US2610186A - Oroshnik - Google Patents
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- US2610186A US2610186A US2610186DA US2610186A US 2610186 A US2610186 A US 2610186A US 2610186D A US2610186D A US 2610186DA US 2610186 A US2610186 A US 2610186A
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- contractions
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- isocytosine
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- 150000001875 compounds Chemical class 0.000 claims description 56
- 210000001519 tissues Anatomy 0.000 description 34
- XQCZBXHVTFVIFE-UHFFFAOYSA-N Isocytosine Chemical class NC1=NC=CC(O)=N1 XQCZBXHVTFVIFE-UHFFFAOYSA-N 0.000 description 30
- 238000007792 addition Methods 0.000 description 30
- 150000003890 succinate salts Chemical class 0.000 description 26
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
- -1 aliphatic radical Chemical class 0.000 description 22
- 150000003839 salts Chemical class 0.000 description 22
- 239000011780 sodium chloride Substances 0.000 description 22
- 239000002585 base Substances 0.000 description 20
- 210000004291 Uterus Anatomy 0.000 description 18
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 16
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 16
- 239000000243 solution Substances 0.000 description 14
- KTOQRRDVVIDEAA-UHFFFAOYSA-N 2-methylpropane Chemical group [CH2]C(C)C KTOQRRDVVIDEAA-UHFFFAOYSA-N 0.000 description 10
- CZPWVGJYEJSRLH-UHFFFAOYSA-N 289-95-2 Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 10
- 229910052739 hydrogen Inorganic materials 0.000 description 10
- 239000001257 hydrogen Substances 0.000 description 10
- WAMMUIYMAYYOAR-UHFFFAOYSA-N 1-[bis(2-methylpropyl)amino]ethanol Chemical compound CC(C)CN(C(C)O)CC(C)C WAMMUIYMAYYOAR-UHFFFAOYSA-N 0.000 description 8
- 238000004821 distillation Methods 0.000 description 8
- 150000003840 hydrochlorides Chemical class 0.000 description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 8
- CTQNGGLPUBDAKN-UHFFFAOYSA-N o-xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 239000001384 succinic acid Substances 0.000 description 8
- 239000008096 xylene Substances 0.000 description 8
- 241000700159 Rattus Species 0.000 description 6
- 125000004432 carbon atoms Chemical group C* 0.000 description 6
- 230000003184 effect on constriction Effects 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 159000000000 sodium salts Chemical class 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- NPTGVVKPLWFPPX-UHFFFAOYSA-N 2-amino-4-chloro-6-methylpyrimidine Chemical compound CC1=CC(Cl)=NC(N)=N1 NPTGVVKPLWFPPX-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
- WCYWZMWISLQXQU-UHFFFAOYSA-N Methyl radical Chemical compound [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 4
- 229910052753 mercury Inorganic materials 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 150000007522 mineralic acids Chemical class 0.000 description 4
- 230000003387 muscular Effects 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
- 239000001184 potassium carbonate Substances 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- LNJMHEJAYSYZKK-UHFFFAOYSA-N 2-methylpyrimidine Chemical class CC1=NC=CC=N1 LNJMHEJAYSYZKK-UHFFFAOYSA-N 0.000 description 2
- PCQHIQNBBCVCED-UHFFFAOYSA-N 4-[2-[bis(2-methylpropyl)amino]ethoxy]pyrimidin-2-amine Chemical compound CC(C)CN(CC(C)C)CCOC1=CC=NC(N)=N1 PCQHIQNBBCVCED-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
- WGVOINHKMPWYQZ-UHFFFAOYSA-N C(C(C)C)N(CC(C)C)CCOC1=NC(=CC=N1)C Chemical compound C(C(C)C)N(CC(C)C)CCOC1=NC(=CC=N1)C WGVOINHKMPWYQZ-UHFFFAOYSA-N 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
- 125000000217 alkyl group Chemical group 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000002844 continuous Effects 0.000 description 2
- 230000000881 depressing Effects 0.000 description 2
- 230000003467 diminishing Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical compound OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxyl anion Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 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
- VZCYOOQTPOCHFL-UPHRSURJSA-L maleate(2-) Chemical compound [O-]C(=O)\C=C/C([O-])=O VZCYOOQTPOCHFL-UPHRSURJSA-L 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 235000015097 nutrients Nutrition 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
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 150000003230 pyrimidines Chemical class 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 239000007787 solid 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
- 230000001225 therapeutic Effects 0.000 description 2
- 238000005303 weighing Methods 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
Definitions
- This invention relates to certain therapeutically eiiective organic compounds which are derivatives of isocytosine, 2-amino-4-hydroxypyrimidine and to their use as therapeutic agents having the ability to depress contractions of the uterus. More specifically this invention relate to Z-amino- 4 dialkylaminoethoxypyrimidines and 2 amino 4 dialkylaminoethoxy 6 methylpyrimidines in which each alkyl group is an isobutyl radical or an aliphatic radical having more than four and less than nine carbon atoms.
- the said isocytosine derivatives having the ability to depress contractions of the uterus may be represented by the following graphic formula:
- R and R" are each an isobutyl radical or an aliphatic radical having more than four and less than nine carbon atoms, and in which R" is hydrogen or methyl.
- the derivatives of isocytosine which embody this invention may be used as such to depress contractions of the uterus. They may also be used as in the form of salts of the isocytosine derivatives with organic or inorganic acids and since the said derivatives are basic in character, they may be readily converted into salts having substantially more solubility in water than the free bases. Salts such as the succinate, maleate,
- 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 depress contractions of the uterus has been 6 Claims. (01. see-256A) shown by a number of experiments in which a salt of the isocytosine derivative was added to a bath of nutrient solution having a strip of albino rat uterine tissue suspended therein. A continu ous kymographic record was made of contractions of the uterine strip before and after addi tion to the bath of a salt of an isocytosine derivative.
- isocytosine which are homologues of the class of isocytosine derivatives specifically mentioned before as having therapeutic value were also tested in the same way to determine their effect on contractions oi the uterus.
- The'succinate salts or the hydrochloride salts of the following compounds were tested for their pharmacologicalproperty of depressing contractionsof the uterus:
- Figures 1-9 are kymographic records of contractions of the strip of uterine tissue before and after addition to the bath of the comtaining no isocytosine derivative. That portion 4 of Figures 1-9 after the letter I) represents contractions as they return t normal and after the uterine strip is no longer in contact with a-compound being tested for its effect on contractions of uterine tissue.
- Figure 1 shows the addition of milligrams of the succinate salt of compound I to the bath produced an almost immediate effect on the contractions of th uterine tissue which amounted to a substantially complete cessation of contractions.
- Figure 2 shows the addition of 5 milligrams of the succinate salt of compound II caused a rapid diminishing of the contractions of the strip of uterine tissue followed by an almost complete cessation of contractions and an appreciable lowering of the tonus of the issue.
- Compound II formed a succinate salt in which four molecules of this compound were combined with five molecules of succinic acid.
- Figure 3 shows that the addition to the bath of 5 milligrams of compound III in the form of its hydrochloride salt produced a gradual decreas in-amplitude of contractions of the uterine strip followed by a short period when the uterine tissue was not contracting.
- Figure 4 shows the addition to the bath of 5 milligrams of compound IV in the form of its hydrochloride salt produced a marked decrease in amplitude of contractions of the uterine tissue and a slight decreasein tonus, as well as a slight decrease in frequency. of contractions.
- Figure 5 shows the addition of 5 milligrams of the succinate salt of compound V produced an immediate cessation of contractions of the strip of uterine tissue and a slight lowering of tonus of the tissue.
- Figure 6 shows the addition of 5 milligrams of the succinate salt of compound VI produced a very rapid decline in amplitude of contractions and a substantiallowering of tonus of the strip of uterine tissue. Frequency of contractions of the tissue was increased.
- Compound VI formed a succinate salt in which four molecules of this compound were combined with five molecules of succinic acid.
- Figures '7, 8, and 9 show only slight effects on the uterine tissue result from the addition to the bath of the sesquisuccinate salts of compounds VII, VIII, and IX.
- Figure 7 shows the addition of milligrams of the sesquisuccinate salt of compound VII pro prised a slight decrease of amplitude of contractions
- Figures 8 and 9 show the addition of 10 milligrams of the sesquisuccinate salts of compounds VIII and IX, respectively, to the bath produced a slight increase in amplitude of contractions and a slight increase in tonus of the uterine muscular tissue; however, compounds VII, and VIII and IX had .no appreciable. elfect on the frequency of contractions 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 4 have defined tonus as the resistance 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 the number of contraction waves in a unit time period.
- Derivatives of isocytosine such as 2-amino-4- dialkylaminoethoxypyrimidine and 2-amino-4- dialkylaminoethoxy-S-methylpyrimidine may be prepared by reacting 2-amino-4-chloropyrimidin or 2-amino-4-chloro-6-methylpyrimidine,
- a water-soluble succinate salt of the compound prepared above was made by dissolving 3.1 grams of free base and 1.4 grams of succinic acid in 12 cc. of boiling acetone. Upon cooling the acetone solution, a succinate salt of the pyrimidine base precipitated and was recrystallized from 10 cc. of hot acetone. 3.4 grams of the succinate salt of the pyrimidine base having a melting point of 98-99 C. were obtained and this crystalline salt had the following formula: V
- reaction mixture was refluxed for one hour and cooled and then 100 parts of water containing 10 parts of dissolvedsodium hydroxide were added with stirring to the cooled reaction mixture. After stirring had been stopped, two layers were formed and the organic layer was decanted, dried over anhydrous potassium carbonate and the solvents, benzene and xylene, were removed by distillation. The residue in the distillation flask was distilled at a temperature of 100-110 C. and a pressure of 0.001 mm. of mercury. 160 parts of Z-amino 4 diisobutylaminoethoxy 6 methylpyrimidine were obtained.
- a water-soluble succinate salt of the pyrimidine base was made by dissolving 4.1 grams of the pyrimidine base and 1.7 grams of succinic acid in 10 cc. of boiling acetone. Upon cooling the acetone solution, a white solid precipitated and it was removed and recrystallized from hot acetone. 3.5 grams of the recrystallized material were obtained and had a melting point of 99-100 C.
- the crystalline succinate salt of the pyrimidine base had the following formula:
- R. and R each is selected from the group 6 of alkyl radicals consisting of an isobutyl radical and alkyl radical having at least five and less than nine carbon atoms, and in which R" is selected from the group of radicals consisting of hydrogen and methyl.
- R and R are each an isobutyl radical and R is hydrogen.
- R and R are each a normal amyl radical and R" is hydrogen.
- R. and R are each an isoamyl radical and R" is hydrogen.
- R and R are each an isobutyl radical and R," is a methyl radical.
- R and R. are each a normal amyl radical and R" is a methyl radical.
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- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Dermatology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Plural Heterocyclic Compounds (AREA)
Description
Sept. 9, 1952 w. OROSHNIK 2,610,185
2-AMINO-4-DIALKYLAMINOETHOXYPYRIMIDINES Filed NOV. 7, 1950 2 SHEETS-SHEET l T1 g1. T4 :12.
I 0 b Q b Fig.3.
l I a b I INVENTOR .W/LL/AM OROSHN/K.
S p 9, 1952 w. OROSHNIK 2,610,186
2-AMINO4DIALKYLAMINOETHOXYPYRIMIDINES "Fig.7.
Filed Nov. '7, 1950 2 SHEETS SHEET 2 Fig.5.
' INVENTOR W/LL/AM OPDSHN/K.
Paten te cl Sept. 9, 1952 William Oroshnik, Plainfield, N. .L, assignor to Ortho Pharmaceutical Corporation, a corporation of New Jersey Application November 7, 1950, Serial No. 194,531
This invention relates to certain therapeutically eiiective organic compounds which are derivatives of isocytosine, 2-amino-4-hydroxypyrimidine and to their use as therapeutic agents having the ability to depress contractions of the uterus. More specifically this invention relate to Z-amino- 4 dialkylaminoethoxypyrimidines and 2 amino 4 dialkylaminoethoxy 6 methylpyrimidines in which each alkyl group is an isobutyl radical or an aliphatic radical having more than four and less than nine carbon atoms. The said isocytosine derivatives having the ability to depress contractions of the uterus may be represented by the following graphic formula:
l R NEE-C .\CLO-CH2-CH2N/ N C--H in which R and R" are each an isobutyl radical or an aliphatic radical having more than four and less than nine carbon atoms, and in which R" is hydrogen or methyl.
A number of derivatives of isocytosine have been prepared and studied for various pharmaceutical and medicinal uses but it is believed that the particular derivatives of isocytosine with which this invention is concerned are new substances. It is also believed the ability of these substances to depress contractions of the uterus has not been known heretofore.
The derivatives of isocytosine which embody this invention may be used as such to depress contractions of the uterus. They may also be used as in the form of salts of the isocytosine derivatives with organic or inorganic acids and since the said derivatives are basic in character, they may 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 depress contractions of the uterus has been 6 Claims. (01. see-256A) shown by a number of experiments in which a salt of the isocytosine derivative was added to a bath of nutrient solution having a strip of albino rat uterine tissue suspended therein. A continu ous kymographic record was made of contractions of the uterine strip before and after addi tion to the bath of a salt of an isocytosine derivative. Additional derivatives of isocytosine which are homologues of the class of isocytosine derivatives specifically mentioned before as having therapeutic value were also tested in the same way to determine their effect on contractions oi the uterus. The'succinate salts or the hydrochloride salts of the following compounds were tested for their pharmacologicalproperty of depressing contractionsof the uterus:
Compound 1-2-amino-4-diisobutylaminoethoxypyrimidine v p Compound II-2 amino-l-di-n-amylaminoethoxypyrimidine Compound III-2 amino-4-diisoamylaminoethoxypyrimidine Compound IV2-amino 4 diisooctylaminoethoxypyrimidine Compound V2-amino 4 diisobutylaminoethoxy-6-methylpyrimidine Compound .VI--2 amino-4-di-n-amy1aminoethoxy-G-methylpyrimidine Compound VlI2-amino 4 dimethylaminoethoxypyrimidine Compound VIII-2-amino 4 diethylaminoethoxypyrimidine Compound IX-2-aminol-diethy1aminoethoxy- G-methylpyrimidine V The following procedure was employed in test" ing the effect of. compounds LIX on. a rat uterus: A female albino rat weighing from 150-390 milligrams was killed by a blow on the head and the uterus was removed. A strip of the uterine tissue was suspended in a cc. bath of an aerated Ringer-Locke solution. One end of the uterine strip was maintained in a stationary position and the other end was attached to a lever which made contact with a kymograph and con tinuously 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 succinate salt or a hydrochloride salt of the isocytosine derivative to be tested for its effect on contractions of uterine tissue was added to the bath. Figures 1-9 are kymographic records of contractions of the strip of uterine tissue before and after addition to the bath of the comtaining no isocytosine derivative. That portion 4 of Figures 1-9 after the letter I) represents contractions as they return t normal and after the uterine strip is no longer in contact with a-compound being tested for its effect on contractions of uterine tissue.
Figure 1 shows the addition of milligrams of the succinate salt of compound I to the bath produced an almost immediate effect on the contractions of th uterine tissue which amounted to a substantially complete cessation of contractions. Figure 2 shows the addition of 5 milligrams of the succinate salt of compound II caused a rapid diminishing of the contractions of the strip of uterine tissue followed by an almost complete cessation of contractions and an appreciable lowering of the tonus of the issue. Compound II formed a succinate salt in which four molecules of this compound were combined with five molecules of succinic acid. Figure 3 shows that the addition to the bath of 5 milligrams of compound III in the form of its hydrochloride salt produced a gradual decreas in-amplitude of contractions of the uterine strip followed by a short period when the uterine tissue was not contracting. Figure 4 shows the addition to the bath of 5 milligrams of compound IV in the form of its hydrochloride salt produced a marked decrease in amplitude of contractions of the uterine tissue and a slight decreasein tonus, as well as a slight decrease in frequency. of contractions. Figure 5 shows the addition of 5 milligrams of the succinate salt of compound V produced an immediate cessation of contractions of the strip of uterine tissue and a slight lowering of tonus of the tissue. Figure 6 shows the addition of 5 milligrams of the succinate salt of compound VI produced a very rapid decline in amplitude of contractions and a substantiallowering of tonus of the strip of uterine tissue. Frequency of contractions of the tissue was increased. Compound VI formed a succinate salt in which four molecules of this compound were combined with five molecules of succinic acid. Figures '7, 8, and 9 show only slight effects on the uterine tissue result from the addition to the bath of the sesquisuccinate salts of compounds VII, VIII, and IX. Figure 7 shows the addition of milligrams of the sesquisuccinate salt of compound VII pro duced a slight decrease of amplitude of contractions and Figures 8 and 9 show the addition of 10 milligrams of the sesquisuccinate salts of compounds VIII and IX, respectively, to the bath produced a slight increase in amplitude of contractions and a slight increase in tonus of the uterine muscular tissue; however, compounds VII, and VIII and IX had .no appreciable. elfect on the frequency of contractions 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 4 have defined tonus as the resistance 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 the number of contraction waves in a unit time period.
Derivatives of isocytosine, such as 2-amino-4- dialkylaminoethoxypyrimidine and 2-amino-4- dialkylaminoethoxy-S-methylpyrimidine may be prepared by reacting 2-amino-4-chloropyrimidin or 2-amino-4-chloro-6-methylpyrimidine,
-respectively, with a sodium salt of a dialkylami- 'noethanol.
EXAMPLE I Preparation of 2 -amino-4-.diisobutylaminocaribou/pyrimidine Twenty-five parts of sodium metal were slowly added to 200 parts of diisobutylaminoethanol, dissolved in 500 parts of xylene. Twelve hundred parts of benzene were then added to the resulting sodium salt of diisobutylaminoethanol. One hundred twenty-nine parts of 2-amino-4-chloropyrimidine were added to the above solution-and during the addition the solution was cooled sufficiently to maintain the temperature at C. After the addition was complete, the reaction mixture was refluxed forone hour and cooled and then parts of water containing 10 parts of dissolved sodium hydroxide were added with stirring to the cooled reaction mixture. At this point two layers were formed and the organic layer was decanted. dried over anhydrous potassium carbonate, and the solvents, benzene and xylene, were removed by distillation. The residue in the distillation flask was distilled at a temperature of 108l12 C. and a pressure of 0.001 mm. of mercury. One hundred seventy-two parts of 2- amino4-diisobutylaminoethoxypyrimidine were obtained.
A water-soluble succinate salt of the compound prepared above was made by dissolving 3.1 grams of free base and 1.4 grams of succinic acid in 12 cc. of boiling acetone. Upon cooling the acetone solution, a succinate salt of the pyrimidine base precipitated and was recrystallized from 10 cc. of hot acetone. 3.4 grams of the succinate salt of the pyrimidine base having a melting point of 98-99 C. were obtained and this crystalline salt had the following formula: V
(C14H26N4'O) (C4H604) EXAMPLE 11' Preparation of Z-amz'rio 4 diisobutylaminoethoxy-fi-methylpyrimidine Twenty-five parts of sodium metal were slowly added to 200 parts of diisobutylaminoethanol, dissolved in 500 parts'of xylene. Twelve hundred parts of benzene were then added to the resulting sodium salt of diisobutylaminoethanol. One hundred forty-three parts of 2-amino-4-chloro- 6-methylpyrimidine were added to the above solution and during the addition the solution was cooled suniciently to maintain the temperature at 80 C. After the addition was complete, the reaction mixture was refluxed for one hour and cooled and then 100 parts of water containing 10 parts of dissolvedsodium hydroxide were added with stirring to the cooled reaction mixture. After stirring had been stopped, two layers were formed and the organic layer was decanted, dried over anhydrous potassium carbonate and the solvents, benzene and xylene, were removed by distillation. The residue in the distillation flask was distilled at a temperature of 100-110 C. and a pressure of 0.001 mm. of mercury. 160 parts of Z-amino 4 diisobutylaminoethoxy 6 methylpyrimidine were obtained.
A water-soluble succinate salt of the pyrimidine base was made by dissolving 4.1 grams of the pyrimidine base and 1.7 grams of succinic acid in 10 cc. of boiling acetone. Upon cooling the acetone solution, a white solid precipitated and it was removed and recrystallized from hot acetone. 3.5 grams of the recrystallized material were obtained and had a melting point of 99-100 C. The crystalline succinate salt of the pyrimidine base had the following formula:
(CH28N40) ((3411604) What is claimed is: l. A compound having the structural formula NH? O in which R. and R each is selected from the group 6 of alkyl radicals consisting of an isobutyl radical and alkyl radical having at least five and less than nine carbon atoms, and in which R" is selected from the group of radicals consisting of hydrogen and methyl.
2. A compound according to claim 1 in which R and R are each an isobutyl radical and R is hydrogen.
3. A compound according to claim 1 in which R and R are each a normal amyl radical and R" is hydrogen.
4. A compound according to claim 1 in which R. and R are each an isoamyl radical and R" is hydrogen.
5. A compound according to claim 1 in which R and R are each an isobutyl radical and R," is a methyl radical.
6. A compound according to claim 1 in which R and R. are each a normal amyl radical and R" is a methyl radical.
WILLIAM OROSHNIK.
REFERENCES CITED The following references are of record in the file of this patent:
Sutherland et al.: J. Org. Chem. 14, 235-238 (1949).
Braker et al.: J. Am. Chem. Soc. '69, 307243078 (1947).
Claims (1)
1. A COMPOUND HAVING THE STRUCTURAL FORMULA
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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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0
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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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