 |
|
 |
| |
 |
Penicillins and salts thereof |
| RE31926 |
Penicillins and salts thereof
|
|
| Patent Drawings: | |
| Inventor: |
Wetzel, et al. |
| Date Issued: |
June 25, 1985 |
| Application: |
06/420,804 |
| Filed: |
September 21, 1982 |
| Inventors: |
Goeth; Hanns (Biberach an der Riss, DE)
Lechner; Uwe (Ummendorf, DE)
Maier; Roland (Biberach an der Riss, DE)
Reuter; Wolfgang (Laupertshausen, DE)
Werner; Rolf (Biberach an der Riss, DE)
Wetzel; Bernd (Biberach an der Riss, DE)
Woitun; Eberhard (Biberach an der Riss, DE)
|
| Assignee: |
Boehringer Ingelheim GmbH (Ingelheim am Rhein, DE) |
| Primary Examiner: |
Trousof; Natalie |
| Assistant Examiner: |
Clarke; Vera C. |
| Attorney Or Agent: |
Hammond & Littell, Weissenberger & Dippert |
| U.S. Class: |
514/157; 514/195; 540/334 |
| Field Of Search: |
424/226; 424/229; 424/246; 424/248.51; 424/251; 424/271; 260/239.1 |
| International Class: |
|
| U.S Patent Documents: |
3634405; 4031230; 4038271; 4103011 |
| Foreign Patent Documents: |
|
| Other References: |
|
|
| Abstract: |
Compounds of the formula ##STR1## wherein A is phenyl; 4-hydroxy-phenyl; 2- or 3-thienyl; cyclohexyl; cyclohexen-1-yl; cyclohexa-1, 4-dien-1-yl; or 3,4-disubstituted phenyl, where the substituents may be identical to or different from each other and are selected from the group consisting of chlorine, hydroxyl or methoxy; andR is an aliphatic, cycloaliphatic; aromatic or heterocyclic group of diverse types;and non-toxic, pharmacologically acceptable salts thereof formed with inorganic or organic bases. The compounds as well as their salts are useful as antibiotics. |
| Claim: |
We claim:
1. A compound of the tautomeric formulas ##STR45## wherein A is phenyl; 4-hydroxyphenyl; 2-thienyl; 3-thienyl; cyclohexyl; cyclohexen-1-yl; cyclohexa-1,4-dien-1-yl; phenyldisubstituted in 3,4-position, where the substituents are each chlorine, hydroxyl or methoxy;
R is hydrogen; aliphatic hydrocarbyl of 1 to 8 carbon atoms optionally containing one to two double bonds or a triple bond; cyclopropyl, which may optionally be substituted with one to two methyl groups, an ethyl group or a phenyl group; cycloalkyl of 4 to 8 carbon atoms optionally containing one or more double bonds; ##STR46## .beta.-phenylethyl; .gamma.-phenyl-propyl; .beta.-phenylethylidine; cyclopropyl-methyl; 1-cyclopropylethyl; hydroxyl; alkoxy of 1 to 8 carbon atoms; alkenyloxy of 1 to 8 carbon atoms; cycloalkoxy of 3 to 6 carbon atoms; phenoxy; benzyloxy; mercapto; alkylmercapto of 1 to 8 carbon atoms; cycloalkylmercapto of 3 to 6 carbon atoms; phenylmercapto; benzylmercapto; p-chloro-benzylmercapto; alkylsulfinyl of 1 to 4 carbon atoms; ##STR47## morpholino; thiomorpholino; thiomorpholino-S-oxide; thiomorpholino-S,S-dioxide; ##STR48## n is 0 or 1;
R.sub.1, R.sub.2 and R.sub.3 are each hydrogen; halogen; amino; alkylamino; dialkylamino of 1 to 4 carbon atoms; hydroxy; alkoxy of 1 to 4 carbon atoms; nitro; formylamino; aliphatic acylamino of 1 to 4 carbon atoms in the alkyl moiety; alkylsulfonylamino of 1 to 4 carbon atoms; alkylcarbonyl of 1 to 4 carbon atoms in the alkyl moiety; alkylcarbonyloxy of 1 to 4 carbon atoms in the alkyl moiety; alkoxycarbonyl of 1 to 4 carbon atoms in the alkyl moiety; aminocarbonyl, optionallysubstituted by one to two alkyl groups of 1 to 3 carbon atoms; cyano; alkylmercapto of 1 to 4 carbon atoms; alkylsulfoxy of 1 to 4 carbon atoms; alkylsulfonyl of 1 to 4 carbon atoms; aminosulfonyl; alkylaminosulfonyl of 1 to 4 carbon atoms; dialkylaminosulfonyl of 1 to 4 carbon atoms in the alkyl moiety; trifluoromethylsulfonyl; alkyl of 1 to 4 carbon atoms; trifluoromethyl; or phenyl;
R.sub.4 and R.sub.5 are each hydrogen; aliphatic hydrocarbyl of 1 to 8 carbon atoms optionally containing one to two double bonds or a triple bond; cycloalkyl of 3 to 8 carbon atoms which may be substituted with one to two methyl or ethylgroups and may contain one or more double bonds; or cycloalkyl-substituted alkyl of 3 to 8 carbon atoms in the cycloalkyl moiety and 1 to 3 carbon atoms in the alkyl moiety;
R.sub.4 and R.sub.5 together can also form an alkylene chain of 2 to 7 carbon atoms, so that a 3- to 8-membered heterocyclic ring is formed, which may optionally be substituted with one to two alkyl groups of 1 to 3 carbon atoms or a benzylgroup, or may contain one to two double bonds or may be fused with a phenyl ring;
R.sub.6 is hydrogen; formyl; acetyl; ethoxycarbonyl; benzyloxycarbonyl; methyl; ethyl; phenyl; or benzyl;
R.sub.7 is hydrogen.[.,.]..Iadd.; .Iaddend.methyl; or ethyl;
m is 0, 1 or 2;
R.sub.8, R.sub.9 and R.sub.10 are each hydrogen; halogen; amino; alkylamino of 1 to 6 carbon atoms; dialkylamino, where each alkyl moiety contains 1 to 6 carbon atoms; pyrrolidyl; piperidyl; hydroxyl; alkoxy of 1 to 6 carbon atoms; formylamino; formylalkylamino of 1 to 3 carbon atoms in the alkyl moiety; aliphatic acylamino of 1 to 3 carbon atoms; acylalkylamino of 1 to 4 carbon atoms in the alkyl moiety and 1 to 3 carbon atoms in the acyl moiety; trifluoroacetylamino; aminocarbonylamino; alkylaminocarbonylamino of 1 to 6 carbon atoms in the alkyl moiety; dialkylaminocarbonylamino of 1 to 6 carbon atoms in each alkyl moiety; nitro; alkylsulfonylamino of 1 to 4 carbon atoms in the alkyl moiety; alkylsulfonylalkylamino of 1 to 4 carbon atoms in each alkyl moiety; hydroxysulfonylamino; hydroxysulfonylalkylamino of 1 to 3 carbon atoms in the alkyl moiety; amidino; guanidino.[.,.]..Iadd.; .Iaddend.formyl.[.,.]..Iadd.; .Iaddend.alkylcarbonylof 1 to 6 carbon atoms; benzoyl; alkylcarbonyloxy; alkoxycarbonyl or alkoxycarbonyloxy .[.groups.]. of 1 to 6 carbon atoms; formyloxy; carboxyl; aminocarbonyl; alkylaminocarbonyl of 1 to 4 carbon atoms in the alkyl moiety; dialkylaminocarbonylof 1 to 4 carbon atoms in each alkyl moiety; aminocarboxyl; alkylaminocarboxyl of 1 to 4 carbon atoms in the alkyl moiety; dialkylaminocarboxyl of 1 to 4 carbon atoms in each alkyl moiety; alkoxycarbonylamino of 1 to 4 carbon atoms in the alkoxymoiety; alkoxycarbonylalkylamino of 1 to 4 carbon atoms in each alkyl moiety; cyano; mercapto, alkylmercapto of 1 to 6 carbon atoms; trifluoromethylmercapto; alkylsulfoxy of 1 to 6 carbon atoms; alkylsulfonyl of 1 to 6 carbon atoms; trifluoromethylsulfonyl; aminosulfonyl; alkylaminosulfonyl of 1 to 4 carbon atoms; dialkylaminosulfonyl of 1 to 4 carbon atoms; hydroxysulfonyl .[.of 1 to 4 carbon atoms.].; alkoxysulfonyl of 1 to 4 carbon atoms; aminosulfonyloxy.[.,.]..Iadd.; .Iaddend.alkylaminosulfonyloxy of 1 to 4 carbon atoms.[.,.]..Iadd.; .Iaddend.dialkylaminosulfonyloxy .[.groups.]. of 1 to 4 carbon atoms in each alkyl moiety; straight or branched alkyl of 1 to 6 carbon atoms, which may contain double bonds or may.Iadd.further .Iaddend.be halo-substituted; azido; dialkylmethyleneimino of 2 to 6 carbon atoms in the alkyl moieties; dialkylaminomethylideneimino groups of 2 to 6 carbon atoms in the alkyl moieties; or phenyl;
R.sub.11 is hydrogen.[.,.]..Iadd.; .Iaddend.alkyl of 1 to 8 carbon atoms; alkenyl of 1 to 8 carbon atoms; cycloalkyl of 3 to 6 carbon atoms; phenyl; benzyl; ##STR49## C.sub.x F.sub.2x+1, where x is 1, 2, 3, or 4; alkoxy of 1 to 4 carbonatoms; benzyloxy.[.,.]..Iadd.; .Iaddend.cycloalkyloxy of 3 to 6 carbon atoms; amino.[.,.]..Iadd.; .Iaddend.alkylamino of 1 to 8 carbon atoms; dialkylamino of 1 to 8 carbon atoms in each alkyl moiety; cycloalkylamino of 3 to 6 carbon atoms; cycloalkyleneamino of 3 to 6 carbon atoms; .[.or.]. ##STR50## .Iadd.or benzylamino; .Iaddend. R.sub.12 and R.sub.13 are each hydrogen; chlorine.[.,.]..Iadd.; .Iaddend.methoxy; .Iadd.or .Iaddend.methyl; .[.or benzylamino;.]. and
R.sub.14 is alkyl of 1 to 6 carbon atoms; cycloalkyl of 3 to 6 carbon atoms; benzyl; phenyl, optionally substituted with one to three methyl groups; amino; alkylamino of 1 to 6 carbon atoms; or dialkylamino of 1 to 6 carbon .[.atons.]. .Iadd.atoms .Iaddend.in each alkyl moiety; or a non-toxic, pharmacologically acceptable salt thereof.
2. A compound of claim 1, where
A is phenyl.[.,.]..Iadd.; .Iaddend.p-hydroxyphenyl; 2- or 3-thienyl; 3-chloro-4-hydroxyphenyl; 3,4-dihydroxy-phenyl; or 1,4-cyclohexadien-1-yl;
R is hydrogen; aliphatic hydrocarbyl of 1 to 4 carbon atoms, which may contain a double or a triple bond; cyclopropyl, which may be substituted by methyl or ethyl; cycloalkyl of 4 to 6 carbon atoms, which may contain a double bond; ##STR51##cyclopropylmethyl; 1-cyclopropylethyl; hydroxyl; alkoxy of 1 to 4 carbon atoms; ##STR52## morpholino; thiomorpholino; thiomorpholino-S-oxide; thiomorpholino-S,S-dioxide; ##STR53## NHCOR.sub.11 ; alkylsulfonylamino of 1 to 3 carbon atoms in thealkyl moiety.[.,.]..Iadd.; .Iaddend.toluenesulfonylamino; aminosulfonylamino; alkylaminosulfonylamino of 1 to 4 carbon atoms; or dialkylaminosulfonylamino of 1 to 4 carbon atoms in each alkyl moiety;
n, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9, R.sub.10 and m have the same meanings as in claim .[.6.]. .Iadd.1.Iaddend.;
R.sub.11 is hydrogen; alkyl of 1 to 4 carbon atoms; cycloalkyl .[.pf.]. .Iadd.of .Iaddend.3 to 6 carbon atoms; phenyl; chloro-substituted phenyl; C.sub.x F.sub.2x+1, where .[.X.]. .Iadd.x .Iaddend.is 1, 2, 3 or 4; alkoxy of 1 to 4 carbonatoms; amino; alkylamino of 1 to 4 carbon atoms; dialkylamino of 1 to 4 carbon atoms in each alkyl moiety; cyclopropylamino; cycloalkyleneamino of 4 to 5 carbon atoms; or ##STR54## and R.sub.12 and R.sub.13 have the meanings defined in claim1.Iadd., or a non-toxic, pharmacologically acceptable salt thereof.Iaddend..
3. A compound of claim 1 where
A is phenyl, p-hydroxyphenyl or 1,4-cyclohexadien-1-yl;
R is hydrogen; methyl; ethyl; isopropyl; vinyl; allyl; propargyl; crotyl; cyclopropyl; 1-methyl-cyclopropyl-(1); 2-methylcyclopropyl-(1); cyclobutyl; ##STR55## 1-phenyl-ethyl; cyclopropylmethyl; hydroxyl; methoxy; ethoxy; ##STR56## morpholino; ##STR57## -NHCOR.sub.11 ; methylsulfonyl-amino; ethylsulfonylamino; or toluenesulfonylamino;
n is 0 or 1;
one to two of R.sub.1, R.sub.2, and R.sub.3 are chlorine, fluorine, methyl, ethyl, methoxy, ethoxy, methylamino, dimethylamino, acetylamino, methylsulfonylamino, acetyl, methoxycarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methylmercapto,methylsulfoxy, methylsulfonyl; methylcarbonyloxy; nitro, cyano, trifluoromethyl or hydroxyl, and the .[.remainer.]. .Iadd.remainder .Iaddend.of R.sub.1, R.sub.2 and R.sub.3 are hydrogen;
R.sub.4 and R.sub.5 have the meanings defined in claim .[.6.]. .Iadd.1.Iaddend.;
R.sub.6 is phenyl, formyl or acetyl;
R.sub.7 is hydrogen or methyl;
m is 0, 1 or 2;
one to two of R.sub.8, R.sub.9, .Iadd.and .Iaddend.R.sub.10 are bromine, chlorine, fluorine, methyl, ethyl, isopropyl, amino, methylamino, dimethylamino, hydroxy, methoxy, ethoxy, nitro, acetylamino, methylsulfonyl, amidino, guanidino, acetyl,methylcarbonyloxy, methoxycarbonyl, carboxyl, aminocarbonyl, methyl and dimethylaminocarbonyl, cyano, methylmercapto, methylsulfoxy, methylsulfonyl, aminosulfonyl or .[.trilfluoromethyl.]. .Iadd.trifluoromethyl .Iaddend.groups, and the remainder ofR.sub.8, R.sub.9 and R.sub.10 are hydrogen; and
R.sub.11 is hydrogen; alkyl of 1 to 4 carbon atoms; cycloalkyl of 3 to 6 carbon atoms; trifluoroacetyl, pentafluoroethyl; heptafluoropropyl; ethoxy; amino; alkylamino of 1 to 4 carbon atoms; dialkylamino of 1 to 4 carbon atoms in eachalkyl moiety; cyclopropylamino; pyrrolidino; piperidino; phenylamino; or p-chlorophenylamino.Iadd., or a non-toxic, pharmacologically acceptable salt thereof.Iaddend..
4. An antibiotic pharmaceutical dosage unit composition consisting essentially of an inert pharmaceutical carrier and an effective antibiotic amount of a compound of claim 1.
5. The method of inhibiting the growth of or destroying bacteria in a warmblooded animal which comprises .[.enterally.]. .Iadd.perorally .Iaddend.or parenterally administering to said animal an effective antibiotic amount of a compound of claim1. .Iadd.6. The compound of claim 1 which is D-.alpha.[3-(2-p-aminosulfonylanilino-4-hydroxy-5-pyrimidyl)-ureido]-p-hyd roxybenzylpenicillin sodium. .Iaddend. .Iadd.7. An antibiotic pharmaceutical dosage unit composition consisting essentially of aninert pharmaceutical carrier and an effective antibiotic amount of the compound
of claim 6. .Iaddend. .Iadd.8. The method of inhibiting the growth of or destroying bacteria in a warmblooded animal which comprises perorally or parenterally administering to said animal an effective antibiotic amount of the compound ofclaim 6. .Iaddend. |
| Description: |
This invention relates to novel penicillins and salts thereof, as well as to methods of preparing these compounds, pharmaceutical compositions containing them as activeingredients, and methods of using them as antibiotics.
BACKGROUND OF THE INVENTION AND PRIOR ART
It is known that penicillin antibiotics inhibit the growth of various grampositive and gramnegative bacteria. It is further known that only few penicillins have a good activity against important gramnegative problematic germs, such asPseudomonas and Klebsiella, which occur primarily in hospitals. During the last years the frequency of occurrence of infections which are caused by these germs, particularly by Pseudomonas, has increased steadily. While penicillin derivatives such asCarbenicillin (U.S. Pat. No. 3,142,673), Sulbenicillin (U.S. Pat. No. 3,660,379) as well as Ticarcillin (U.S. Pat. No. 3,282,926) are described as antipseudomonal antibiotics, they show in vivo as well as in vitro only a poor activity. Animportant further development are acylated derivatives of .alpha.-aminobenzylpenicillins, e.g. Ampicillin and Amoxycillin. These kinds of compounds have been intensively studied during the last years, and as a result Azlocillin, i.e.6-{D-.alpha.-[(2-oxoimidazolidine-1-yl)carbonylamino]-4-phenylacetamino}-p encillanic acid sodium salt (e.g. Belgian Pat. No. 767,647), has recently been introduced on the market as a further antipseudomonas penicillin. For a successful treatment,however, this penicillin must be administered at high dosages. Moreover, it has only a moderate activity against Klebsiella and various kinds of E. coli. Therefore, it is still a need to search for new penicillins having an increased effectivenessagainst bacteria such as Pseudomonas resp. Klebsiella and E. coli.
While, as mentioned above, much research work has been and is still being done concerning acyl derivatives of .alpha.-aminobenzylpenicillins, there is little knowledge about derivatives in which a heterocycle is attached over a ureido bridge. ##STR2## to the .alpha.-benzyl carbon atoms of .alpha.-amino-benzylpenicillins. Only in German Offenlegungsschriften Nos. 2,450,668 and 25 35 655 and in U.S. Pat. No. 4,031,230 hydroxypyridylureido-benzyl-penicillins of the formula ##STR3## aredisclosed. These compounds are nearest in their structure to the novel penicillins of the present invention. As shown in table I below, a number of the novel penicillins according to the present invention distinguish themselves by a significantlystronger antibacterial activity, particularly against bacteria such as E. coli, Pseudomonas and Klebsiella.
DESCRIPTION OF THE INVENTION
More particularly, the present invention relates to novel penicillins represented by the formula ##STR4## wherein A represents the phenyl, 4-hydroxyphenyl, 2- or 3-thienyl, cyclohexyl, cyclohexen-1-yl or cyclohexa-1,4-dien-1-yl group; as well asa phenyl group disubstituted in 3,4-position, where the substituents may be the same or different and can represent chlorine atoms, hydroxy or methoxy groups;
R represents a hydrogen atom, an aliphatic straight or branched hydrocarbon radical with 1 to 8 carbon atoms optionally containing one or two double bonds or optionally containing a triple bond; the cyclopropyl radical, which optionally may besubstituted with one or two methyl groups or an ethyl group or a phenyl group; a cycloalkyl radical with 4 to 8 carbon atoms optionally containing one or more double bonds;
a group of the general formula ##STR5## where n represents 0 or 1, and
R.sub.1, R.sub.2 and R.sub.3, which may be the same or different from each other, represent hydrogen or halogen atoms, free amino groups, alkylamino or dialkylamino groups of 1 to 4 carbon atoms, hydroxy groups, alkoxy groups of 1 to 4 carbonatoms, nitro groups, formylamino groups, aliphatic acylamino groups of 1 to 4 carbon atoms in the alkyl moiety; alkylsulfonylamino groups of 1 to 4 carbon atoms; alkylcarbonyl groups of 1 to 4 carbon atoms in the alkyl moiety; alkylcarbonyloxy groups of1 to 4 carbon atoms in the alkyl part; alkoxy-carbonyl groups of 1 to 4 carbon atoms in the alkyl moiety; aminocarbonyl groups optionally substituted by one or two alkyl groups of 1 to 3 carbon atoms; cyano groups; alkylmercapto, alkylsulfoxy oralkylsulfonyl groups of 1 to 4 carbon atoms; aminosulfonyl, alkylaminosulfonyl or dialkylaminosulfonyl groups of 1 to 4 carbon atoms in the alkyl moiety; trifluoromethylsulfonyl groups; straight or branched alkyl groups of 1 to 4 carbon atoms;trifluoromethyl groups; or phenyl groups;
R furthermore represents the .beta.-phenylethyl group, the .gamma.-phenyl-propyl group or the .beta.-phenylethylidene group; the cyclopropyl-methyl or the 1-cyclopropylethyl group; the hydroxy group; an alkoxy or alkenyloxy group of 1 to 8 carbonatoms; a cycloalkoxy group of 3 to 6 carbon atoms; the phenoxy or benzyloxy group; the free mercapto group; an alkylmercapto group of 1 to 8 carbon atoms; a cycloalkylmercapto group of 3 to 6 carbon atoms; the phenylmercapto, benzylmercapto orp-chlorobenzylmercapto group; an alkylsulfinyl group of 1 to 4 carbon atoms; a group of the formula ##STR6## where R.sub.4 and R.sub.5, which may be the same or different, represent hydrogen atoms; aliphatic straight or branched hydrocarbon radicals of 1to 8 carbon atoms optionally containing one or two double bonds or a triple bond; cycloalkyl radicals of 3 to 8 carbon atoms which may be substituted with one or two methyl groups or ethyl groups and may contain one or more double bonds;cycloalkyl-substituted alkyl groups of 3 to 8 carbon atoms in the cycloalkyl moiety and 1 to 3 carbon atoms in the alkyl moiety; or R.sub.4 and R.sub.5 together can also form an alkylene chain of 2 to 7 carbon atoms, so that a 3- to 8-memberedheterocyclic ring is formed, which may optionally be substituted with one or two alkyl groups of 1 to 3 carbon atoms or a benzyl group, or may contain one or two double bonds or may be fused with a phenyl ring;
R represents, moreover, a group of the formula ##STR7## where R.sub.6 represents a hydrogen atom; the formyl, acetyl, ethoxycarbonyl, benzyloxycarbonyl, methyl, ethyl, phenyl or benzyl group;
R also represents the morpholino, thiomorpholino, thiomorpholino-S-oxide or thiomorpholino-S,S-dioxide group; or a group of the formula ##STR8## where R.sub.7 represents a hydrogen atom or the methyl or ethyl group; n represents the numbers 0, 1or 2; and
R.sub.8, R.sub.9 and R.sub.10, which may be the same or different from each other, represent hydrogen; halogen; free amino groups; alkylamino or dialkylamino groups, where each alkyl moiety contains 1 to 6 carbon atoms, preferably 1 to 3 carbonatoms; pyrrolidyl; piperidyl; hydroxy or alkoxy groups of 1 to 6 carbon atoms, preferably 1 to 3 carbon atoms; formylamino and formylalkylamino groups of 1 to 3 carbon atoms; aliphatic acylamino and acylalkylamino groups of 1 to 4 carbon atoms in thealkyl moiety and 1 to 3 carbon atoms in the acyl moiety; trifluoroacetylamino groups; aminocarbonylamino, alkylaminocarbonylamino or dialkylaminocarbonylamino groups of 1 to 6, preferably 1 to 3 carbon atoms in each alkyl group; nitro; alkylsulfonylaminoand alkylsulfonylalkylamino groups of 1 to 4 carbon atoms in each alkyl moiety; hydroxysulfonylamino or hydroxysulfonylalkylamino groups of 1 to 3 carbon atoms in the alkyl moiety; amidino; guanidino; formyl or alkylcarbonyl groups of 1 to 6, preferably1 to 3 carbon atoms; benzoyl groups; alkylcarbonyloxy, alkoxycarbonyl or alkoxycarbonyloxy groups of 1 to 6, preferably 1 to 3 carbon atoms; formyloxy; carboxyl; aminocarbonyl; alkyl- or dialkylaminocarbonyl, aminocarboxyl, alkylaminocarboxyl ordialkylaminocarboxyl groups, each of 1 to 4 carbon atoms; alkoxycarbonylamino and alkoxycarbonylalkylamino groups of 1 to 4 carbon atoms in each alkyl moiety; cyano; mercapto; alkylmercapto, trifluoromethylmercapto, alkylsulfoxy and alkylsulfonyl groupsof 1 to 6, preferably 1 to 3 carbon atoms; trifluoromethylsulfonyl, aminosulfonyl, alkyl- or dialkylaminosulfonyl groups of 1 to 4 carbon atoms; hydroxysulfonyl, alkoxysulfonyl, aminosulfonyloxy, alkyl- or dialkylaminosulfonyloxy groups of 1 to 4 carbonatoms; straight or branched alkyl groups of 1 to 6, preferably 1 to 3 carbon atoms, which may also contain double bonds or may be substituted with further halogen atoms; azido, dialkylmethyleneimino or dialkylaminomethylideneimino groups of 2 to 6 carbonatoms; or phenyl groups;
R may further represent a group of the formula ##STR9## where R.sub.11 represents a hydrogen atom; an alkyl or alkenyl group of 1 to 8 carbon atoms; a cycloalkyl group of 3 to 6 carbon atoms; a phenyl or benzyl group; or a group of the formula##STR10## where R.sub.12 and R.sub.13, which may be the same or different from each other, represent hydrogen or chlorine atoms; methoxy or methyl groups;
R.sub.11 may also represent a group of the formula C.sub.n F.sub.2n+1, where n represents the numbers 1 to 4; an alkoxy group of 1 to 4 carbon atoms; the benzyloxy group; a cycloalkoxy group of 3 to 6 carbon atoms; the free amino group; an alkyl-or dialkylamino group of 1 to 8 carbon atoms in the alkyl moiety; a cycloalkylamino group of 3 to 6 carbon atoms; a cycloalkyleneamino group with 3 to 6 carbon atoms; .[.or.]. a group of the formula ##STR11## where R.sub.12 and R.sub.13 have themeanings defined above; or the benzylamino group; or
R may also represent a group of the formula NHSO.sub.2 R.sub.14,
where
R.sub.14 represents an alkyl group of 1 to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, the benzyl group, phenyl optionally substituted with one to three methyl groups, the free amino group or an alkyl- or dialkylamino group of 1 to6 carbon atoms in the alkyl moiety.
Preferred compounds of the formula I are those where
A represents the phenyl, p-hydroxyphenyl, 2- or 3-thienyl, 3-chloro-4-hydroxyphenyl, 3,4-dihydroxyphenyl or 1,4-cyclohexadien-1-yl group; and
R is a hydrogen atom; an aliphatic straight or branched hydrocarbon group of 1 to 4 carbon atoms, which may contain a double or a triple bond; the cyclopropyl group which may be substituted by a methyl or ethyl group; a cycloalkyl group of 4 to 6carbon atoms which may contain a double bond; a group of the formula ##STR12## where .[.N.]. .Iadd.n .Iaddend.and R.sub.1, R.sub.2 and R.sub.3 have the meaning previously defined; the cyclopropylmethyl and the 1-cyclopropylethyl groups; the hydroxygroup; and alkoxy group of 1 to 4 carbon atoms; a group of the formula ##STR13## where R.sub.4 and R.sub.5 have the previously defined meanings; a group of the formula ##STR14## where R.sub.6 has the previously defined meanings, the morpholino,thiomorpholino, thiomorpholino-S-oxide or thiomorpholino-S,S-dioxide group; a group of the formula ##STR15## where R.sub.7 to R.sub.10 and n have the previously defined meanings; a group of the formula NHCOR.sub.11, where R.sub.11 represents a hydrogenatom, an alkyl group of 1 to 4 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, an optionally chlorine substituted phenyl group, a group of the formula C.sub.n F.sub.2n+1, where n represents the numbers 1 to 4, an alkoxy group of 1 to 4 carbonatoms, the free amino group, an alkyl- or dialkylamino group of 1 to 4 carbon atoms in the alkyl moiety, a cyclopropylamino group, a cycloalkyleneamino group of 4 to 5 carbon atoms or a group of the formula ##STR16## where R.sub.12 and R.sub.13 have thepreviously defined meanings; or R further represents an alkylsulfonylamino group of 1 to 3 carbon atoms in the alkyl moiety, the toluenefonylamino group, the aminosulfonylamino group or an alkyl- or dialkylaminosulfonylamino group of 1 to 4 carbon atomsin the alkyl moiety.
Especially preferred compounds of the formula I are those where
A represents the phenyl, p-hydroxyphenyl or 1,4-cyclohexadien-1-yl group; and
R is a hydrogen atom; the methyl, ethyl, isopropyl, vinyl, allyl, propargyl or crotyl group; the cyclopropyl group; the 1- or 2-methylcyclopropyl-(1)-group; the cyclobutyl group; or a group of the formula ##STR17## where n represents the numbers0 or 1, and one or two of the radicals R.sub.1, R.sub.2 and R.sub.3 represent halogen atoms, particularly chlorine or fluorine atoms; methyl, ethyl, methoxy, ethoxy, methylamino, dimethylamino, acetylamino, methylsulfonylamino, acetyl, methoxycarbonyl,methylaminocarbonyl, dimethylaminocarbonyl, methylmercapto, methylsulfoxy, methylsulfonyl, methylcarbonyloxy, nitro, cyano, trifluoromethyl or hydroxy groups, and the other radicals R.sub.1, R.sub.2 and R.sub.3 represent hydrogen atoms; or
R represents the 1-phenyl-ethyl group, the cyclopropylmethyl group, the hydroxy, methoxy or ethoxy group or a group of the formula ##STR18## where R.sub.4 and R.sub.5 have the previously defined meanings; or
R represents a group of the formula ##STR19## where R.sub.6 represents the phenyl, formyl or acetyl group; or
R represents the morpholino group or a group of the formula ##STR20## where R.sub.7 represents a hydrogen atom or the methyl group;
n represents the numbers 0, 1 or 2; and one or two of the radicals R.sub.8, R.sub.9, R.sub.10 represent halogen atoms, especially bromine, chlorine or fluorine atoms; methyl, ethyl, isopropyl, amino, methylamino, dimethylamino, hydroxy, methoxy,ethoxy, nitro, acetylamino, methylsulfonyl, amidino, guanidino, acetyl, methylcarbonyloxy, methoxycarbonyl, carboxyl, aminocarbonyl, methyl and dimethylaminocarbonyl, cyano, methylmercapto, methylsulfoxy, methylsulfonyl, aminosulfonyl or trifluoromethylgroups, and the remaining radicals R.sub.8, R.sub.9 and R.sub.10 represent hydrogen; or
R represents a group of the general formula NHCOR.sub.11,
where
R.sub.11 represents a hydrogen atom, an alkyl group of 1 to 4 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, the trifluoroacetyl, pentafluoroethyl, heptafluoropropyl group, an ethoxy group, an amino, alkyl- or dialkylamino group of 1 to4 carbon atoms, in the alkyl moiety, a cyclopropylamino group, a pyrrolidino or piperidino group, a phenylamino or p-chlorophenylamino group; or
R represents the methyl-, ethyl- or toluene-sulfonylamino group.
The penicillin compounds of the formula I can occur in two tautomeric forms (i.e. of the lactim or of the lactam type). Which of the forms I or I' is predominant, depends especially on the respective solvent and on the type of substituent R:##STR21##
It goes without saying that the compounds of type I mentioned hereinbefore, always include both tautomers.
The compounds of the formula I may be present with regard to the chiral centre C+ in both possible R- and S-configurations, but also as a mixture of both these configurations. Especially preferred compounds are those to which theD=R-configuration applies.
The compounds of the formula I may be prepared by the following methods:
Method A
By reacting a compound of the formula ##STR22## wherein A has the same meanings as in formula I, with a pyrimidine derivative of the formula ##STR23## wherein R has the same meanings as in formula I, and B represents the group --NCO or a reactivederivative of the group NHCOOH, such as for example, the groups --NHCOCl, --NHCOBr or ##STR24## where the group NHCOCl is especially preferred. Also, mixtures of those pyrimidine derivatives of the formula IV can be used, where B has two of theabove-mentioned meanings, for example the groups --NCO and ##STR25##
The starting compounds of the formula III can be used in the form of their inorganic or organic salts, e.g. as the triethylammonium salt or the sodium salt. The reaction can be carried out in any desired mixtures of water and these organicsolvents which can be mixed with water; for instance in ketones, such as acetone; in cyclic ethers, such as tetrahydrofuran or dioxane; in nitriles, such as acetonitrile; in formamides, such as dimethylformamide; in dimethylsulfoxide; or in alcohols,such as isopropanol or in hexametapol. The pH-value of the reaction mixture is kept by addition of bases or by use of buffer solutions, within a pH-range of about 2.0 to 9.0, preferably between a pH-value 6.5 and 8.0. But it is also possible to carryout the reaction in anhydrous organic solvents, such as halogenated hydrocarbons like chloroform or methylene chloride, in the presence of a base, preferably triethylamine, diethylamine or N-ethyl-piperidine. The reaction can also be carried out in amixture consisting of water and a solvent immiscible with water, like ethers such as diethylether; halogenated hydrocarbons such as chloroform or methylene chloride; carbon disulfide; ketones such as isobutyl methyl ketone; esters such as ethyl acetate;or aromatic solvents such as benzene; under these conditions it is advantageous to stir vigorously and to keep the pH-value, by addition of bases or by using of buffer solutions, in a range of about pH 2.0 to 9.0, preferably between 6.5 and 8.0. Thereaction can also be carried out in water alone in the presence of an organic or inorganic base or by adding of buffering agents.
If silyl derivatives of the compounds of the formula III (for instance mono- or di-trimethylsilyl derivatives) are used as starting compounds for this method and they are reacted with compounds of the formula IV, it is advantageous to work inanhydrous solvents free from hydroxyl groups, for example in halogenated hydrocarbons, such as methylene chloride or chloroform, benzene, tetrahydrofuran, acetone or dimethylformamide, etc. The addition of bases is not necessary, but can be of advantagein individual cases to improve the yield and the purity of the products. As optionally added bases tertiary aliphatic or aromatic amines, such as pyridine or triethylamine, or due to steric hindrance difficulty acylatable secondary amines, such asdicyclohexylamine are used.
Instead of silyl esters all other carboxyl derivatives of .alpha.-aminobenzyl penicillins which are known in the field of preparation of semi-synthetized penicillins can also be used. Typical examples are the trityl esters, the p-nitrobenzylesters or the phenacyl esters. Subsequent to the reactions, these derivatives can be converted into the penicillins of the present invention by known methods. The amount of bases used is fixed, for example, by the desired adherence to a certainpH-value.
Where a pH-measurement and adjustment is not carried out or is not possible or purposeful because of the lack of sufficient water in the diluting agent, preferably 1.0 to 2.0 mol equivalents of bases are used if the starting compound is anon-silylated compound of the formula II. If a silylated compound is used, preferably up to one mol equivalent of base is supplied.
In principle, all bases are used which are usually used in organic chemistry as organic or inorganic bases, such as alkali metal hydroxides and alkaline earth metal hydroxides, alkaline earth metal oxides, alkali metal carbonates and alkalineearth metal carbonates and bicarbonates, ammonia, primary, secondary and tertiary aliphatic and aromatic amines, as well as heterocyclic bases. Examples are sodium, potassium or calcium hydroxide, calcium oxide, sodium or potassium carbonate, sodium orpotassium bicarbonate, ethylamine, methylethylamine, triethylamine, hydroxy ethylamine, aniline, pyridine and piperidine. When using silylated starting materials, however, the above-mentioned restrictions concerning the kind of bases should be noted.
As buffer systems all usual buffer mixtures can be used, such as phosphate buffer, citrate buffer and tris(hydroxy-methyl)-amino methane buffer.
The reaction temperature can be varied within a wide range. In general, it is between about -20.degree. and about +50.degree. C., preferably between 0.degree. and +20.degree. C.
The reaction partners of the formula II and III can be reacted with each other in equimolar amounts. However, in individual cases it can be of advantage to use one of the two reaction partners in excess, in order to facilitate the purificationof the end product or to increase the yield.
Method B
By reacting a ureido-carboxylic acid of the formula ##STR26## wherein A and R have the same meanings as in formula I, or a salt or reactive derivative thereof, with 6-aminopenicillanic acid of the formula ##STR27## or with an inorganic or organicsalt or derivative thereof which is easily convertible into 6-aminopenicillanic acid. The reaction product obtained is optionally subsequently hydrolyzed or catalytically hydrogenated into a penicillin or the formula I.
Suitable reactive derivatives of the ureido-carboxylic acids of the formula V are, for example, acid anhydrides, such as those which derive from chloroformates, for instance ethyl chloroformate or isobutyl chloroformate, or their reactive esterssuch as the p-nitrophenyl ester or the N-hydroxysuccinimid ester, or their reactive amides such as the N-carbonylimidazole, or also their acid halides such as the corresponding acid chloride, or their acid azides. In principle, however, all reactionmethods can be used which are known from the .beta.-lactam chemistry.
The 6-amino-penicillanic acid is advantageously used in the form of one of its derivatives. Suitable derivatives thereof are, for example the trimethylsilyl ester, the trityl ester, the p-nitrobenzylester, the phenacyl ester and theO,N-bis-trimethylsilyl derivative. These derivatives are reacted preferably in an aprotic solvent like methylene chloride or tetrahydrofuran. But the 6-amino-penicillanic acid can also be used in the form of its salts, for example its triethylammoniumsalt; in that case methylene chloride or a protic solvent or an aqueous medium or an aqueous-organic solvent, such as tetrahydrofuran-water mixtures, are used.
The ureido-carboxylic acid, its salts or its reactive derivatives are reacted with the 6-amino-penicillanic acid or its derivatives in a solvent at temperatures between -40.degree. and +40.degree. C., optionally in the presence of a base. If,for example, an anhydride of the ureido-carboxylic acid such as the anhydride with ethylchloroformate, is reacted with a derivative of the 6-aminopenicillanic acid, the reaction is carried out while cooling, for example at temperatures between-10.degree. and +10.degree. C., in the presence of a tertiary amine such as triethylamine or N,N-dimethylaniline, in a solvent such as acetone, tetrahydrofuran, dimethylformamide, chloroform, dichloromethane, hexametapol or a mixture of these solvents. If, for example, an N-hydroxy-succinimid ester of the ureido-carboxylic acid is reacted with 6-amino-penicillanic acid, the reaction is preferably carried out at temperatures between 0.degree. and 20.degree. C. in the presence of a base such astriethylamine, in a solvent like dimethylformamide, dichloromethane, dioxane or a mixture of such solvents.
The reaction of a ureido-carboxylic acid of the formula IV itself or a salt thereof with 6-amino-penicillanic acid or its salts is carried out advantageously in the presence of a condensation agent such as N,N'-dicyclohexlcarbodiimide.
If a derivative of 6-amino-penicillanic acid is used, for example one of the above-mentioned esters, a reaction product can be obtained which, for example, still contains the ester function, depending on the reaction conditions. Such a reactionproduct is easily convertible into a penicillin of the formula I. If, for example, the carboxylic group of the 6-amino-penicillanic acid is present in the form of a silyl ester, this group can also be present after the reaction in the obtained penicillinof the formula I in the form of the silyl ester. In this case, subsequent to the actual reaction, this silyl ester group is hydrolyzed off, whereby the corresponding compound of the formula I results. In other cases, for example if a p-nitrobenzylester is present, this p-nitrobenzyl ester group is split off by hydrogenation after the actual reaction, whereby the corresponding penicillin of the formula I is obtained.
Further processing of the reaction mixtures resulting from methods A and B is carried out according to methodswhich are conventional for .beta.-lactam-antibiotics; the same is the case for the isolation and purification of the end products, forexample for liberating the acid from its salts and converting the free acid in other salts with inorganic or organic bases. For the preparation of the potassium or sodium salts, particularly the precipitation of these salts from an alcoholic-etherealsolution of the free acid by adding of potassium- or sodium-2-ethylhexanoate is suitable.
The starting compounds of the formula III are known from the literature; see, for example, E. H. Flynn, Cephalosporin and Penicillins, Academic Press, New York and London (1972).
The starting compounds of the formula IV can be obtained, for example, by reaction of the corresponding 5-amino-pyrimidines of the formula ##STR28## wherein R has the same meanings as in formula I, with phosgene. This reaction is preferablycarried out in a solvent not containing hydroxyl groups, such as tetrahydrofuran, methylene chloride, chloroform, dimethoxyethane or hexametapol, at temperatures between -40.degree. and +60.degree. C., preferably between -10.degree. and +20.degree. C., where it is advisable to bind the resulting hydrogen chloride by equimolar amounts of an inert organic base like triethylamine or pyridine. An excess of pyridine can also be used as the solvent. If the corresponding aminopyrimidines of the formulaVII are difficultly soluble in one of the mentioned solvents, the phosgenation can also be carried out in a heterogeneous phase. Furthermore, the aminopyrimidines of the formula VII can, by treatment with a silylating agent like hexamethyldisilazane ortrimethyl-chlorosilane/triethylamine, be converted into a mono- or, depending upon the number of exchangeable hydrogen atoms, multi-silylated aminopyrimidine which is easily soluble in the abovementioned solvents. The thus obtained aminopyrimidine isreacted with phosgene into the corresponding compound of the formula IV. Depending on the kind of the solvent, the height of the temperature, the amount and the kind of the base used, either mainly the corresponding isocyanate or carbamic acid halide ora mixture of these two compounds is obtained. Depending on the reaction conditions, the compound of the formula IV can also be present, slightly or partly as an isocyanate isomer, that is, as a tetrahydro-oxazolo-pyrimidine of the formula ##STR29##
The starting compounds of the formula IV or their mixtures obtained by phosgenation are, in general, readily soluble in the above-mentioned solvents, and after removal of the excess phosgene, they can be reacted directly without furtherpurification with the corresponding penicillin derivatives of the formula III.
2-Substituted 5-amino-4-hydroxy-pyrimidines of the formula VII are sparsely described in the literature; for example, for
______________________________________ R = hydrogen: J. Chem. Soc. 1952, 4942; = ethylthio: J. Chem. Soc. 1952, 4942; = hydroxy: J. Am. Chem. Soc. 46, 702(1924); = dimethylamino: J. Chem. Soc. 1956, 3232. ______________________________________
For the preparation of pyrimidines of the formula VII therefore, several processes were developed, of which the most important ones are indicated below, where, depending upon the meaning of R, the most favorable method should be used for thesynthesis of compound VII.
(a) Reaction of ethyl-carbethoxyamino-formyl acetate sodium salt of the formula VIII with compounds of the formula IX, wherein R has the meanings previously defined, and subsequent alkaline hydrolysis, pursuant to the reaction sequence: ##STR30##
(b) Reaction of ethyl ethoxymethylene-nitroacetate of the formula X with compounds of the formula IX and subsequent reduction of the nitro group according to known methods pursuant to the reaction sequence. ##STR31##
(c) Reaction of 2-phenyl-4-ethoxymethylene-5-oxo-2-oxazoline of the formula XI with compounds of the formula IX and subsequent acid or alkaline hydrolysis (see also Clarke, Johnson and Robinson. The Chemistry of Penicillins, Princeton UniversityPress 1949, page 803). ##STR32##
(d) Acylation of 2-amino-4-hydroxy-5-nitropyrimidines of the formula XII and subsequent reduction ##STR33## By this method compounds of the formula VII are obtained where R represents the group--NHCOR.sub.11.
(e) Reaction of 2-methylmercapto-4-hydroxy-5-nitropyrimidines of the formula XIIIa [literature reference: Vorbruggen and Strehlke, Chem. Ber. 106, p. 3039 (1973)] or of 5-benzoylamino-4-hydroxy-2-methylmercapto-pyrimidines of the formula XIIIb(or its derivatives oxidized at the sulfur atom) with substituted amines, and subsequent reduction or hydrolysis: ##STR34##
By this method compounds of the formula VII are obtained, where R represents the group --NR.sub.4 R.sub.5.
In order to characterize the thus obtained starting compounds of the formula VII the following typical representatives should be mentioned.
5-Amino-2-methyl-4-hydroxy-pyrimidine
5-Amino-2-ethyl-4-hydroxy-pyrimidine
5-Amino-2-isopropyl-4-hydroxy-pyrimidine
5-Amino-2-allyl-4-hydroxy-pyrimidine
5-Amino-2-propargyl-4-hydroxy-pyrimidine
5-Amino-2-cyclopropyl-4-hydroxy-pyrimidine
5-Amino-2-(1'-methyl)-cyclopropyl-4-hydroxy-pyrimidine
5-Amino-2-(2'-methyl)-cyclopropyl-4-hydroxy-pyrimidine
5-Amino-2-cyclobutyl-4-hydroxy-pyrimidine
5-Amino-2-cyclohexyl-4-hydroxy-pyrimidine
5-Amino-2-benzyl-4-hydroxy-pyrimidine
5-Amino-2-(p-chlorobenzyl)-4-hydroxy-pyrimidine
5-Amino-2-(m-chlorobenzyl)-4-hydroxy-pyrimidine
5-Amino-2-(o-chlorobenzyl)-4-hydroxy-pyrimidine
5-Amino-2-(p-fluorobenzyl)-4-hydroxy-pyrimidine
5-Amino-2-(p-hydroxybenzyl)-4-hydroxy-pyrimidine
5-Amino-2-(p-acetylbenzyl)-4-hydroxy-pyrimidine
5-Amino-2-(p-nitrobenzyl)-4-hydroxy-pyrimidine
5-Amino-2-(p-dimethylaminobenzyl)-4-hydroxy-pyrimidine
5-Amino-2-(p-methylbenzyl)-4-hydroxy-pyrimidine
5-Amino-2-(o,p-dichlorobenzyl)-4-hydroxy-pyrimidine
5-Amino-2-(m,p-dichlorobenzyl)-4-hydroxy-pyrimidine
5-Amino-2-(p-amino-m,m-dichlorobenzyl)-4-hydroxy-pyrimidine
5-Amino-2-phenyl-4-hydroxy-pyrimidine
5-Amino-2-(p-chlorophenyl)-4-hydroxy-pyrimidine
5-Amino-2-(m-trifluoromethyl-phenyl)-4-hydroxy-pyrimidine 5-Amino-2-(p-methoxyphenyl)-4-hydroxy-pyrimidine
5-Amino-2-(p-dimethylamino-phenyl)-4-hydroxy-pyrimidine
5-Amino-2-(m-chlorophenyl)-4-hydroxy-pyrimidine
5-Amino-2-(p-amino-m,m-dichlorophenyl)-4-hydroxy-pyrimidine
5-Amino-2-(1'-phenylethyl)-4-hydroxy-pyrimidine
5-Amino-2-cyclopropylmethyl-4-hydroxy-pyrimidine
5-Amino-2,4-dihydroxy-pyrimidine
5-Amino-2-methoxy-4-hydroxy-pyrimidine
2,5-Diamino-4-hydroxy-pyrimidine
5-Amino-2-ethoxy-4-hydroxy-pyrimidine
5-Amino-2-methylamino-4-hydroxy-pyrimidine
5-Amino-2-dimethylamino-4-hydroxy-pyrimidine
5-Amino-2-ethylamino-4-hydroxy-pyrimidine
5-Amino-2-diethylamino-4-hydroxy-pyrimidine
5-Amino-2-propylamino-4-hydroxy-pyrimidine
5-Amino-2-isopropylamino-4-hydroxy-pyrimidine
5-Amino-2-butylamino-4-hydroxy-pyrimidine
5-Amino-2-hexylamino-4-hydroxy-pyrimidine
5-Amino-2-allylamino-4-hydroxy-pyrimidine
5-Amino-2-propargylamino-4-hydroxy-pyrimidine
5-Amino-2-cyclopropylamino-4-hydroxy-pyrimidine
5-Amino-2-cyclobutylamino-4-hydroxy-pyrimidine
5-Amino-2-cyclohexylamino-4-hydroxy-pyrimidine
5-Amino-2-cycloheptylamino-4-hydroxy-pyrimidine
5-Amino-2-(1'-methyl)-cyclopropylamino-4-hydroxy-pyrimidine
5-Amino-2-cyclopropylmethylamino-4-hydroxy-pyrimidine
5-Amino-2-(N-methyl)-N-cyclohexylamino-4-hydroxy-pyrimidine
5-Amino-2-pyrrolidino-4-hydroxy-pyrimidine
5-Amino-2-piperidino-4-hydroxy-pyrimidine
5-Amino-2-morpholino-4-hydroxy-pyrimidine
5-Amino-2-piperazino-4-hydroxy-pyrimidine
5-Amino-2-(N-formyl)-piperazino-4-hydroxy-pyrimidine
5-Amino-2-(N-ethoxycarbonyl)-piperazino-4-hydroxy-pyrimidine
5-Amino-2-(N-acetyl)-piperazino-4-hydroxy-pyrimidine
5-Amino-2-(N-phenyl)-piperazino-4-hydroxy-pyrimidine
5-Amino-2-anilino-4-hydroxy-pyrimidine
5-Amino-2-p-chloroanilino-4-hydroxy-pyrimidine
5-Amino-2-p-dimethylaminoanilino-4-hydroxy-pyrimidine
5-Amino-2-o-chloroanilino-4-hydroxy-pyrimidine
5-Amino-2-m,p-dichloroanilino-4-hydroxy-pyrimidine
5-Amino-2-p-hydroxyanilino-4-hydroxy-pyrimidine
5-Amino-2-p-methylanilino-4-hydroxy-pyrimidine
5-Amino-2-p-acetylamino-anilino-4-hydroxy-pyrimidine
2-Amino-2-p-fluoroanilino-4-hydroxy-pyrimidine
5-Amino-2-m-chloroanilino-4-hydroxy-pyrimidine
5-Amino-2-p-bromoanilino-4-hydroxy-pyrimidine
5-Amino-2-(p-chloro-m-trifluoromethyl)-anilino-4-hydroxy-pyrimidine
5-Amino-2-trifluoromethylanilino-4-hydroxy-pyrimidine
5-Amino-2-p-hydroxyanilino-4-hydroxy-pyrimidine
5-Amino-2-benzylamino-4-hydroxy-pyrimidine
5-Amino-2-p-chlorobenzylamino-4-hydroxy-pyrimidine
5-Amino-2-(N-methyl)-anilino-4-hydroxy-pyrimidine
5-Amino-2-(N-methyl)-p-chloroanilino-4-hydroxy-pyrimidine
5-Amino-2-formylamino-4-hydroxy-pyrimidine
5-Amino-2-acetylamino-4-hydroxy-pyrimidine
5-Amino-2-propionylamino-4-hydroxy-pyrimidine
5-Amino-2-isobutyrylamino-4-hydroxy-pyrimidine
5-Amino-2-butyrylamino-4-hydroxy-pyrimidine
5-Amino-2-cyclopropionylamino-4-hydroxy-pyrimidine
5-Amino-2-cyclohexanoylamino-4-hydroxy-pyrimidine
5-Amino-2-benzoylamino-4-hydroxy-pyrimidine
5-Amino-2-p-chlorobenzoylamino-4-hydroxy-pyrimidine
5-Amino-2-trifluoroacetylamino-4-hydroxy-pyrimidine
5-Amino-2-pentafluoropropionylamino-4-hydroxy-pyrimidine
5-Amino-2-heptafluorobutyrylamino-4-hydroxy-pyrimidine
5-Amino-2-ethoxycarbonylamino-4-hydroxy-pyrimidine
5-Amino-2-ureido-4-hydroxy-pyrimidine
5-Amino-2-(3'methyl)-ureido-4-hydroxy-pyrimidine
5-Amino-2-(3'-dimethyl)-ureido-4-hydroxy-pyrimidine
5-Amino-2-pyrrolidinocarbonylamino-4-hydroxy-pyrimidine
5-Amino-2-(3'-phenyl)-ureido-4-hydroxy-pyrimidine
5-Amino-2-methylsulfonylamino-4-hydroxy-pyrimidine
5-Amino-2-toluenesulfonylamino-4-hydroxy-pyrimidine
5-Amino-2-mercapto-4-hydroxy-pyrimidine
5-Amino-2-methylmercapto-4-hydroxy-pyrimidine
5-Amino-2-ethylmercapto-4-hydroxy-pyrimidine
5-Amino-2-p-chlorophenylmercapto-4-hydroxy-pyrimidine
5-Amino-2-methylsulfinyl-4-hydroxy-pyrimidine
5-Amino-2-ethylsullfinyl-4-hydroxy-pyrimidine
The ureido-carboxylic acids of the formula V can be easily obtained by reaction of the pyrimidine derivatives of the formula IV with glycine derivatives of the formula ##STR35## wherein A has the meanings previously defined. The reaction iscarried out at temperatures between -20.degree. and +40.degree. C., preferably between 0.degree.and +20.degree. C. in a solvent. As solvents can be used, for example, mixtures of water and watermiscible organic solvents, such as acetone,tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, ethanol or dimethylsulfoxide. In some instances the use of a halogen hydride-binding agent is necessary. As such agents, for example, trialkylamines such as triethylamine or inorganic basessuch as dilute sodium hydroxide solution are suitable
The following examples illustrate the present invention and will enable others skilled in the art to understand it more completely. It should be understood, However, that the invention is not limited solely to the particular examples givenbelow.
The R.sub.f values refer to the system n-butanol-waterglacial acetic acid=60:25:15, SiO.sub.2 -plate. "Ampicillin" means .alpha.-aminobenzylpenicillin, "amoxycillin" means .alpha.-amino-p-hydroxy-benzylpenicillin and "epicillin" means.alpha.-amino- .alpha.-(1,4-cyclohexadien-1-yl)-methylpenicillin, each with the D=R-configuration in the side chain.
1. PREPARATION OF THE STARTING MATERIALS
EXAMPLE A
5-Amino-2-p-chlorobenzyl-4-hydroxy-pyrimidine
27.1 gm of p-chlorobenzylamidine hydrochloride (0.132 mol) are stirred for 1 hour with ice cooling in a solution of 3.03 gm of sodium in 200 ml of absolute ethanol. The common salt is subsequently separated off. 30 gm (0.13 mol) ofethylcarbethoxyamino-formyl acetate sodium salt (for preparation see M. Boarland and Mc. Omie, J. Chem. Soc. 1952, page 4942) are added thereto. The mixture is stirred for 3 hours at 0.degree. C. and 3 hours at room temperature and subsequentlyevaporated to dryness in vacuo. The residue is taken up in dilute sodium hydroxide solution and mixed with concentrated hydrochloric acid until a pH value of 5.0 is obtained. The precipitated product is extracted, by filtration washed with water anddissolved in 80 ml of water with 12 gm of sodium hydroxide solution. The solution is refluxed for 30 minutes. It is thereafter cooled, acidified with acetic acid and the precipitated product is extracted.
Yield: 13 gm (42.5%).
M.p.: 245.degree. C. from ethanol.
Calculated: C,53.80; H,4.49; N,18.76. Found: C,53.03; H,4.51; N,18.32.
The pyrimidines listed in the following table were synthesized according to this method:
______________________________________ ##STR36## R Yield in % Melting Point ______________________________________ C.sub.2 H.sub.5 44 189.degree. C. CH(CH.sub.3).sub.2 31 202.degree. C. C(CH.sub.3).sub.3 39 218.degree. C. C.sub.5 H.sub.11 46 200.degree. C. C.sub.8 H.sub.17 23 sinters >130.degree. C. Cyclobutyl 41 208.degree.-210.degree. C. Cyclopentyl 52 235.degree. C. Cyclohexyl 58 230.degree.-231.degree. C. CH.sub.2CH.sub.2C.sub.6 H.sub.5 54 193.degree.-195.degree. C. (CH.sub.2).sub.3C.sub.6 H.sub.5 48 176.degree. C. CH(CH.sub.3)C.sub.6 H.sub.5 44 197.degree.-199.degree. C. CHCHC.sub.6 H.sub.5 36 115.degree.-118.degree. C. ______________________________________
or
______________________________________ ##STR37## Yield in n R.sub.1, R.sub.2, R.sub.3 % Melting Point ______________________________________ (b) 1 p-Fluoro 41 242.degree. C. (c) 1 Hydrogen 47 202.degree.-204.degree. C. (d) 1 o,o'Dichloro31 252.degree.-255.degree. C. (e) 0 p-Hydroxy 34 210.degree.-215.degree. C. (decomp.) (f) 0 p-dimethylamino 40 250.degree. C. (decomp.) (g) 1 o-Methoxy 51 247.degree.-250.degree. C. (h) 1 p-ethoxy 54 265.degree.-268.degree. C. (decomp.) (i) 1p-Nitro 46 >300.degree. C. (k) 1 p-CH.sub.3CO 29 250.degree.-251.degree. C. (l) 0 p-Methylamino 24 232.degree.-235.degree. C. (decomp.) (m) 0 o-Chloro 42 243.degree.-245.degree. C. (n) 1 p-methylmercapto 38 242.degree.-244.degree. C. (decomp.) (o) 1 p-Methylsulphoxy 37 265.degree.-267.degree. C. (decomp.) (p) 1 p-Methoxy 58 228.degree. C. ______________________________________
EXAMPLE B
(a) 5-Amino-4-hydroxy-2-phenyl-pyrimidine
20 gm (0.089 mol) of ethylcarbethoxyamino-formyl acetate sodium salt are dissolved at room temperature in 40 ml of water. Added thereto is a solution which has been prepared from 16.7 gm (0.09 mol) benzamidine hydrochloride and 3.6 gm (0.09 mol)of sodium hydroxide solution in 15 ml of water. The mixture is stirred overnight at room temperature and subsequently refluxed for 1 hour. Concentrated hydrochloric acid is then added thereto with cooling, so that the pH value is approximately 5.5. The precipitated product is extracted and washed with water.
This compound is refluxed crude for half an hour with a solution of 8 gm of sodium hydroxide solution in 50 ml of water. It is allowed to cool and concentrated hydrochloric acid is carefully added thereto until a pH value of 5.0 is obtained. The precipitated product is extracted, washed with a little water and dried.
Yield: 11.4 gm (67%).
M.p.: 220.degree. C. (decomposition).
Calculated: C, 64.16; H, 4.85; N, 22.45. Found: C, 63.92; H, 4.79; N, 22.69.
The following pyrimidines were synthesized according to this method:
______________________________________ n R.sub.1, R.sub.2, R.sub.3 Yield Melting Point ______________________________________ (b) 1 m-Chloro 39 220.degree. C. (decomp.) (c) 1 p-Bromo 53 232.degree. C. (d) 1 m,p-Dichloro 48245.degree.-250.degree. C. (e) 0 p-methoxy 40 221.degree. C. (f) 0 p-CONH.sub.2 28 189.degree.-190.degree. C. (g) 1 m,p-dimethoxy 58 230.degree.-235.degree. C. (h) 0 m-Trifluoromethyl 31 202.degree. C. (i) 0 p-Chloro 42 195.degree.-197.degree. C. (k) 0 m-Methyl 27 191.degree. C. (l) 0 m-Chloro 51 214.degree.-216.degree. C. (m) 1 m,m,p-Trimethoxy 54 234.degree.-238.degree. C. (n) 1 o,p-Dichloro 48 245.degree.-248.degree. C. (o) 1 p-Dimethylamino 35 251.degree. C. (decomp.) (p) 1m,m'-Dichloro 18 189.degree.-192.degree. C. (decomp.) p-amino (q) 1 p-Cyano 47 227.degree. C. (decomp.) ______________________________________
EXAMPLE C
If the p-chlorobenzylamidine hydrochloride of Example A is replaced by the corresponding S- or O-alkylisothiourea, then the pyrimidines of the following table are obtained:
______________________________________ R Yield Melting Point ______________________________________ CH.sub.3 O 32 140.degree. C. (decomp.) C.sub.2 H.sub.5 O 38 155.degree. C. (decomp.) OC.sub.6 H.sub.5 64 206.degree. C. (decomp.) C.sub.2H.sub.5 S 71 166.degree. C. ##STR38## 26 141.degree.-145.degree. C. (decomp.) ______________________________________
EXAMPLE D
(a) 5-Amino-2-cyclopropyl-4-hydroxy-pyrimidine
120 gm of 2-phenyl-4-ethoxymethylene-5-oxo-2-oxaline (0.55 mol), 71 gm of cyclopropylformamidinehydrochloride (0.59 mol) and 98 gm of sodium acetate are refluxed for 3 hours in 3 liters of absolute ethanol. The mixture is subsequently evaporatedin vacuo to 1.2 liters and poured into 5 liters of ice water. The precipitated product is extracted and recrystallized from glacial acetic acid.
M.p. 258.degree. C.
Yield: 118 gm (84%).
(b) 90 gm (0.35 mol) of the product thus prepared are refluxed for 2 hours with 140 gm of sodium hydroxide solution and 560 ml of water. The mixture is cooled and acidified with concentrated hydrochloric acid to pH 1.5 with cooling. Theprecipitated benzoic acid is taken up in ether. The aqueous phase is brought to pH 6.5 and evaporated to dryness. The desired product is extracted with tetrahydrofurane.
Yield: 44 gm (83%).
M.p.: 206.degree. C.
The following pyrimidines are synthesized according to this method:
______________________________________ R Yield Melting Point ______________________________________ 2-Methyl-cyclopropyl 64% 192.degree.-195.degree. C. 1-Methyl-cyclopropyl 56% 186.degree. C. Allyl 36% 174.degree.-175.degree. C. Propargyl31% 177.degree.-180.degree. C. Crotyl 38% 154.degree.-155.degree. C. Cyclopropylmethyl 51% 216.degree. C. 2-Phenyl-cyclopropyl 64% 248.degree.-250.degree. C. Cyclohexen-(2)-yl 46% 189.degree.-190.degree. C. ______________________________________
If the amidine is replaced by corresponding guanidines and the benzoyl group is split off refluxing with 5 N hydrochloric acid, then the following pyrimidines are obtained
______________________________________ Pyrrolidino 64 Decomposition from 230.degree. C. Hexahydroazepino 51 Decomposition from 218.degree.-220.degree. C. Diethylamino 56 211.degree.-212.degree. C. ______________________________________
EXAMPLE E
1.4-Hydroxy-2-methylmercapto-5-nitro-pyrimidine
104.5 gm of S-methyl-isothiourea (0.75 mol) and 53.3 gm (1.333 mol) of sodium hydroxide solution are stirred together for 10 minutes in 350 ml of water. 114.5 gm (0.605 mol) of ethyl-ethoxymethylene-nitroacetate are then slowly added thereto,the temperature being kept at 20.degree. C. by cooling. The precipitate is extracted and washed with a little ice-cold water. It is dissolved in approximately 9 liters of hot water and acidified with concentrated hydrochloric acid with cooling. Theprecipitated product is extracted and washed with ether.
Yield: 65 gm (58%).
M.p.: 220.degree.-222.degree. C.
2.2-Anilino-4-hydroxy-5-nitro-pyrimidine
4.65 gm of 4-hydroxy-2-methylmercapto-5-nitropyrimidine (0.025 mol) are dissolved with heating in 150 ml of ethanol and refluxed for 5 hours with 4.68 gm of aniline (0.05 mol). The precipitated product is extracted in the cold, washed withethanol and dried.
Yield: 4.1 gm (70%).
M.p.: >300.degree. C.
Calculated: C, 51.73; H, 3.47; N, 24.13. Found: C, 51.70; H, 3.39; N, 23.95.
3.5-Amino-2-anilino-4-hydroxy-pyrimidine
2.3 gm of the nitro compound (0.01 mol) of Example 2 are hydrogenated in 100 ml of dimethyl formamide with 500 mg of Raney-nickel until absorption of hydrogen is completed. The catalyst is separated, the solvent is evaporated in vacuo and alittle ethanol is added. The precipitated crystalline product is extracted and dried.
Yield: 1.1 gm (55%)
M.p.: 240.degree.-242.degree. C.
Calculated: C, 59.40; H, 4.98; N, 27.71. Found: C, 58.70; H, 5.08; N, 27.10.
The following pyrimidines of the general formula were synthesized analogously:
______________________________________ ##STR39## R.sub.8, R.sub.9, R.sub.10 Melting Point Yield ______________________________________ p-Chloro 240.degree.-242.degree. C. 44% p-methoxy 220.degree.-222.degree. C. 61% p-hydroxy290.degree.-293.degree. C. 37% m,p-dichloro 280.degree. C. 47% p-methyl 212.degree.-215.degree. C. 34% p-acetylamino 255.degree.-256.degree. C. 51% o-chloro 219.degree.-220.degree. C. 42% p-fluoro 238.degree.-240.degree. C. 54% m-chloro241.degree.-242.degree. C. 46% o,p-dichloro 264.degree.-265.degree. C. 40% p-dimethylamino 264.degree.-265.degree. C. 48% p-nitro >300.degree. C. 34% m-trifluoromethyl- 283.degree.-285.degree. C. 61% p-chloro o-methyl220.degree.-222.degree. C. 31% p-bromo 235.degree.-236.degree. C. 44% m,m'-dichloro- 275.degree. C. (decomp.) 38% p-amino ______________________________________
By reaction of 4-hydroxy-2-methylmercapto-5-nitropyrimidine with aliphatic or araliphatic amines and subsequent reduction of the nitro group the following pyrimidines were obtained:
______________________________________ R Yield Melting Point ______________________________________ CH.sub.2 .dbd.CH--CH.sub.2 NH 43% sinters from 80.degree. C. CH.sub.3 --CH.dbd.CH--CH.sub.2 NH 39% decomp. 114.degree. C. HC.tbd.C--CH.sub.2NH 48.5% 186.degree.-187.degree. C. (CH.sub.2 .dbd.CH--CH.sub.2).sub.2N 53% 139.degree.-140.degree. C. Cyclopropylamino 58% 246.degree. C. Cyclobutylamino 41% 261.degree. C. Cyclopentylamino 52% 270.degree. C. Cyclohexylamino 41% sinters from170.degree. C. Dimethylamino 58% 225.degree. C. Formylpiperazino 21% 246.degree.-249.degree. C. Acetylpiperazino 27% 255.degree.-260.degree. C. (decomp.) Carbethoxypiperazino 38% 205.degree. C. Benzyloxycarbonylpiperazino 44% sinters from180.degree. C. Phenylpiperazino 46.5% 264.degree.-265.degree. C. Methylpiperazino 42% 176.degree.-180.degree. C. Morpholino 59% 175.degree.-185.degree. C. Thiomorpholino 46% 183.degree.-186.degree. C. Thiomorpholino-s-oxide 37% >300.degree. C. Thiomorpholino-S,S--dioxide 34% >300.degree. C. Methylamino 52% 196.degree.-198.degree. C. Phenethylamino 55% 89.degree.-90.degree. C. Benzylamino 40% sinters from 140.degree. C. p-Chlorobenzylamino 39% sinters from 90.degree. C. l-Phenylethylamino 46% 166.degree.-169.degree. C. ______________________________________
EXAMPLE F
5-Benzoylamino-4-hydroxy-2-methylmercapto-pyrimidine
120 gm of 2-phenyl-4-ethoxymethylene-5-oxo-2-oxaline (0.55 mol) are refluxed for 6 hours together with 115 gm of S-methyl-isothiourea sulphate and 99 gm of sodium acetate in 2 liters of absolute ethanol. Ethanol is drawn off in vacuo and theresidue is stirred in 3 liters of ice water. It is extracted and recrystallized from 1.2 liters of glacial acetic acid.
Yield: 87 gm (60%)
Melting Point: 270.degree. C.
5-Amino-2-cyclohexylmethylamino-4-hydroxy-pyrimidine
A mixture of 10.2 gm of cyclohexylmethylamine (0.09 mol) and 5.4 gm of glacial acetic acid (0.09 mol) is melted at 180.degree. C. for 1 hour with 7.8 gm of the above compound. The residue is triturated with 50% ethanol and extracted.
Yield: 8.6 gm (88%).
The product obtained is refluxed for 1 hour in 100 ml of concentrated hydrochloric acid, the precipitated benzoic acid is removed with ether and the residue is brought with concentrated sodium hydroxide solution to pH 6.5 with cooling. Theproduct obtained is extracted.
Yield: 4.8 gm (84%).
Melting point: decomposition >90.degree. C.
In the case of R=substituted anilino, separation of the benzoyl group is effected more conveniently with a mixture of concentrated sulphuric acid and glacial acetic acid.
The following pyrimidines were prepared according to this method:
______________________________________ ##STR40## R.sub.8, R.sub.9, R.sub.10 Yield Melting Point ______________________________________ p-CF.sub.3 51% 214.degree. C. p-C.sub.2 H.sub.5 61% 224.degree.-225.degree. C. p-CH(CH.sub.3).sub.2 54%200.degree.-202.degree. C. p-CH.sub.3 NH 46% 244.degree.-245.degree. C. p-CH.sub.3 SO.sub.2 54% 288.degree.-290.degree. C. p-CH.sub.3 CO 67% >300.degree. C. p-H.sub.2 NCO 61% 279.degree.-280.degree. C. p-CN 44% 246.degree.-250.degree. C. m,p-CH.sub.3 O 54% 234.degree.-235.degree. C. m,m-Cl 42% 280.degree.-282.degree. C. p-CH.sub.3 SO 51% 259.degree.-260.degree. C. ______________________________________
or
______________________________________ ##STR41## R Yield Melting Point ______________________________________ ##STR42## 64% 192.degree.-193.degree. C. Ethylamino 41% decomp. >150.degree. C. Propylamino 56% 141.degree.-144.degree. C. Isopropylamino 52% 138.degree.-140.degree. C. Butylamino 34% 146.degree.-148.degree. C. Isobutylamino 48% 162.degree.-163.degree. C. Hexylamino 58% sinters over 115.degree. C. Octylamino 37% sinters over 100.degree. C. Hexahydroazepinylamino 33%193.degree.-196.degree. C. Cyclopenten-2-ylamino 33% 176.degree.-178.degree. C. Cyclohexen-3-ylamino 42% 184.degree.-185.degree. C. 4-Methyl-cyclohexylamino 61% sinters >120.degree. C. Ncyclohexyl-Nmethylamino 62% 181.degree.-182.degree. C. Ncyclopropyl-Nmethylamino 48% 144.degree.-146.degree. C. Cyclopropylmethylamino 47% 164.degree.-167.degree. C. 2-cyclohexylethylamino 64% 204.degree.-206.degree. C. ______________________________________
EXAMPLE G
5-Amino-4-hydroxy-2-propionylamino-pyrimidine
7.8 gm (0.055 mol) of 2-amino-4-hydroxy-5-nitropyrimidine are heated for 4 hours to 140.degree. C. in 50 ml of propionic acid anhydride. The mixture is cooled and the precipitated product is extracted and washed with ether. The compound issuspended in 200 ml of dimethyl formamide and hydrogenated at room temperature and normal pressure with 1 gm of Pd/C as catalyst.
Yield: 6.8 gm (71%); decomposition >240.degree. C.
The following pyrimidines were prepared according to this method:
______________________________________ ##STR43## R.sub.11 Yield Melting Point ______________________________________ Propyl 69% 202.degree. C. Isopropyl 74% 214.degree. C. Butyl 81% 237.degree. C. Trifluoromethyl 32% decomp. 110.degree. C. Pentafluoroethyl 31% decomp. 90.degree. C. Heptafluoropropyl 43% decomp. 105.degree. C. ______________________________________
If an acid chloride or an isocyanate is used as acylating agent in this method, the reaction is effected in dry pyridine as solvent. Reduction of the acylated nitro compound obtained is effected analogously to above Examples.
The following pyrimidines can thus be synthesized:
______________________________________ Yield Melting Point ______________________________________ R.sub.11 Cyclopropyl 46% decomp. 160.degree. C. Cyclohexyl 42% 247-248.degree. C. Phenyl 61% 218-220.degree. C. Ethoxy 32% 244-245.degree. C. Dimethylamino 28% 251-254.degree. C. Methylamino 47% 196.degree. C. Cyclopropylamino 41% 185.degree. C. Amino 22% 220-225.degree. C. Anilino 47% 264-265.degree. C. Pyrrolidino 39% 214-215.degree. C. or R.sub.14 Methyl- 34% 151-152.degree. C. Ethyl- 31% 164-168.degree. C. Tolyl- 56% 166-170.degree. C. ______________________________________
EXAMPLE H
D-.alpha.-[3-(2-p-fluorobenzyl-4-hydroxy-5-pyrimidyl)-ureido]-phenylglycine
2.18 gm of 5-amino-2-p-fluorobenzyl-4-hydroxy-pyrimidine (0.01 mol) are dissolved in the heat in 120 ml of absolute tetrahydrofurane and mixed with 1.35 ml of triethylamine. The solution is dropped into an ice-cold solution of 1.05 gm ofphosgene in 40 ml of tetrahydrofurane. The mixture is subsequently evaporated in vacuo to approximately 50 ml and then dropped with ice-cooling into a solution of 1.51 gm (0.01 mol) of D-phenylglycine which has been dissolved with N/10 sodium hydroxidesolution at pH 9 in a 1:1 mixture of tetrahydrofurane and water. After addition, the mixture is stirred at room temperature for 2 hours, the pH value being kept between 9 and 9.5 with N/10 sodium hydroxide solution.
Tetrahydrofurane is subsequently removed in vacuo. The aqueous solution is shaken at pH 7 twice with ethyl acetate, then acidified to pH 2 and carefully shaken with ethyl acetate. After drying and evaporation in a rotary evaporator 2.7 gm ofcolorless product remain (69%).
IR spectrum: 1720, 1650, 1550 cm.sup.-1
NNR spectrum (DMSO+CD.sub.3 OD), signals at ppm: 3.9 (2H), 5.4 (1H), 7.4 (m, 9H), 8.6 (1H).
Calculated: C, 60.60; H, 4.32; N, 14.14. Found: C, 60.40; H, 4.64; N, 14.34.
The following starting materials were synthesized analogously.
(a) D-.alpha.-[3-(2-benzyl-4-hydroxy-5-pyrimidyl)-ureido]-phenylglycine,
(b) D-.alpha.-[3-(2-benzyl-4-hydroxy-5-pyrimidyl)-ureido]-p-hydroxy-phenyl glycine.
(c) D-.alpha.-[3-(2-p-chlorophenyl-4-hydroxy-5-pyrimidyl)-ureido]-p-hydroxy-ph enylglycine.
(d) D-.alpha.-[3-(2-o-chlorobenzyl-4-hydroxy-5-pyrimidyl)-ureido]-p-hydroxyphe nylglycine.
(e) D-.alpha.-[3-(2-m-chlorobenzyl-4-hydroxy-5-pyrimidyl)-ureido]-phenylglycin e.
EXAMPLE J
D-.alpha.-[3-(2-p-chloroanilino-4-hydroxy-5-pyrimidyl)-ureido]-phenylglycin
2.36 gm (0.01 mol) of 5-amino-2-p-chloroanilino-4-hydroxypyrimidine are reacted, as specified in Example H, with 1.05 gm of phosgene and 1.35 ml of triethylamine in absolute tetrahydrofurane. The solution is dropped at 0.degree. to 5.degree. C. into a solution of 1.73 gm of the sodium salt of D-.alpha.-phenylglycine in 50 ml of 80% aqueous tetrahydrofurane. During the addition, the pH value of the solution is kept at 9.5 to 10 by the addition of 2 N sodium hydroxide solution. The solutionis kept for 1 hour at 5.degree. C. and for 2 hours at room temperature. After the reaction, the tetrahydrofurane is removed under reduced pressure and the remaining aqueous phase is shaken twice with ethyl acetate at pH 7.5. The mixture is thenbrought to pH 1.5 with ice-cooling (dilute hydrochloric acid). The aqueous phase is shaken twice, each time with 100 ml of ethyl acetate. The organic phases are washed with water and dried over anhydrous sodium sulphate. To the organic phase then wasadded to it the calculated quantity of the sodium salt of 2-ethylhexanic acid, aqueous crystals being separated, which are extracted and dried. Yield: 2.57 gm (56%).
The following can be prepared analogously:
D-.alpha.[3-(2-m,p-dichloroanilino-4-hydroxy-5-pyrimidyl)-ureido]-phenylgly cine sodium.
D-.alpha.-[3-(4-hydroxy-2-o-methylanilino-5-pyrimidyl)-ureido]phenylglycine .
D-.alpha.-[3-(2-p-chloro-m-trifluoromethylanilino)-4-hydroxy-5-pyrimidyl)-u reido]phenylglycine
D-.alpha.-[3-(2-p-bromoanilino-4-hydroxy-5-pyrimidyl)-ureido]phenylglycine.
II. PREPARATION OF THE FINAL PRODUCTS
EXAMPLE 1
D-.alpha.-[3-(4-hydroxy-5-pyrimidyl)-ureido]-p-hydroxybenzylpenicillin sodium
1.1 gm (0.01 mol) of 4-hydroxy-5-amino-pyrimidine are dissolved with heating in 800 ml of absolute tetrahydrofurane. The solution is mixed with 1.35 ml of triethylamine (0.01 mol). The mixture is dropped at 0.degree. C. into a solution of 1.05gm (0.01 mol) of phosgene in 50 ml of absolute tetrahydrofurane. The mixture obtained is subsequently evaporated in vacuo to approximately 100 ml.
4.2 gm (0.01 mol) of amoxycillin trihydrate are suspended in 60 ml of 80% aqueous tetrahydrofurane and mixed slowly at 0.degree. C. with triethylamine until everything has dissolved. The solution prepared above is then added thereto withice-cooling, the pH value being kept at 7.5 by the addition of triethylamine. After addition, the mixture is stirred for 1 hour at 5.degree. C. and for 1 hour at room temperature and the tetrahydrofurane is subsequently removed in vacuo. The mixturediluted with water to 50 ml and shaken twice at pH 7.0, each time with 50 ml of ethyl acetate. The aqueous phase is then covered with a layer of 300 ml of ethyl acetate and brought to pH 2.0 with 2 N hydrochloric acid with ice-cooling and stirring. Theorganic phase is separated, the aqueous phase is shaken once again with 50 ml of ethyl acetate and the organic phases are united, dried with sodium sulphate and evaporated to dryness in vacuo.
The remaining product is mixed with a solution of 1.28 gm (0.007 mol) of sodium hexanoate in 25 ml of dry methanol and is thereby dissolved. 300 ml of dry diethyl ether are added thereto while stirring. The precipitated solid product isextracted and dried in vacuo.
Yield: 3.26 gm (62%)
Rf: 0.54.
IR spectrum: 1770, 1650, 1600, 1490 cm.sup.-1
NMR spectrum (DMSO+CD.sub.3 OD): Signals at ppm: 1.55 (d,6H), 4.05 (1H), 5.40 (q,2H), 5.5. (1H), 6.8 (d,2H), 7.35 (d,2H), 7.9 (1H), 8.6 (1H).
EXAMPLE 2
D-.alpha.-[3-(4-hydroxy-5-pyrimidyl)-ureido]-benzylpenicillin sodium
1.1 gm (0.01 mol) of 4-hydroxy-5-amino-pyrimidine are refluxed for 3 hours with 20 ml of hexamethyl disilazane and a few grains of ammonium sulphate. Excess hexamethyl disilazane is subsequently blown off with nitrogen. The residue is dissolvedin 30 ml of absolute tetrahydrofurane, mixed with 1.38 ml of triethylamine and dropped with ice-cooling into a solution of 1 gm of phosgene in 50 ml of absolute tetrahydrofurane. The mixture is then stirred at 0.degree. C. for approximately 1 hour. Triethylamine hydrochloride is filtered off under nitrogen and the solution is evaporated to dryness in vacuo.
4 gm of ampicillin trihydrate (0.01 mol) are dissolved with 2.5 ml of triethylamine in 80 ml of methylene chloride. The solution is dried over magnesium sulphate, filtered and cooled to 0.degree. C. A solution of the solid product obtainedabove is then dropped into 80 ml of absolute methylene chloride. The mixture is stirred for 1 hour and for 2 hours at room temperature. It is then evaporated to dryness in vacuo. The solid product obtained is mixed with 50 ml of ethyl acetate and 50ml of water and the pH value adjusted to 7.5. The aqueous phase is shaken twice with a little ethyl acetate. The aqueous phase is then covered with a layer of 500 ml of ethyl acetate and the pH value is slowly brought with dilute hydrochloric acid to2.0 with ice-cooling. It is filtered off from the hardly soluble product and the aqueous phase is shaken once again with 100 ml of ethyl acetate. After drying and evaporation of the solvent, the sodium salt is prepared, as described in Example 1. Yield: 2.45 gm (48%).
Rf: 0.57.
IR spectrum: 1770, 1660, 1610, 1525 cm.sup.-1.
NMR (D.sub.2 O) signals at ppm: 1.4 (3H), 1.5 (3H), 4.25 (1H), 5.3-5.6 (3H), 7.5 (5H), 8.3 (1H), 8.6 (1H).
EXAMPLE 3
D-.alpha.-[3-(4-hydroxy-5-pyrimidyl)-ureido]-cyclohexa-1,4-dien-1-yl-methyl -penicillin sodium
This penicillin is synthesized analogously to Example 1 by starting from the reaction product of 550 mg (0.005 mol ) of 5-amino-4-hydroxy-pyrimidine with 0.68 ml (0.005 mol) of triethylamine and 0.50 gm of phosgene (0.005 mol) as well as 1.87 gm(0.005 mol) of epicillin sodium.
Yield: 3.12 gm of sodium salt (61%).
IR spectrum: 1770, 1655, 1605, 1535 cm.sup.-1.
NMR spectrum (DMSO+CD.sub.3 OD) signals at ppm: 1.50 (6H), 2.50 (4H), 4.05 (1H), 4.90 (1H), 5.30 (2H), 5.65 (3H), 7.9 (1H), 8.55 (1H).
The following are synthesized analogously to Example 1.
D-.alpha.-[3-(4-hydroxy-5-pyrimidyl)-ureido]-2-thienylmethyl-penicillin sodium.
D-.alpha.-[3-(4-hydroxy-5-pyrimidyl)-ureido]-m,p-dihydroxy benzyl-pencillin sodium.
D-.alpha.-[3-(4-hydroxy-5-pyrimidyl)-ureido]-m-chloro-p-hydroxy-benzyl-peni cillin sodium.
EXAMPLE 4
D-.alpha.-[3-(4-hydroxy-2-methyl-5-pyrimidyl)-ureido]-p-hydroxybenzyl-penic illin sodium.
Analogously to Example 1, starting from 2.5 gm of 5-amino-4-hydroxy-2-methyl-pyridimide (0.02 mol) which has firstly been reacted with 2.1 gm of phosgene and 2.7 ml of triethylamine and then with 8.5 gm of amoxycillin trihydrate (0.002 mol).
Yield: 6.45 gm of sodium salt (60%).
Rf. 0.55.
IR spectrum: 1770, 1660, 1610, 1545 cm.sup.-1.
NMR spectrum (D.sub.2 O) signals at ppm: 1.45 (6H), 2.4 (3H), 4.2 (1H), 5.3 (1H), 5.45 (2H), 6.9 (2H), 7.35 (2H), 8.3 (1H).
EXAMPLE 5
D-.alpha.-[3-(4-hydroxy-2-methyl-5-pyrimidyl]-ureido]-benzyl-penicillin sodium
Analogously to Example 1, starting from 750 mg of the pyrimidine of Example 4 (0.006 mol), 0.8 ml of triethylamine, 600 mg of phosgene and 2.25 gm (0.006 mol) of ampicillin sodium salt.
Yield: 1.76 gm of sodium salt (56%).
IR spectrum: 1770, 1660, 1610, 1530 cm.sup.-1.
NMR spectrum (D.sub.2 O) signals at ppm: 1.50 (6H), 2.45 (3H), 4.15 (1H), 5.3-5.6 (3H), 7.5 (5H), 8.3 (1H).
The following are synthesized analogously:
D-.alpha.[3-(4-hydroxy-2-methyl-5-pyrimidyl)-ureido]-2-thienyl methyl-penicillin sodium.
D-.alpha.-[3-(4-hydroxy-2-methyl-5-pyrimidyl)-ureido]-m,p-dihydroxybenzyl-p enicillin sodium.
D-.alpha.-[3-(4-hydroxy-2-methyl-5-pyrimidyl)-ureido]-m-chloro-p-hydroxyben zyl-penicillin sodium.
D-.alpha.-[3-(4-hydroxy-2-methyl-5-pyrimidyl)-ureido]-cyclo-hexa-1,4-dien-1 -yl-methyl-penicillin sodium.
EXAMPLE 6
D-.alpha.-[3-(2-ethyl-4-hydroxy-5-pyrimidyl)-ureido]-p-hydroxybenzyl-penici llin sodium
This penicillin is synthesized in the way specified in Example 1 by starting from 2.1 gm (0.005 mol) of amoxycillin trihydrate and the reaction product of 0.7 gm (0.005 mol) of 5-amino-2-ethyl-4-hydroxy-pyrimidine with 500 mg of phosgene and 0.68ml of triethylamine
Yield: 1.62 gm (57%).
Rf: 0.58.
IR spectrum: 1770, 1650, 1600, 1540, 1510 cm.sup.-1.
NMR spectrum (DMSO+CD.sub.3 OD) signals at ppm: 1.2 (3H); 1.55 (6H), 2.45 (2H), 4.1 (1H), 5.4 (3H), 6.8 (2H), 7.3 (2H), 8.5 (1H).
The following are synthesized analogously:
D-.alpha.[3-(2-ethyl-4-hydroxy-5-pyrimidyl)-ureido]-benzyl-penicillin sodium.
D-.alpha.-[3(2-ethyl-4-hydroxy-5-pyrimidyl)-ureido]-cyclohexa-1,4-dien-1-yl -methyl-penicillin sodium
EXAMPLE 7
D-.alpha.-[3-(4-hydroxy-2-isopropyl-5-pyrimidyl)-ureido -p-hydroxybenzyl-penicillin sodium
Analogously to Example 1, starting from 4.2 gm of amoxycillin trihydrate (0.01 mol) as well as the reaction product of 1.52 gm (0.01 mol) of 5-amino-4-hydroxy-2-isopropyl-pyrimidine with 1.05 gm of phosgene and 1.35 ml of triethylamine.
Yield: 3.0 gm (53%) of sodium salt.
Rf: 0.69
IR spectrum: 1765, 1650, 1610, 1550 cm.sup.-1
NMR spectrum (D.sub.2 O) signals at ppm: 1.25 (6H), 1.45 (6H), 2.9 (1H), 4.2 (1H), 5.4 (3H), 6.9 (2H), 7.3 (2H), 8.35 (1H).
EXAMPLE 8
D-.alpha.-[3-(2-t-butyl-4-hydroxy-5-pyrimidyl)-ureido]-p-hydroxybenzyl-peni cillin sodium
This pyrimidine is synthesized analogously to Example 1 by starting from 1.26 gm of amoxycillin trihydrate (0.003 mol) as well as the reaction product of 0.47 gm (0.003 mol) of 5-amino-2-t-butyl-4-hydroxy-pyrimidine with 300 mg of phosgene and0.41 ml of triethylamine.
Yield: 850 mg of sodium salt (49%).
Rf: 0.64
IR spectrum: 1770, 1650, 1600, 1550 cm.sup.-1.
NMR spectrum (D.sub.2 O) signals at ppm: 1.3 (9H), 1.45 (6H), 4.2 (1H), 5.4 (3H), 6.9 (2H), 7.3 (2H), 8.35 (1H).
EXAMPLE 9
D-.alpha.-[3-(2-amyl-4-hydroxy-5-pyrimidyl)-ureido]-p-hydroxybenzyl-penicil lin sodium
Synthesis analogous to Example 1, starting from 2.1 gm of amoxycillin trihydrate (0.005 mol) as well as the reaction product of 0.85 gm (0.005 mol) of 5-amino-2-amyl-4-hydroxy-pyrimidine with 500 mg of phosgeneand 0.68 ml of triethylamine.
Yield: 1.9 gm of sodium salt (65%).
Rf: 0.70.
IR spectrum: 1770, 1650, 1600, 1550 cm.sup.-1.
NMR spectrum (DMSO+CD.sub.3 OD) signals at ppm: 0.9 (3H), 1.3 (6H), 1.55 (6H), 2.5 (2H), 4.05 (1H), 5.45 (3H), 6.8 (2H), 7.3 (2H), 8.55 (1H).
EXAMPLE 10
D-.alpha.-[3-(4-hydroxy-2-octyl-5-pyrimidyl)-ureido]-p-hydroxy-benzyl-penic illin sodium
Synthesis analogous to Example 1, starting from 840 mg of amoxycillin trihydrate (0.002 mol) and the reaction product of 420 mg (0.002 mol) of 5-amino-4-hydroxy-2-octyl-pyrimidine with 200 mg of phosgene and 0.27 ml of triethylamine.
Yield: 440 mg of sodium salt (35%).
IR spectrum: 1770, 1650, 1600, 1545 cm.sup.-1
NMR Spectrum (DMSO+CD.sub.3 OD) signals at ppm: 0.9 (3H), 1.3 (12H), 1.55 (6H), 2.45 (2H), 4.1 (1H), 5.40 (3H), 6.85 (2H), 7.30 (2H), 8.45 (1H).
EXAMPLE 11
D-.alpha.-[3-(2-cyclopropyl-4-hydroxy-5-pyrimidyl)-ureido]-p-hdroxybenzyl-p enicillin sodium
18.2 gm of 5-amino-2-cyclopropyl-4-hydroxy-pyrimidine (0.12 mol) are dissolved with heating in 800 ml of absolute tetrahydrofurane and mixed with 16.5 ml of triethylamine. This solution is dropped at 0.degree. C. into a solution of 12 gm ofphosgene in 250 ml of absolute tetrahydrofurane. The mixture is stirred with ice-cooling for approximately 30 minutes. Nitrogen is subsequently bubbled through the solution in order to remove unreacted phosgene.
50.4 gm of amoxycillin trihydrate are suspended in1.6 liters of aqueous 80% tetrahydrofurane and cooled to 0.degree. C. Enough triethylamine is then added thereto for a solution to be obtained (16.5 ml). The suspension prepared above is addedwithin 60 minutes, the pH value being kept at 7.5 with triethylamine. A further 100 ml of water are added and the reaction mixture is kept at 0.degree.-2.degree. C. for 1 hour. The cooling is removed and the mixture is stirred for 1 hour at roomtemperature.
500 ml of water are then added thereto and the tetrahydrofurane is removed in vacuo. The remaining water phase is washed twice with 280 ml of ethyl acetate. It is diluted with ice water to 2.5 liters and covered with a layer of 6 liters ofethyl acetate. 2 N hydrochloric acid is slowly added thereto with constant stirring until pH 2.0, the temperature being kept below 5.degree. C. Any insoluble product is filtered off and the layers are separated. The water phase is washed again with 1liter of ethyl acetate. The organic phase is dried over sodium sulphate and the solvent is removed in vacuo.
The product is suspended in a little water and, with ice-cooling and stirring, mixed dropwise with N/10 sodium hydroxide solution until a pH value of 6.8. The solution obtained is freeze-dried.
Yield: 60.2 gm of sodium salt (89%).
Rf: 0.71.
IR spectrum: 1775, 1660, 1615, 1555 cm.sup.-1.
NMR Spectrum (DMSO+CD.sub.3 OD) signals at ppm: 0.95 (4H), 1.55 (6H), 1.9 (1H), 4.05 (1H), 5.35 (2H), 5.45 (1H), 6.8 (2H), 7.3 (2H), 8.48 (1H).
EXAMPLE 12
D-.alpha.-[3-(2-cyclopropyl-4-hydroxy-5-pyrimidyl)-ureido]-benzyl-penicilli n sodium
This penicillin is prepared analogously to Example 11, starting from 4.0 gm of ampicillin trihydrate as well as the reaction product of 1.51 gm (0.01 mol) of the pyrimidine of Example 11 with 1.0 gm of phosgene and 1.35 ml of triethylamine.
Yield: 4.2 gm of sodium salt (78%).
Rf: 0.74.
IR spectrum: 1770, 1655, 1615, 1540 cm.sup.-1.
NMR spectrum (DMSO+CD.sub.3 OD) signals at ppm: 0.95 (4H), 1.55 (6H), 1.9 (1H), 4.0 (1H), 5.45 (3H), 7.45 (5H), 8.40 (1H).
EXAMPLE 13
D-.alpha.-[3-(2-cyclopropyl-4-hydroxy-5-pyrimidyl)-ureido]-cyclohexa-1,4-di en-1-yl-methyl-penicillin sodium
This penicillin is prepared analogously to Example 11, starting from 1.87 gm of epicillin sodium (0.005 mol) as well as the reaction product of 0.75 gm (0.005 mol) of the pyrimidine of Example 11 with 500 mg of phosgene and 0.68 ml oftriethylamine.
Yield: 2.03 gm of sodium salt (74%).
IR spectrum: 1770, 1660, 1605, 1550 cm.sup.-1,
NMR spectrum (DMSO+CD.sub.3 OD) signals at ppm: 0.9 (4H), 1.5 (6H), 1.95 (1H), 2.50 (4H), 4.05 (1H), 4.95 (1H), 5.30 (2H), 5.65 (3H), 8.40 (1H).
The following are synthesized analogously:
D-.alpha.-[3-(2-cyclopropyl-4-hydroxy-5-pyrimidyl)-ureido]-2-thienylmethyl- penicillin sodium.
D-.alpha.-[3-(2-cyclopropyl-4-hydroxy-5-pyrimidyl)-ureido]-m,p-dihydroxyben zyl-penicillin sodium.
D-.alpha.-[3-(2-cyclopropyl-4-hydroxy-5-pyrimidyl)-ureido]-m-chloro-p-hydro xybenzyl-penicillin sodium.
D-.alpha.-[3-(2-cyclopropyl-4-hydroxy-5-pyrimidyl)-ureido]-m-fluoro-p-hydro xybenzyl-penicillin sodium.
EXAMPLE 14
D-.alpha.-[3-(2-cyclobutyl-4-hydroxy-5-pyrimidyl)-ureido]-p-hydroxybenzyl-p enicillin sodium
This penicillin is prepared analogously to Example 11, starting from 4.2 gm of amoxycillin trihydrate (0.01 mol) as well as the reaction product of 1.65 gm (0.01 mol) of 5-amino-2-cyclobutyl-4-hydroxy-pyrimidine with 1.0 gm of phosgene and 1.38ml of triethylamine.
Yield: 4.85 gm of sodium salt (84%)
Rf: 0.73.
IR spectrum: 1770, 1660, 1605, 1545 cm.sup.-1.
NMR spectrum (DMSO+CH.sub.3 OD) signals at ppm: 1.55 (6H), 1.8-2.5 (m,6H), 3.4 (1H), 5.4 (q,2H), 5.5 (1H), 6.8 (2H), 7.3 (2H), 8.6 (1H).
The following are synthesized analogously:
D-.alpha.-[3-(2-cyclobutyl-4-hydroxy-5-pyrimidyl)-ureido]-benzyl-penicillin sodium.
D-.alpha.-[3-(2-{2'-ethyl-cyclopropyl}-4-hydroxy-5-pyrimidyl)-ureido]-p-hyd roxybenzyl-penicillin sodium.
D-.alpha.-[3(2-{2'-ethyl-cyclopropyl}-4-hydroxy-5-pyrimidyl)-ureido]-benzyl -penicillin sodium.
D-.alpha.-(3-4-hydroxy-2-{2'-phenyl-cyclopropyl}-5-pyrimidyl)-ureido]-p-hyd roxybenzyl-penicillin sodium.
D-.alpha.-[3-(4-hydroxy-2-{2'-phenyl-cyclopropyl}-5-pyrimidyl)-ureido]-benz yl-penicillin sodium.
EXAMPLE 15
D-.alpha.-[3-(2-cyclopentyl-4-hydroxy-5-pyrimidyl)-ureido]-p-hydroxybenzyl- penicillin sodium
This penicillin is prepared analogously to Example 11, starting from 420 mg of amoxycillin sodium (0.001 mol) as well as the reaction product of 180 mg of 5-amino-2-cyclopentyl-4-hydroxy-pyrimidine (0.001 mol) with 100 mg of phosgene and 0.14 mlof triethylamine.
Yield: 405 mg of sodium salt (69%).
Rf: 0.65.
IR spectrum: 1770, 1650, 1600, 1550 cm.sup.-1.
NMR spectrum (DMSO+CD.sub.3 OD) signals at ppm: 1.0-2.1 (m,15H), 4.0 (1H), 5.5 (3H), 6.8 (2H), 7.3 (2H), 8.55 (1H).
EXAMPLE 16
D-.alpha.-[3-(2-cyclohexyl-4-hydroxy-5-pyrimidyl)-ureido]-p-hydroxybenzyl-p enicillin sodium
This penicillin is prepared analogously to Example 11, starting from 840 mg of amoxycillin trihydrate (0.002 mol) as well as the reaction product of 385 mg of 5-amino-2-cyclohexyl-4-hydroxy-pyrimidine (0.002 mol) with 200 mg of phosgene and 0.27ml of triethylamine.
Yield: 720 mg of sodium salt (60%).
Rf: 0.62.
IR spectrum: 1770, 1645, 1600, 1545 cm.sup.-1.
NMR spectrum (DMSO+CD.sub.3 OD) signnals at ppm: 1.0-2.1 (m,17H), 4.05 (1H), 5.35 (2H), 5.45 (1H), 6.85 (2H, 7.3 (2H), 8.50 (1H).
EXAMPLE 17
D-.alpha.-[3-(4-hydroxy-2-{2'-methyl-cyclopropyl}-5-pyrimidyl)-ureido]-p-hy droxybenzyl-penicillin sodium
This penicillin is prepared analogously to Example 11, starting from 4.2 gm of amoxycillin of trihydrate as well as the reaction product of 1.65 gm (0.01 mol) of 5-amino-4-hydroxy-2-(2'-methyl-cyclopropyl)-pyrimidine with 1.0 gm of phosgene and1.37 ml of triethylamine.
Yield: 3.81 gm of sodium salt (66%).
IR spectrum: 1770, 1650, 1600, 1550 cm.sup.-1.
NMR spectrum (DMSO+CD.sub.3 OD) signals at ppm: 0.9-1.7 (m,12H), 1.95 (1H), 4.05 (1H), 5.45 (3H), 6.8 (2H), 7.3 (2H), 8.45 (1H).
The following are prepared analogously:
D-.alpha.-[3-(4-hydroxy-2-{2'-methyl-cyclopropyl}-5-pyrimidyl)-ureido]-benz yl-penicillin sodium.
D-.alpha.-[3-(4-hydroxy-2-{2'-methyl-cyclopropyl}-5-pyrimidyl)-ureido]-cycl ohexa-1,4-dien-1-yl-methyl-penicillin sodium. D-.alpha.-[3-(2-cyclohexen-2'-yl-4-hydroxy-5-pyrimidyl)-ureido]-p-hydroxyb enzyl-penicillin sodium.
EXAMPLE 18
D-.alpha.-[3-(4-hydroxy-2-{1'-methyl-cyclopropyl}-5-pyrimidyl)-ureido]-p-hy droxy-benzyl-penicillin sodium
This penicillin is prepared analogously to Example 11, starting from 2.1 gm of amoxycillin trihydrate (0.005 mol) as well as the reaction product of 0.83 gm (0.005 mol) of 5-amino-4-hydroxy-2-(1'-methyl-cyclopropyl)-pyrimidine with 500 mg ofphosgene and 0.67 ml of triethylamine.
Yield: 1.54 gm of sodium salt (53%).
Rf: 0.70
IR spectrum: 1765, 1655, 1610, 1550 cm.sup.-1.
NMR spectrum (DMSO+CD.sub.3 OD) signals at ppm: 0.9-1.4 (7H), 1.55 (6H), 4.0 (1H), 5.35 (2H), 5.45 (1H), 6.8 (2H), 7.3 (2H), 8.50 (1H).
The following are synthesized analogously:
D-.alpha.-[3-(4-hydroxy-2-}1'-methyl-cyclopropyl}-5-pyrimidyl)-ureido]-benz yl-penicillin sodium.
D-.alpha.-[3-(2-cyclopropylmethyl-4-hydroxy-5-pyrimidyl)-ureido]-p-hydroxyb enzyl-penicillin sodium.
D-.alpha.-[3-(2-cyclopropylmethyl-4-hydroxy-5-pyrimidyl)-ureido]-benzyl-pen icillin sodium.
EXAMPLE 19
D-.alpha.-[3-(2-allyl-4-hydroxy-5-pyrimidyl)-ureido]-p-hydroxybenzyl-penici llin sodium
This penicillin is prepared analogously to Example 11, starting from 4.2 gm of amoxycillin trihydrate (0.01 mol) as well as the reaction product of 1.5 1 gm (0.01 mol) of 2-allyl-5-amino-4-hydroxy-pyrimidine with 1.0 gm of phosgene and 1.37 ml oftriethylamine.
Yield: 2.54 gm of sodium salt (44%).
IR Spectrum: 1765, 1645, 1610, 1550 cm.sup.-1.
NMR spectrum (DMSO+CD.sub.3 OD) signals at ppm: 1.55 (6H), 4.05 (1H), 4.1 (2H), 5.0 (2H), 5.3-6.0 (1,4H), 6.8 (2H), 7.3 (2H), 8.40 (1H).
The following are synthesized analogously.
D-.alpha.-[3-(2-allyl-4-hydroxy-5-pyrimidyl)-ureido]-benzyl-penicillin sodium.
D-.alpha.-[3-(2-allyl-4-hydroxy-5-pyrimidyl)-ureido]-cyclohexa-1,4-dien-1-y l-methyl-penicillin sodium.
EXAMPLE 20
D-.alpha.-[3-(4-hydroxy-2-vinyl-5-pyrimidyl)-ureido]-p-hydroxy-benzyl-penic illin sodium
This penicillin is prepared analogous to Example 11, starting from 1.68 gm of amoxycillin trihydrate (0.004 mol) as well as the reaction product of 520 mg (0.004 mol) of 5-amino-4-hydroxy-2-vinyl-pyrimidine with 400 mg of phosgene and 0.54 ml oftriethylamine.
Yield: 1.02 gm of sodium salt (51%).
Rf: 0.56.
IR spectrum: 1770, 1655, 1610, 1545 cm.sup.-1.
NMR spectrum (DMSO+CD.sub.3 OD) signals at ppm: 1.55 (6H), 4.05 (1H), 5.0-7.0 (m,6H), 6.8 (2H), 7.3 (2H), 8.35 (1H).
The following are synthesized analogously:
D-.alpha.-[3-(4-hydroxy-2-vinyl-5-pyrimidyl)-ureido[-benzyl-penicillin sodium.
D-.alpha.-[3-(4-hydroxy-2-vinyl-5-pyrimidyl)-ureido]-cyclohexa-1,4-dien-1-y l-methyl-penicillin sodium.
EXAMPLE 21
D-.alpha.-[3-(4-hydroxy-2-propargyl-5-pyrimidyl)-ureido]-p-hydroxybenzyl-pe nicillin sodium
This penicillin is prepared analogous to Example 11, starting from 2.52 gm of amoxycillin trihydrate (0.006 mol) as well as the reaction product of 900 mg (0.006 mol) of a 5-amino-4-hydroxy-2-propargyl-pyrimidine with 600 mg of phosgene and 0.8ml of triethylamine.
Yield: 1.67 gm of sodium salt (46%).
IR spectrum: 1770, 1660, 1610, 1550 cm.sup.-1.
NMR spectrum (DMSO+CO.sub.3 OD) signals at ppm: 1.55 (6H), 2.1 (1H), 4.0 (2H), 4.05 (1H), 5.45 (3H), 6.8 (2H), 7.3 (2H), 8.6 (1H).
The following is prepared analogously.
D-.alpha.-[3-(4-hydroxy-2-propargyl-5-pyrimidyl)-ureido]-benzyl-penicillin sodium.
EXAMPLE 22
D-.alpha.-[3-(2-crotyl-4-hydroxy-5-pyrimidyl)-ureido]-p-hydroxybenzyl-penic illin sodium
This penicillin is prepared analogous to Example 11, starting from 4.2 gm of amoxycillin trihydrate (0.01 mol) as well as the reaction product of 1.66 gm (0.01 mol) of 5-amino-2-crotyl-4-hydroxy-pyrimidine with 1.0 gm of phosgene and 1.35 ml oftriethylamine.
Yield: 2.33 gm of sodium salt (38%).
Rf. 0.62
IR spectrum: 1765, 1655, 1600, 1550 cm.sup.-1.
NMR spectrum: (DMSO+CD.sub.3 CD) signals at ppm: 1.55 (6H), 2.05 (3H), 3.95 (2H), 4.05 (1H), 4.85-6.05 (m,5H), 6.8 (2H), 7.3 (2H), 8.45 (1H).
EXAMPLE 23
D-.alpha.-[3-(2-p-chlorobenzyl-4-hydroxy-5-pyrimidyl)-ureido]-p-hydroxybenz yl-penicillin sodium
2.35 gm (0.01 mol) of 5-amino-2-p-chlorobenzyl-4-hydroxy-pyrimidine are dissolved with heating in 100 ml of absolute tetrahydrofurane. 1.0 gm (0.01 mol) of triethylamine is added to this solution. The mixture is dropped with ice-cooling into asolution of 1.05 gm of phosgene (0.01 mol) in absolute tetrahydrofurane. The mixture is then evaporated in vacuo to approximately 40 ml.
4.2 gm of amoxycillin trihydrate are dissolved with ice-cooling in 80 ml of tetrahydrofurane-water mixture (4:1) by means of triethylamine. The mixture prepared above is dropped with cooling into this solution, the pH value being kept atapproximately 7.5 by means of triethylamine. After the addition, the mixture is stirred for 1 hour in an ice bath and for 1 hour at room temperature. The tetrahydrofurane is subsequently removed in vacuo. The remaining aqueous solution is shaken at pH7.0 twice with a little ethyl acetate. The aqueous phase is thereafter covered with a layer of ethyl acetate and slowly brought with dilute hydrochloric acid to pH 2.0 with cooling and stirring. The ethyl acetate phase is removed and the aqueous phaseis shaken once again with ethyl acetate. The acid ethyl acetate phases are united, dried with sodium sulphate and evaporated to dryness.
The penicillin obtained is dissolved in a little methanol and mixed with the calculated quantity of sodium hexanoate and the sodium salt obtained is precipitated by the addition of ether. After drying, 4.7 gm of sodium salt (73% yield) areobtained.
Rf: 0.79.
IR spectrum: 1770, 1650, 1610, 1550 cm.sup.-1.
NMR spectrum (DMSO+CD.sub.3 OD) signals at ppm: 1.5 (6H), 3.8 (2H), 4.0 (1H), 5.4 (q,2H), 5.45 (1H, 7.0 (dD,4H), 7.35 (4H), 8.45 (1H).
EXAMPLE 24
D-.alpha.-[3-(2-p-chlorobenzyl-4-hydroxy-5-pyrimidyl)-ureido]-benzyl-penici llin sodium
1.17 gm (0.005 mol) of pyrimidine of Example 23 are reacted, as specified above, with phosgene and triethylamine. The mixture obtained is dropped with ice-cooling into a solution of 2.0 gm of ampicillin trihydrate and triethylamine in 80%tetrahydrofurane. Treatment is effected analogous to Example 23.
Yield: 2.55 gm of sodium salt (79% yield).
Rf. 0.80.
IR spectrum: 1765, 1650, 1600, 1540 cm.sup.-1.
NMR spectrum (DMSO/CD.sub.3 OD): signals at ppm: 1.5 (6H), 3.85 (2H), 4.0 (1H), 5.4 (2H), 5.65 (1H), 7.4 (9H), 8.4 (1H).
EXAMPLE 25
D-.alpha.-[3-(2-p-chlorobenzyl-4-hydroxy-5-pyrimidyl)-ureido]-1,4-cyclohexa dien-1-yl-methyl-penicillin sodium
This penicillin is prepared in the way described in Example 23 from 3.7 gm of epicillin sodium salt (0.01 mol) and the reaction product of 2.35 gm (0.01 mol) of 5-amino-2-p-chlorobenzyl-4-hydroxy-pyrimidine and 1.0 gm of phosgene as well as 1.0gm of triethylamine.
Yield: 4.9 gm of sodium salt (77%).
IR spectrum: 1770, 1660, 1610, 1550, 1510 cm.sup.-1.
NMR spectrum (DMSO): signals at ppm: 1.5 (6H), 2.7 (4H), 3.85 (2H), 4.0 (1H), 5.05 (1H), 5.4 (2H), 5.75 (3H), 7.4 (m,4H), 8.5 (1H).
The following are synthesized analogously:
D-.alpha.-[3-(2-p-chlorobenzyl-4-hydroxy-5-pyrimidyl)-ureido]-m,p-dihydroxy benzyl-penicillin sodium.
D-.alpha.-[3-(2-p-chlorobenzyl-4-hydroxy-5-pyrimidyl)-ureido]-m-chloro-p-hy droxybenzyl-penicillin sodium.
EXAMPLE 26
D-.alpha.-[3-(2-p-fluorobenzyl-4-hydroxy-5-pyrimidyl)-ureido]-p-hydroxybenz yl-penicillin sodium
This penicillin is synthesized in the way described in Example 23, starting from 4.2 gm of amoxycillin trihydrate (0.01 mol) and the reaction product of 2.2 gm (0.01 mol) of 5-amino-2-p-fluorobenzyl-4-hydroxypyrimidine with 1.01 gm of phosgeneand 1.0 gm of triethylamine. Treatment is effected analogous to Example 23.
Yield: 5.1 gm of sodium salt (80%)
Rf: 0.78
NMR spectrum (DMSO/CD.sub.3 OD): signals at ppm: 1.5 (6H), 3.85 (2H), 4.0 (1H), 5.35 (q,2H), 5.5 (1H), 6.95 (m,4H), 7.35 (m,4H), 8.55 (1H).
EXAMPLE 27
D-.alpha.-[3-(2-p-fluorobenzyl-4-hydroxy-5-pyrimidyl)-ureido]-1,4-cyclohexa dien-1-yl-methyl-penicillin sodium
3.7 gm (0.01 mol) of epicillin sodium are dissolved in 50 ml of a tetrahydrofurane-water mixture. With ice-cooling the reaction product of 2.2 gm (0.01 mol) of the pyrimidine of Example 26 with 1.01 gm of phosgene and 1.0 gm of triethylamine isadded thereto. The pH value is kept at 7.5 with triethylamine and the mixture is allowed to react for 1 hour with ice-cooling and for 2 hours at room temperature. Treatment of the mixture is effected analogous to Example 23.
Yield: 5.2 gm of sodium salt (84%).
Rf: 0.85.
IR spectrum: 1765, 1660, 1610, 1550 cm.sup.-1.
NMR spectrum (DMSO+CD.sub.3 OD): signals at ppm: 1.55 (6H), 2.75 (4H), 3.90 (2H), 4.05 (1H), 5.1 (1H), 5.45 (2H), 5.75 (3H), 7.4 (m,4H), 8.55 (1H).
The following is synthesized analogously:
D-.alpha.-[3-(2-p-fluorobenzyl-4-hydroxy-5-pyrimidyl-ureido]m,p-dihydroxybe nzyl-penicillin sodium.
EXAMPLE 28
D-.alpha.-[3-(2-m-chlorophenyl-4-hydroxy-5-pyrimidyl)-ureido]-p-hydroxybenz yl-penicillin sodium
Analogous to Example 23 from 8.4 gm of amoxycillin trihydrate (0.02 mol) and the reaction product of 4.43 gm (0.02 mol) of 5-amino-2-m-chlorophenyl-4-hydroxypyrimidine with 2.1 gm of phosgene and 2.0 gm of N-methyl morpholine.
Yield: 9.4 gm of sodium salt (74%).
Rf: 0.77.
IR spectrum: 1770, 1650, 1600, 1550 cm.sup.-1.
NMR spectrum: (DMSO+CD.sub.3 OD): signals at ppm: 1.55 (6H), 4.1 (1H), 5.45 (q,2H), 5.6 (1H), 7.1 (dd/4H), 7.6 (2H), 8.1 (2H), 8.6 (1H).
EXAMPLE 29
D-.alpha.-[3-(2o'-dichlorobenzyl-4-hydroxy-5-pyrimidyl)-ureido]-benzyl-peni cillin sodium
Analogous to Example 23 from 1.9 gm of ampicillin sodium (0.005 mol) and the reaction product of 1.35 gm (0.005 mol) of 5-amino-2-o', o'-dichlorobenzyl-4-hydroxypyrimidine with 500 mg of phosgene and 0.68 ml of triethylamine.
Yield: 2.67 gm (80%) of sodium salt.
Rf: 0.80.
IR spectrum: 1770, 1655, 1610, 1545 cm.sup.-1.
NMR spectrum (DMSO+CD.sub.3 OD): signals at ppm: 1.5 (6H), 4.0 (1H), 4.3 (2H), 5.4 (q,2H), 5.7 (1H), 7.5 (m,8H), 8.45 (1H).
EXAMPLE 30
D-.alpha.-[3-(2-o,p-dichlorobenzyl-4-hydroxy-5-pyrimidyl)-ureido]-p-hydroxy benzyl-penicillin sodium
2.16 gm of 5-amino-2-o,p-dichlorobenzyl-4-hydroxypyrimidine (0.008 mol) are dissolved with heating in 100 ml of tetrahydrofurane. 1.1 ml of triethylamine (0.0078 mol) are added to this solution and the mixture is dropped rapidly into anice-cooled solution of 850 mg (0.0085 mol) of phosgene in 30 ml of tetrahydrofurane. After approximately 20 minutes excess phosgene is blown off with nitrogen and the mixture is evaporated in vacuo to approximately 40 ml. 3.4 gm of amoxycillintrihydrate (0.008 mol) are dissolved with triethylamine in 60 ml of 80% aqueous tetrahydrofurane. The mixture prepared above is dropped into this solution with ice-cooling. The pH value is kept at approximately 7.5 by the addition of triethylamine. After the addition, the mixture is stirred for two hours with ice-cooling and for 1 hour at room temperature. Tetrahydrofuran is subsequently removed in vacuo and the mixture is filled up with water to approximately 100 ml and shaken twice, each timewith 50 ml of ethyl acetate. The aqueous phase is then brought with hydrochloric acid to pH 2 with vigorous cooling. The precipitated product is extracted immediately, washed with a little cold water and ether and dried in vacuo. The sodium salt isprepared in the way specified in Example 23.
Yield: 3.5 gm of sodium salt (66%).
RF: 0.91.
IR spectrum: 1770, 1660, 1605, 1545 cm.sup.-1.
NMR spectrum (DMSO+CD.sub.3 OD): signals at ppm: 1.55 (6H), 4.05 (1H), 4.1 (2H), 5.45 (q,2H) 5.55 (1H), 7.1 (dd,4H), 7.45 (2H), 7.65 (1H), 8.55 (1H).
EXAMPLE 31
D-.alpha.-[3-(2-o,p-dichlorobenzyl-4-hydroxy-5-pyrimidyl)-ureido]-benzyl-pe nicillin sodium
This penicillin is prepared analogous to Example 30 from 2.7 gm (0.01 mol) of the pyrimidine of Example 30 and 4.0 gm of ampicillin trihydrate (0.01 mol).
Yield: 5.03 gm of sodium salt (76%).
Rf: 0.91.
IR spectrum: 1765, 1660, 1610, 1540 cm.sup.-1. NMR spectrum (DMSO+CD.sub.3 OD); signals at ppm: 1.5 (6H), 4.05 (3H), 5.4 (q,2H), 5.7 (1H), 7.45 (8H), 8.55 (1H).
EXAMPLE 32
D-.alpha.-[3-(2-m,p-dichlorobenzyl-4-hydroxy-5-pyrimidyl)-uredio]-benzyl-pe nicillin sodium
Analogous to Example 30 from 2.0 gm of ampicillin trihydrate (0.005 mol) and 1.35 gm (0.005 mol) of 5-amino-2-m,p-dichlorobenzyl-4-hydroxy-pyrimidine.
Yield: 2.5 gm of sodium salt (75%).
Rf: 0.89.
IR spectrum: 1775, 1655, 1615, 1555 cm.sup.-1.
NMR spectrum (DMSO+CD.sub.3 OD): signals at ppm: 1.55 (6H), 4.05 (1H), 4.2 (2H), 5.45 (q,2H), 5.65 (1H), 7.5 (m,8H), 8.50 (1H).
EXAMPLE 33
D-.alpha.-[3-(2-p-amino-m,m-dichlorobenzyl-4-hydroxy-5-pyrimidyl)-ureido]-p -hydroxybenzyl-penicillin sodium
This penicillin is prepared analogous to Example 30 by starting from 2.5 gm of amoxycillin (0.006 mol) and the reaction product of 1.71 gm of 5-amino-2-(p-amino-m,m-dichloro)-benzyl-4-hydroxy-pyrimidine (0.006 mol) with 600 mg of phosgene and0.82 ml of triethylamine.
Yield: 2.95 gm of sodium salt (54%).
Rf: 0.88.
IR spectrum: 1770, 1650, 1615, 1550 cm.sup.-1.
NMR spectrum (DMSO+CD.sub.3 OD): signals at ppm: 1.55 (6H), 4.0 (1H), 4.10 (2H), 5.45 (q,2H), 5.65 (1H), 6.9 (m,4H), 7.3 (d,2H), 8.50 (1H).
EXAMPLE 34
D-.alpha.-[3-(2-o-chlorobenzyl-4-hydroxy-5-pyrimidyl)-ureido]-benzyl-penici llin sodium
Analogously to Example 30 starting from 4.0 gm of ampicillin trihydrate (0.01 mol) and 2.35 gm (0.01 mol) of 5-amino-2-o-chlorobenzyl-4-hydroxy-pyrimidine.
Yield: 5.8 gm of sodium salt (91%).
Rf: 0.70.
IR spectrum: 1770, 1660, 1610, 1540 cm.sup.-1.
NMR spectrum (DMSO+CD.sub.3 OD): signals at ppm: 1.55 (6H), 3.95 (1H), 4.05 (2H), 5.5 (q,2H), 5.75 (1H), 7.5 (m,9H), 8.6 (1H).
EXAMPLE 35
D-.alpha.-[3-(2-m-chlorobenzyl-4-hydroxy-5-pyrimidyl)-ureido]-p-hydroxybenz yl-penicillin sodium
This penicillin is prepared analogous to Example 30, starting from 840 mg of amoxycillin trihydrate (0.002 mol) and the reaction product of 470 mg of 5-amino-2-m-chlorobenzyl-4-hydroxy-pyrimidine (0.002 mol) with 200 mg of phosgene and 0.27 ml oftriethylamine.
Yield: 1.3 gm of sodium salt (88%).
Rf: 0.73.
IR spectrum: 1770, 1665, 1610, 1550 cm.sup.-1.
NMR spectrum (DMSO+CD.sub.3 OD): signals at ppm: 1.5 (6H), 3.95 (1H), 4.10 (2H), 5.45 (q,2H), 5.55 (1H), 6.85 (d,2H), 7.45 (m,6H), 8.60 (1H).
EXAMPLE 36
D-.alpha.-[3-(2-o-chlorophenyl-4-hydroxy-5-pyrimidyl)-ureido]-p-hydroxybenz yl-penicillin sodium
2.16 gm (0.01 mol) of 5-amino-2-o-chlorophenyl-4-hydroxy-pyrimidine. 1.05 gm of phosgene and 1.35 ml of triethylamine are reacted, as described in Example 30 in absolute tetrahydrofurane. Triethylamine hydrochloride is filtered off and thesolution is evaporated to approximately 50 ml. This solution is dropped with ice-cooling into the solution, prepared with triethylamine, of 4.2 gm of amoxycillin trihydrate in 60 ml of 80% aqueous tetrahydrofurane. Treatment is effected, as describedin Example 23, by shaking the desired penicillin acid from water at pH 2 with ethyl acetate.
Yield: 5.3 gm of sodium salt (84%).
Rf: 0.80.
IR spectrum: 1770, 1660, 1600, 1545 cm.sup.-1.
NMR Spectrum (DMSO+CD.sub.3 OD): signals at ppm: 1.55 (6H), 4.1 (1H), 5.5 (q,2H), 5.6 (1H), 6.9 (d,2H), 7.4 (d,2H), 7.7 (4H), 8.8 (1H).
The following penicillins are prepared analogous to Example 36 from amoxycillin and the reaction product of the corresponding pyrimidine with phosgene.
D-.alpha.-[3-(4-hydroxy-2-o-methylphenyl-5-pyrimidyl)-ureido]-p-hydroxybenz yl-penicillin sodium.
D-.alpha.-[3-(4-hydroxy-2-p-methoxycarbonylbenzyl-5-pyrimidyl)-ureido]-p-hy droxybenzyl-penicillin sodium.
D-.alpha.-[3-(2-p-dimethylaminocarbonyl-benzyl-4-hydroxy-5-pyrimidyl)-ureid o]-p-hydroxybenzyl-penicillin sodium.
D-.alpha.-[3-(4-hydroxy-2-m-methylbenzyl-5-pyrimidyl)-ureido]-p-hydroxybenz yl-penicillin sodium.
D-.alpha.-[3-(2-p-ethylbenzyl-4-hydroxy-5-pyrimidyl)-ureido]-p-hydroxybenzy l-penicillin sodium.
D-.alpha.-[3-(2-p-ethoxybenzyl-4-hydroxy-5-pyrimidyl)-ureido]-p-hydroxybenz yl-penicillin sodium.
EXAMPLE 37
D-.alpha.-[3-(4-hydroxy-2-p-methoxyphenyl-5-pyrimidyl)-ureido]-p-hydroxyben zyl-penicillin sodium
This penicillin is prepared analogous to Example 36, starting from 4.2 gm of amoxycillin trihydrate (0.01 mol) and the reaction product of 2.17 gm (0.01 mol) of 5-amino-4-hydroxy-2-p-methoxyphenyl-pyrimidine with 1.05 gm of phosgene.
Yield: 5.4 gm of sodium salt (77%).
Rf: 0.69.
IR spectrum: 1765, 1655, 1610, 1550, 1510 cm.sup.-1.
NMR spectrum (DMSO+CD.sub.3 OD): signals at ppm: 1.5 (6H), 3.85 (s,3H), 4.05 (1H), 5.4 (q,2H), 5.5 (1H), 6.8 (d,2H), 7.1 (d,2H), 7.3 (d,2H), 8.1 (d,2H), 8.5 (s,1H).
EXAMPLE 83
D-.alpha.-[3-(4-hydroxy-2-m-trifluoromethylphenyl-5-pyrimidyl)-ureido]-p-hy droxybenzyl-penicillin sodium
Analogous to Example 23, starting from 2.1 gm of amoxycillin trihydrate (0.005 mol) and 1.28 gm of 5-amino-4-hydroxy-2-m-trifluoromethylphenyl-pyrimidine (0.005 mol).
Yield: 2.45 gm of sodium salt (73%).
Rf: 0.78
IR spectrum: 1765, 1660, 1600, 1550 cm.sup.-1.
NMR spectrum (DMSO+CD.sub.3 OD): signals at ppm: 1.5 (6H), 4.0 (1H), 5.35 (q,2H), 5.5 (1H), 7.0 (dD,4H), 7.8 (m,2H), 8.4 (m,2H), 8.8 (1H).
EXAMPLE 39
D-.alpha.-[3-(4-hydroxy-2-m-methylphenyl-5-pyrimidyl)-ureido]-benzyl-penici llin sodium
Analogous to Example 23 from 4.0 gm of ampicillin trihydrate (0.01 mol) and 2.0 gm (0.01 mol) of 5-amino-4-hydroxy-2-m-methylphenyl-pyrimidine.
Yield: 4.14 gm (69%).
Rf: 0.78.
IR spectrum: 1770, 1650, 1600, 1550 cm.sup.-1.
NMR spectrum (DMSO+CD.sub.3 OD): signals at ppm: 1.55 (6H), 2.4 (3H), 4.0 (1H), 5.4 (q,2H), 5.5 (1H), 7.5 (m,7H), 8.0 (m,2H), 8.7 (1H).
EXAMPLE 40
D-.alpha.-[3-(4-hydroxy-2-p-methylbenzyl-5-pyrimidyl)-ureido]-benzyl-penici llin sodium.
Analogous to Example 23 from 1.6 gm of ampicillin trihydrate (0.004 mol) and 860 mg (0.04 mol) of 5-amino-4-hydroxy-2-p-methylbenzyl-pyrimidine.
Yield: 1.5 gm of sodium salt (64%).
Rf: 0.73.
IR spectrum: 1770, 1660, 1600, 1540 cm.sup.-1.
NMR spectrum (CD.sub.3 OD): signals at ppm: 1.55 (6H), 2.3 (3H), 3.9 (2H), 4.2 (1H), 5.5 (q,2H), 5.5 (1H), 7.5 (m,9H), 8.6 (1H).
EXAMPLE 41
D-.alpha.-[3-(4-hydroxy-2-o-methylbenzyl-5-pyrimidyl)-ureido]-benzyl-penici llin sodium
Analogous to Example 23 from 2.4 gm of ampicillin trihydrate (0.006 mol) and 1.28 gm (0.006 mol) of 5-amino-4-hydroxy-2-o-methylbenzyl-pyrimidine.
Yield: 2.0 gm of sodium salt (55%).
Rf: 0.66.
IR spectrum: 1775, 1660, 1605, 1545 cm.sup.-1.
NMR spectrum (DMSO+CD.sub.3 OD): signals at ppm: 1.5 (6H), 2.3 (3H), 4.9 (2H), 4.05 (1H), 5.4 (q,2H), 5.7 (1H), 7.4 (m,9H), 8.55 (1H).
EXAMPLE 42
D-.alpha.-[3-(4-hydroxy-2-p-methylmercaptobenzyl-5-pyrimidyl)-ureido]-p-hyd roxybenzyl-penicillin sodium
Analogous to Example 36, starting from 420 mg of amoxycillin trihydrate (0.001 mol) and the reaction product of 250 mg (0.001 mol) of 5-amino-4-hydroxy-2-p-methylmercaptobenzyl-pyrimidine with 105 mg of phosgene. Treatment is effectedanalogously to Example 23.
Yield: 320 mg of sodium salt (50%).
Rf: 0.84.
IR spectrum: 1765, 1665, 1610, 1545 cm.sup.-1.
NMR spectrum (DMSO+CD.sub.3 OD): signals at ppm: 1.55 (6H), 2.95 (3H), 4.0 (2H), 4.1 (1H), 5.40 (q,2H), 5.65 (1H), 7.1 (dd,4H), 7.5 (dd,4H), 8.6 (1H).
The following are synthesized analogously:
(a) D-.alpha.-[3-(4-hydroxy-2-p-methylsulphinylbenzyl-5-pyrimidyl)-ureido]-p-h ydroxybenzyl-penicillin sodium.
(b) D-.alpha.-[3-(4-hydroxy-2-p-methylsulphonylbenzyl-5-pyrimidyl)-ureido]-p-h ydroxybenzyl-penicillin sodium.
EXAMPLE 43
D-.alpha.-[3-(4-hydroxy-2-p-methoxybenzyl-5-pyrimidyl)-ureido]-p-hydroxyben zyl-penicillin sodium
Analogous to Example 23, starting from 16.8 gm of amoxycillin trihydrate (0.04 mol) and the reaction product of 9.08 gm (0.04 mol) of 5-amino-4-hydroxy-2-p-methylbenzyl-pyrimidine with 4.1 gm of phosgene and 5.4 ml of triethylamine.
Yield: 18.6 gm of sodium salt (72%).
Rf: 0.79.
IR spectrum: 1770, 1660, 1615, 1550 cm.sup.-1.
NMR spectrum (DMSO+CD.sub.3 OD): signals at ppm: 1.55 (6H), 3.75 (2H), 3.95 (1H), 5.35 (q,4H), 5.45 (1H), 7.0 (m,8H), 8.4 (1H).
The following are synthesized analogously:
(a) D-.alpha.-[3-(2-p-acetoxybenzyl-4-hydroxy-5-pyrimidyl)-ureido]-p-hydroxybe nzyl-penicillin sodium.
(b) D-.alpha.-[3-(2-p-acetylaminobenzyl-4-hydroxy-5-pyrimidyl)-ureido]-p-hydro xybenzyl-penicillin sodium.
(c) D-.alpha.-[3-(2-p-aminocarbonylbenzyl-4-hydroxy-5-pyrimidyl)-ureido]-p-hyd roxybenzyl-penicillin sodium.
(d) D-.alpha.-[3-(4-hydroxy-2-p-methylsulphonylaminobenzyl-5-pyrimidyl)-ureido ]-p-hydroxybenzyl-penicillin sodium.
(e) D-.alpha.-[3-(4-hydroxy-2-o-methoxybenzyl-5-pyrimidyl)-ureido]-p-hydroxybe nzyl-penicillin sodium
EXAMPLE 44
D-.alpha.-[3-(2-m,p-dimethoxybenzyl-4-hydroxy-5-pyrimidyl)-ureido]-benzyl-p enicillin sodium
This penicillin is synthesized analogous to Example 23, starting from 1.3 gm (0.005 mol) of 5-amino-4-hydroxy-2-m,p-dimethoxybenzyl-pyrimidine and 530 mg of phosgene as well as 2.0 gm of ampicillin trihydrate (0.005 mol). Treatment is effectedanalogous to Example 23.
Yield: 2.24 gm of sodium salt (68%).
Rf: 0.82.
NMR spectrum (DMSO+CD.sub.3 OD): signals at ppm: 1.5 (6H), 3.75 (6H), 3.8 (2H), 4.0 (1H), 5.45 (q,2H), 5.7 (1H), 7.0 (d,2H), 7.5 (m,5H), 8.6 (1H).
The following is synthesized analogously.
D-.alpha.-[3-(4-hydroxy-2-m,m,p-trimethoxybenzyl-5-pyrimidyl)ureido]-p-hydr oxybenzyl-penicillin sodium.
EXAMPLE 45
D-.alpha.-[3-(2-p-bromobenzyl-4-hydroxy-5-pyrimidyl)-ureido]-p-hydroxybenzy l-penicillin sodium
2.79 gm (0.01 mol) of 5-amino-2-p-bromobenzyl-4-hydroxy-pyrimidine are reacted in the conventional way with 1.05 gm of phosgene and 1.35 ml of triethylamine in 100 ml of absolute tetrahydrofurane. Triethylamine hydrochloride is filtered off andthe solution obtained is dropped with ice-cooling into 4.2 gm (0.01 mol) of amoxycillin trihydrate which has been dissolved with N/100 sodium hydroxide solution in 80 ml of 80% aqueous tetrahydrofurane with control of the pH value. Further reaction andtreatment are effected analogous to Example 23.
Yield: 4.05 gm of sodium salt (59%).
Rf: 0.81
IR spectrum: 1770, 1655, 1610, 1545 cm.sup.-1.
NMR spectrum (DMSO+CD.sub.3 OD): signals at ppm: 1.55 (6H), 3.9 (1H), 4.1 (2H), 5.45 (q,2H), 5.6 (1H), 6.8 (d,2H), 7.45 (m,6H), 6.8 (1H).
EXAMPLE 46
D-.alpha.-[3-(4-hydroxy-2-p-nitrobenzyl-5-pyrimidyl)-ureido]-p-hydroxybenzy l-penicillin sodium
500 mg of 5-amino-4-hydroxy-2-p-nitrobenzylpyrimidine (0.002 mol) are dissolved with heating in 50 ml of dry pyridine. This solution is dropped rapidly into a solution of 210 mg of phosgene in 50 ml of absolute tetrahydrofurane. The mixtureobtained is evaporated to dryness in vacuo. The remaining solid product is added with ice-cooling portionwise to 850 mg (0.002 mol) of amoxycillin trihydrate which has been dissolved with triethylamine in 40 ml of 80% tetrahydrofurane. In so doing, thepH value is kept at approximately 7.5.
The mixture is left to react for 1 hour with ice-cooling and for 2 hours at room temperature. The tetrahydrofurane is then removed in vacuo and the aqueous solution is shaken twice with a little ethyl acetate. The mixture is subsequently cooledwith ice and carefully acidified to pH 2 with 2 N hydrochloric acid. The precipitated product is filtered off and dried. The sodium salt is prepared in a conventional way. Yield: 650 mg of sodium salt (49%).
Rf: 0.87.
IR spectrum: 1770, 1655, 1605, 1545 cm.sup.-1.
NMR spectrum (DMSO+CD.sub.3 OD): signals at ppm: 1.5 (6H), 3.95 (1H), 4.2 (2H), 5.5 (q,2H), 5.75 (1H), 7.1 (dd,4H), 8.0 (m,4H), 8.8 (1H).
The following is synthesized analogously:
D-.alpha.-[3-(2-p-cyanobenzyl-4-hydroxy-5-pyrimidyl)-ureido]-p-hydroxybenzy l-penicillin sodium.
EXAMPLE 47
D-.alpha.-[3-(2-p-dimethylaminophenyl-4-hydroxy-5-pyrimidyl)-ureido]-p-hydr oxybenzyl-penicillin sodium
Analogous to Example 23, starting from 5.0 gm of amoxycillin trihydrate (0.012 mol) and 2.9 gm (0.012 mol) of 5-amino-2-p-dimethylaminophenyl-4-hydroxypyrimidine. Treatment analogous to Example 23.
Yield: 3.0 gm of sodium salt (39%).
Rf: 0.82.
IR spectrum: 1775, 1660, 1615, 1570 cm.sup.-1.
NMR spectrum (DMSO+CD.sub.3 OD): signals at ppm: 1.6 (6H), 3.05 (6H), 4.05 (1H), 5.45 (q,2H), 5.5 (1H), 6.9 (4H), 7.45 (2H), 8.1 (2H), 8.7 (1H).
The following are synthesized analogously:
(a) D-.alpha.-[3-(2-p-dimethylaminobenzyl-4-hydroxy-5-pyrimidyl)-ureido]-p-hyd roxybenzyl-penicillin sodium,
(b) D-.alpha.-[3-(4-hydroxy-2-p-methylaminophenyl-5-pyrimidyl)-ureido]-benzyl- penicillin sodium.
(c) D-.alpha.-[3-(2-p-hydroxyphenyl-4-hydroxy-5 -pyrimidyl)-ureido]-p-hydroxybenzyl-penicillin sodium.
EXAMPLE 48
D-.alpha.-[3-(2-p-acetylbenzyl-4-hydroxy-5-pyrimidyl)-ureido]-p-hydroxybenz yl-penicillin sodium
Analogous to Example 23 starting from 1.21 gm (0.005 mol) of 5-amino-2-p-acetylbenzyl-4-hydroxypyrimidine and 2.1 gm of amoxycillin trihydrate (0.005 mol).
Yield: 2.45 mg of sodium salt (75%).
Rf: 0.79.
IR spectrum: 1770, 1665, 1610, 1550 cm.sup.-1.
NMR spectrum (DMSO+CD.sub.3 OD): signals at ppm: 1.55 (6H), 2.6 (3H), 4.0 (2H), 4.05 (1H), 5.5 (q,4H), 5.55 (1H), 6.85 (d,2H), 7.4 (d,2H), 7.6 (d,2H), 8.05 (d,2H), 8.65 (1H).
EXAMPLE 49
D-.alpha.-[3-(2-p-fluorobenzyl-4-hydroxy-5-pyrimidyl)-ureido]-benzyl-penici llin sodium
1.98 gm of D-.alpha.-[3-(2-p-fluorobenzyl-4-hydroxy-5-pyrimidyl)-ureido]-phenylglycin e (0.005 mol) are dissolved with 500 mg (0.005 mol) of N-methylmorpholine in 40 ml of absolute tetrahydrofuran. The mixture is cooled to -15.degree. C. and asolution of 550 mg (0.0055 mol) of ethyl chloroformate in 5 ml of absolute tetrahydrofurane is added thereto. The clear solution is stirred for 30 minutes at -10.degree. C. A solution os 1.58 gm of 6-aminopenicillin acid-triethyl ammonium salt (0.005mol) in 20 ml of methylene chloride is then added thereto in such a way that the temperature does not exceed -10.degree. C. The mixture is allowed to react for 1 hour at -5.degree. C., for 1 hour at 5.degree. C. and for 1 hour at room temperature. Itis subsequently evaporated to dryness in vacuo, 50 ml of water are added thereto and the pH value is brought to 7.0. The aqueous phase is shaken out twice with ethyl acetate, the mixture is then covered with a layer of 200 ml of ethyl acetate and dilutehydrochloric acid is added thereto with cooling and stirring until the pH value has reached 2.0 The ethyl acetate phase is removed, the aqueous phase is shaken once again with 50 ml of ethyl acetate and the two ethyl acetate phases are united, dried oversodium sulphate and evaporated to dryness. The free acid is then converted into the sodium salt in methanol/ether with sodium hexanoate.
Yield: 1.57 gm of sodium salt (51%).
Rf: 0.67.
IR spectrum: 1770, 1660, 1610, 1550 cm.sup.-1.
NMR spectrum (DMSO+CD.sub.3 OD): signals at ppm: 1.5 (6H), 3.9 (2H), 4.1 (1H), 5.45 (q,2H), 5.7 (1H), 7.5 (m,9H), 8.6 (1H).
EXAMPLE 50
D-.alpha.-[3-(2-benzyl-4-hydroxy-5-pyrimidyl)-ureido]-benzylpenicillin sodium
Analogous to Example 49, starting from 3.15 gm of 6-aminopenicillanic acid-triethylammonium salt (0.01 mol) and 3.78 gm (0.01 mol) of D-.alpha.-[3-(2-benzyl-4-hydroxy-5-pyrimidyl)-ureido]-phenylglycine.
Yield: 3.55 gm of sodium salt (60%).
Rf: 0.71.
IR spectrum: 1775, 1665, 1620, 1550 cm.sup.31 1.
NMR spectrum (DMSO+CD.sub.3 OD): signals at ppm: 1.5 (6H), 4.0 (1H), 4.1 (2H), 5.40 (q,2H),5.5 (1H), 7.5 (m,10H), 8.5 (1H).
EXAMPLE 51
D-.alpha.-[3-(2-benzyl-4-hydroxy-5-pyrimidyl)-ureido]-p-hydroxybenzyl-penic illin sodium
Analogous to Example 49, starting from 950 mg of 6-aminopenicillanic acid-triethylammonium salt (0.003 mol) and 1.15 gm (0.003 mol) of D-.alpha.-[3-(2-benzyl-4-hydroxy-5-pyrimidyl)-ureido]-p-hydroxyphenylglyci ne.
Yield: 980 mg of sodium salt (55%).
Rf: 0.68.
IR spectrum: 1770, 1660, 1610, 1545 cm.sup.-1.
NMR spectrum (DMSO+CD.sub.3 OD): signals at ppm: 1.55 (6H), 4.05 (1H), 4.15 (2H), 5.45 (q,2H), 5.60 (1H), 6.9 (d,2H), 7.5 (m,7H), 8.55 (1H).
EXAMPLE 52
D-.alpha.-[3-(2-p-chlorophenyl-4-hydroxy-5-pyrimidyl)-ureido]-p-hydroxybenz yl-penicillin sodium
Analogous to Example 49 from 1.67 gm of 6-aminopenicillanic acid-triethylammonium salt (0.005 mol) and 2.05 gm of D-.alpha.-[3-(2-p-chlorophenyl-4-hydroxy-5-pyrimidyl)ureido]-p-hydroxyphen yl glycine (0.005 mol).
Yield: 1.94 gm of sodium salt (61%).
Rf. 0.78.
IR spectrum: 1770, 1655, 1610, 1550 cm.sup.-1.
NMR spectrum (DMSO+CD.sub.3 OD): signals at ppm: 1.55 (6H), 4.0 (1H), 5.45 (q,2H), 5.55 (1H), 6.8 (d,2H), 7.35 (d,2H), 7.6 (d,2H), 8.2 (d,2H), 8.8 (1H).
EXAMPLE 53
D-.alpha.-[3-(2-m-chlorobenzyl-4-hydroxy-5-pyrimidyl)-ureido]-benzyl-penici llin sodium
A suspension of 2.16 gm (0.01 mol) of 6-aminopenicillanic acid and 3 ml of N,O-bis-(trimethylsilyl)acetamide in dry dimethyl formamide (30 ml) is stirred for 2 hours at room temperature. This solution is dropped at -10.degree. C. into asolution prepared at -15.degree. C. of 4.25 gm (0.01 mol) of D-.alpha.-[3-(2-m-chlorobenzyl-4-hydroxy-5-pyrimidyl)-ureido]-phenylglycin e, 1.0 gm of N-methylmorpholine and 1.0 gm of ethyl chloroformate in absolute tetrahydrofurane. The mixture isstirred for 1 hour at 0.degree. C. and for 1 hour at room temperature, tetrahydrofurane and a part of the dimethyl formamide are removed in vacuo and the product is then mixed with 250 ml of ice water. The aqueous solution is adjusted to pH 7.0 andextraced twice with ethyl acetate. It is then cooled, covered with a layer of 200 ml of ethyl acetate and adjusted to pH 2 with dilute hydrochloric acid. The aqueous phase is extracted once again with ethyl acetate, the ethyl acetate phases are unitedand dried and the solvent is removed in vacuo. The sodium salt is prepared in a conventional way from the penicillin acid.
Yield: 2.92 gm of sodium salt (46%).
Rf: 0.76%.
IR spectrum: 1770, 1665, 1610, 1545 cm.sup.-1.
NMR spectrum (DMSO+CD.sub.3 OD): signals at ppm: 1.55 (6H), 3.8 (2H), 4.0 (1H), 5.40 (q,2H), 5.6 (1H), 7.4 (m,9H), 8.5 (1H).
The following is synthesized analogously:
D-.alpha.-[3-(4-hydroxy-2-phenyl-5-pyrimidyl)-ureido]-p-hydroxybenzyl-penic illin sodium.
EXAMPLE 54
D-.alpha.-[3-(2-o-chlorobenzyl-4-hydroxy-5-pyrimidyl)-ureido]-p-hydroxybenz yl-penicillin sodium
Analogous to Example 53, starting from 1.13 gm (0.005 mol) of 6-amino-penicillanic acid and 2.2 gm (0.005 mol) of D-.alpha.-[3-(2-o-chlorobenzyl-4-hydroxy-5-pyrimidyl)-ureido]-p-hydroxyphe nylglycin. Treatment analogous to Example 53.
Yield: 2.27 gm of sodium salt (70%).
Rf: 0.80.
IR spectrum: 1770, 1655, 1610, 1540 cm.sup.-1.
NMR spectrum (DMSO+CD.sub.3 OD): signals at ppm: 1.55 (6H), 4.05 (1H), 4.1 (2H), 5.4 (q,2H), 5.45 (1H), 6.8 (d,2H), 7.4 (M,6H), 8.55 (1H).
EXAMPLE 55
D-.alpha.-[3(4-hydroxy-2-{1'-phenylethyl.gamma.-5-pyrimidyl)-ureido]-p-hydr oxybenzyl-penicillin sodium.
This penicillin is prepared analogously to Example 11, starting from 4.2 gm of amoxycillin trihydrate as well as the reac | | | |
