 2-BENZENE - SULFONAMIDO - 5-ALKOXY-PYRIMIDINE OF THE FORMULA:
US118534A 1960-07-06 1961-06-21 Certain 2-(benzenesulfonamido)-5-alkoxypyrimidines Expired - Lifetime US3207758A (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3293259A (en) * 1965-08-13 1966-12-20 American Home Prod Certain 1-arylsulfonyl-1, 2, 4-triazoles
US3331841A (en) * 1961-02-22 1967-07-18 Schering Ag Certain derivatives of 2-amino-5-alkoxypyrimidine
US3980781A (en) * 1966-03-31 1976-09-14 Imperial Chemical Industries Limited Fungicidal composition and method containing 2-amino-pyrimidines

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2535635A (en) * 1948-05-06 1950-12-26 American Cyanamid Co Substituted pyrimidines and preparation of the same
US2563725A (en) * 1949-05-10 1951-08-07 American Cyanamid Co Phenolsulfonamides

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB860423A (en) * 1958-10-25 1961-02-08 Basf Ag Production of compounds of the pyrimidine series

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2535635A (en) * 1948-05-06 1950-12-26 American Cyanamid Co Substituted pyrimidines and preparation of the same
US2563725A (en) * 1949-05-10 1951-08-07 American Cyanamid Co Phenolsulfonamides

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3331841A (en) * 1961-02-22 1967-07-18 Schering Ag Certain derivatives of 2-amino-5-alkoxypyrimidine
US3293259A (en) * 1965-08-13 1966-12-20 American Home Prod Certain 1-arylsulfonyl-1, 2, 4-triazoles
US3980781A (en) * 1966-03-31 1976-09-14 Imperial Chemical Industries Limited Fungicidal composition and method containing 2-amino-pyrimidines

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CH437311A (en) 1967-06-15
DE1445028B1 (en) 1970-03-26

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