US2610185A - Oroshnik - Google Patents
Oroshnik Download PDFInfo
- Publication number
- US2610185A US2610185A US2610185DA US2610185A US 2610185 A US2610185 A US 2610185A US 2610185D A US2610185D A US 2610185DA US 2610185 A US2610185 A US 2610185A
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- Prior art keywords
- contractions
- bath
- compound
- amino
- increase
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- 150000001875 compounds Chemical class 0.000 claims description 28
- 150000003839 salts Chemical class 0.000 description 22
- 239000011780 sodium chloride Substances 0.000 description 22
- 210000001519 tissues Anatomy 0.000 description 20
- XQCZBXHVTFVIFE-UHFFFAOYSA-N Isocytosine Chemical compound NC1=NC=CC(O)=N1 XQCZBXHVTFVIFE-UHFFFAOYSA-N 0.000 description 12
- 210000004291 Uterus Anatomy 0.000 description 10
- 230000003387 muscular Effects 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 150000003840 hydrochlorides Chemical class 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- XEHUWMGUPPPJFE-UHFFFAOYSA-N 1-(dipropylamino)propan-1-ol Chemical compound CCCN(CCC)C(O)CC XEHUWMGUPPPJFE-UHFFFAOYSA-N 0.000 description 4
- AMFQYEHVISAILF-UHFFFAOYSA-N 3-pyrimidin-2-yloxypropan-1-amine Chemical class NCCCOC1=NC=CC=N1 AMFQYEHVISAILF-UHFFFAOYSA-N 0.000 description 4
- DBGFGNCFYUNXLD-UHFFFAOYSA-N 4-chloropyrimidin-2-amine Chemical compound NC1=NC=CC(Cl)=N1 DBGFGNCFYUNXLD-UHFFFAOYSA-N 0.000 description 4
- -1 aliphatic organic acids Chemical class 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- 150000007522 mineralic acids Chemical class 0.000 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 159000000000 sodium salts Chemical class 0.000 description 4
- 239000008096 xylene Substances 0.000 description 4
- IPXQGBTVHWZGQC-UHFFFAOYSA-N 2-ethoxy-4-methylpyrimidine Chemical compound CCOC1=NC=CC(C)=N1 IPXQGBTVHWZGQC-UHFFFAOYSA-N 0.000 description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N 289-95-2 Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 2
- FKLJPTJMIBLJAV-UHFFFAOYSA-N 5-(7-(4-(4,5-DIHYDRO-2-OXAZOLYL)PHENOXY)HEPTYL)-3-METHYL ISOXAZOLE Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 2
- 206010022000 Influenza Diseases 0.000 description 2
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 description 2
- 210000003205 Muscles Anatomy 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 229940035295 Ting Drugs 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000004429 atoms Chemical group 0.000 description 2
- 125000004432 carbon atoms Chemical group C* 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000003184 effect on constriction Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical compound OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 238000007654 immersion Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-L maleate(2-) Chemical compound [O-]C(=O)\C=C/C([O-])=O VZCYOOQTPOCHFL-UPHRSURJSA-L 0.000 description 2
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 2
- 229910052753 mercury Inorganic materials 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 235000015097 nutrients Nutrition 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N o-xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 150000002894 organic compounds Chemical class 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 239000001184 potassium carbonate Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 229940086735 succinate Drugs 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 2
- 229940095064 tartrate Drugs 0.000 description 2
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
Definitions
- This; invention relates: to certain therapew' tically' effective organiccompounds which are derivatives of" isocytosine; 2ie-axnino t li'ydroiky-- pyrimidine;- and: to their use as therapeutic agents: having the: ability 1 to '5 stimulate contractions of the uterus: Morespecifically this invention' relates: to; z'eamino adialkylaminopror 2 bino rat-r uterine tissue: suspended: therein; "A continuous kymographicw record” was: madeof contractions of'the-uterine strip-before-andfafter poxypyrimidinesfin which: each alkyl group 'hasat leastt-hreafl and notrmoreth'an five,acarbon atoms; The said isocytosine derivitivesehaving thezabih ity to stimulate contractionsnctkthe uterus may be represented w by the following; tormula:
- the new and novel derivatives of isocytosine to which the present invention is directed have considerable value which renders their use as pharmaceutical products highly advantageous either alone or with known pharmacological products.
- the ability of these novel substances to stimulate contractions of the uterus has been shown by a number of experiments in which a salt of isocytosine derivative was added to a bath of nutrient solution having a strip of a1- additiomto the bath of Pa salt of Fanuisoeytosine derivatives Additional?
- Figures 1-6 are kymographic records of contractions; of the strip of uterine tissue before and after addition to the bath. of the compounds to be tested. Normal contractions are recorded in the figures up to the point designated a and at thisi time a portion of the compound to be tested was added to the bath.
- the portion of the figures between letters a and b represents a record ofcontractions after addition to the bath of the compound being tested.
- the letter b in the-figures designates the time at which the bath containing the compound be- I, II, and III, respectively, as the hydrochloride.”
- FIG. 1 shows the addition to the bath of 5
- milligrams of compound II in the form of its hydrochloride salt produced an increase in frequency of contractions, a very marked increase in tonus and some increase in amplitude of con tractions of the uterine muscular tissue.
- Figure 3 shows the addition to the bath of 5 milligrams of compound III-in the form of its hydrochloride salt produced a very marked increase in amplitude of contractions, a substantial increase in frequency of contractions, and a marked'increase in tonus of the uterine muscular tissue.
- Tonus is a natural property of muscle and is a measure of degree'of contraction independent of external influences. The degree of contraction produced by a stimulant depends upon the level of tonus, and, therefore, some investigators have defined "tonus as theresistance offered -to extension.
- Amplitude may .be defined as the height of a contraction wave measured from the base level to the peak of the wave; base level being the average lower level of-the contractions.
- Frequency is thenumber of contraction'waves gin a-um'ttime period.
- a Y Derivatives. of isocytosine such as 2- amino-4- -dialkylaminopropoxypyrimidine maybe prepared by reacting 2-amino-4-chloropyrimidine with the 4 sodium salt of a dialkylaminopropanol. The following is an example of the preparation of 2- amino-i-di-n-propylaminopropoxypyrimidine, in which the parts are given by weight.
- R and R each representan alkyl group having at least three but not more thanfive carbon atoms.
- R are each a normal propyl radical.
- R and R. are each a normal butyl radical.
Description
Sept. 9, 1952 w, QRQSHNIK 2,610,185
Z-AMINO-4-DIALKYLAMINOPROPOXYPYRIMIDiNES Filed NOV. 7, 1950 I 2 SHEETS SHEET l v [Ni/ENTOR c i new 4 ATTOR EY S p 9, 1952 V w. OROSHNIK 2,610,135
2-AMINO4-DIALKYLAMINOPROPOXYPYRIMIDINES Filed Nov. 7, 1950 2 SHEETS-SHEET 2 a b ATTORNE V Patented Sept. 9, 1952 -smmowmstxrmnmomoroxra Pmmflmmus" William,:(lroshnih-Bl i fl N: J'-, ammon a: Qrtho, Ilxannaccutical;,Ccrporation;,.aacornorarionctblewlevscy ApplieationNoveinber 7, 1950,, Serial ism-194,500
This; invention: relates: to certain therapew' tically' effective organiccompounds which are derivatives of" isocytosine; 2ie-axnino t li'ydroiky-- pyrimidine;- and: to their use as therapeutic agents: having the: ability 1 to '5 stimulate contractions of the uterus: Morespecifically this invention' relates: to; z'eamino adialkylaminopror 2 bino rat-r uterine tissue: suspended: therein; "A continuous kymographicw record" was: madeof contractions of'the-uterine strip-before-andfafter poxypyrimidinesfin which: each alkyl group 'hasat leastt-hreafl and notrmoreth'an five,acarbon atoms; The said isocytosine derivitivesehaving thezabih ity to stimulate contractionsnctkthe uterus may be represented w by the following; tormula:
rivatiyes with organic or inorganic acids andsince the said derivatives are basic in character, theymay be readily converted into salts having substantially more solubility in water than the free bases. Salts such as the succinate, maleate, tartrate, lactate, fumarate and the like are preferred, but salts of simple low-molecular weight aliphatic organic acids as well as salts of the free bases with inorganic acids, may be readily prepared from the free bases and are highly effective therapeutically.
The new and novel derivatives of isocytosine to which the present invention is directed have considerable value which renders their use as pharmaceutical products highly advantageous either alone or with known pharmacological products. The ability of these novel substances to stimulate contractions of the uterus has been shown by a number of experiments in which a salt of isocytosine derivative was added to a bath of nutrient solution having a strip of a1- additiomto the bath of Pa salt of Fanuisoeytosine derivatives Additional? derivatives, of iSQOYbOssine-whichare-homologues of62 aminoi diallc'yls aminopropoxypyrimidines specifically mentioned before as havingtherapeutic value were P also testedgrinthe same wayitodetermine their effect on'contracti'onsof'theuterus; Water-soluble hydrochloridc saltsor the sesquisuccinate saltsi-:of the: followingojcompounds were n'tested i for their pharmacological" property or: stiniula'ting i contractionsnotithe uterusi eqmpoundgla zf; amino...+ 34 --di1 11- prowl: aminonropoxynyrimidme CompoundJIs-Z: amine-Andi. n=- amylaminopropoxypyrimidine V mp III.='-2... amino ,1 4- di..- .nbutylr aminopropoxypyrimidine qompoundlv z, amino 3. dimethylaminoethoxynyrimidine I (lomnound vwz amina 4 1. diethylaminoe ethoxynrr midine y a a Comppund,;VI-- 2. amino x. 4 diethylaminoe ethoxy 6 methylpyrimidine l The following procedure was employed in testingthe. eifect- 'of compounds-Pin on a rat uterus: A- female albino rat-weighing-from 150--30tl"mi1ligrams was=killed byablow-on-the head and the uterus=was-removedz A- strip of the-auterine tissue was suspended in a ccibathofana'erated Ringer-Locke solution-51' Gne end ofthemterine strip was-maintained in; astationary}- position amt-the otherend was: attached-tea levenwhich made contact with akymograph and continuously recorded contractions. After a short period of immersion in the bath, the strip of uterine tissue was contracting {rhythmically and normally, and at this point an aqueous solution of a salt of an isocytosine derivative to be tested for its effect on contractions of uterine tissue was added to the bath. Figures 1-6 are kymographic records of contractions; of the strip of uterine tissue before and after addition to the bath. of the compounds to be tested. Normal contractions are recorded in the figures up to the point designated a and at thisi time a portion of the compound to be tested was added to the bath. The portion of the figures between letters a and b represents a record ofcontractions after addition to the bath of the compound being tested. The letter b in the-figures designates the time at which the bath containing the compound be- I, II, and III, respectively, as the hydrochloride."
salts thereof. Figure 1 shows the addition to the bath of 5 milligrams of compound I in the form. v of its hydrochloride salt produced a marked increase in amplitude of contractions, some increase in tonus, and a small increase in frequency of contractions of the uterine muscular tissue.
Figure 2 shows the addition to the bath of 5;
milligrams of compound II in the form of its hydrochloride salt produced an increase in frequency of contractions, a very marked increase in tonus and some increase in amplitude of con tractions of the uterine muscular tissue. Figure 3 shows the addition to the bath of 5 milligrams of compound III-in the form of its hydrochloride salt produced a very marked increase in amplitude of contractions, a substantial increase in frequency of contractions, and a marked'increase in tonus of the uterine muscular tissue.
Figures 4, 5, and 6 show only slight efiects on the uterine muscular tissue result from the addition of sesquisucci-nate salts "of compounds IV, V, andVI to the bath; Figure 4 shows the addition of 10 milligrams of the sesquisuccinate salt of compound IV produced a slight decrease in amplitude of contractions and Figures 5 and 6 show the addition to the bath of 10 milligrams of the sesquisuccinate salts of compounds V and respectively, produced a slight increase in amplitudeof contractions and a slight increase in terms of the uterine muscular tissue.
Tonus is a natural property of muscle and is a measure of degree'of contraction independent of external influences. The degree of contraction produced by a stimulant depends upon the level of tonus, and, therefore, some investigators have defined "tonus as theresistance offered -to extension.
Amplitude may .be defined as the height of a contraction wave measured from the base level to the peak of the wave; base level being the average lower level of-the contractions.
Frequency is thenumber of contraction'waves gin a-um'ttime period. a Y Derivatives. of isocytosine such as 2- amino-4- -dialkylaminopropoxypyrimidine maybe prepared by reacting 2-amino-4-chloropyrimidine with the 4 sodium salt of a dialkylaminopropanol. The following is an example of the preparation of 2- amino-i-di-n-propylaminopropoxypyrimidine, in which the parts are given by weight. Twentyfive parts of sodium metal were slowly added to 175 parts of di-n-propylaminopropanol, dissolved in 500.parts of-xylene.' Five hundred parts of benzene were then added to the resulting sodium salt of di-n-propylaminopropanol. One hundred twenty-nine parts of 2-amino-4-chloropyrimidine wereadded to the above solution and duringthe addition the solution was cooled sufiiciently to maintain the temperature at C. After the additionwas complete, the reaction mixture wasQre'flu'xed for one hour and cooled and then "pa'rts' of water containing 10 parts ,of dissolved sodium hydroxide were added with stirring. At this point two layers were formed; the organic layer was decanted, dried over anhydrous potassium carbonate, and the solvents, benzene and xylene. were removed by distillation.- The residuein the distillation flask was distilled at a temperature of 125 C. and a pressure of 0.002 mm. of mercury. One hundred seventy-four parts of '2-amino-4-di-n-propylaminopropoxypyrimidine were obtained. The free pyrimidine base was only slightly soluble in water but reacted readily with hydrochloric acid in equimolar amounts to' produce a water-soluble hydrochloridesalt.
What is-claimed is:
1. A compound having the structural formula in which R and R each representan alkyl group having at least three but not more thanfive carbon atoms. 2., A compound according to claim 1 in which and R are each a normal propyl radical. 3. A compound accordingto claim 1 in which R and R. are each a normal butyl radical.
4. A compound according to claim 1 in which R and R are each a normal amyl radical.
, WILLIAM O'ROSHNIK.
REFERENCES CITED The following references are of record in the file of this patent:'
"Sutherland et 2.1.: J. Org. chem-"14, 235-238 (1949).
Claims (1)
1. A COMPOUND HAVING THE STRUCTURAL FORMULA
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US2610185A true US2610185A (en) | 1952-09-09 |
Family
ID=3439233
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US2610185D Expired - Lifetime US2610185A (en) | Oroshnik |
Country Status (1)
| Country | Link |
|---|---|
| US (1) | US2610185A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3980781A (en) * | 1966-03-31 | 1976-09-14 | Imperial Chemical Industries Limited | Fungicidal composition and method containing 2-amino-pyrimidines |
| US4000138A (en) * | 1966-03-31 | 1976-12-28 | Imperial Chemical Industries Limited | Organic compounds and compositions containing them |
-
0
- US US2610185D patent/US2610185A/en not_active Expired - Lifetime
Non-Patent Citations (1)
| Title |
|---|
| None * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3980781A (en) * | 1966-03-31 | 1976-09-14 | Imperial Chemical Industries Limited | Fungicidal composition and method containing 2-amino-pyrimidines |
| US4000138A (en) * | 1966-03-31 | 1976-12-28 | Imperial Chemical Industries Limited | Organic compounds and compositions containing them |
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