US3574212A - Quinazolinylureas - Google Patents

Quinazolinylureas Download PDF

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Publication number
US3574212A
US3574212A US702534A US3574212DA US3574212A US 3574212 A US3574212 A US 3574212A US 702534 A US702534 A US 702534A US 3574212D A US3574212D A US 3574212DA US 3574212 A US3574212 A US 3574212A
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Prior art keywords
quinazolinyl
amino
alkyl
carbon atoms
piperazinyl
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Expired - Lifetime
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US702534A
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English (en)
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Hans-Jurgen Hess
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Pfizer Corp Belgium
Pfizer Corp SRL
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Pfizer Corp Belgium
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim

Definitions

  • This invention relates to novel chemotherapeutic agents; in particular, it relates to certain novel quinazolinylureas which are useful as hypotensive agents.
  • the novel compounds of the instant invention are quinazolinylureas of the formulae R and R are each selected from the group consisting of hydrogen, alkyl having from 1 to carbon atoms, alkenyl having from 3 to 5 carbon atoms, hydroxylalkyl having from 2 to 5 carbon atoms, phenyl, benzyl, phenylethyl, 2-furfuryl, 2,2,2,-trifluoroethyl and cycloalkyl having from 3 to 8 carbon atoms;
  • R is H or alkyl having from 1 to 6 carbon atoms
  • R and R are each selected from hydrogen and alkoxy having from 1 to 3 carbon atoms, at least one of R and R being alkoxy;
  • Z is selected from the group consisting of morpholino
  • Y is selected from the group consisting of hydrogen, alkyl having from 1 to 5 carbon atoms, hydroxyalkyl where alkyl has from 2 to 5 carbon atoms, alkanoyl having from 2 to 7 carbon atoms, allyl, propargyl, 2-methylallyl, phenyl, benzyl, benzoyl, halobenzoyl and halophenyl where halo is chloro or bromo,
  • alkyl has from 1 to 6 carbon atoms when X' is phenyl.
  • quinazolinylureas are efiective hypotensive agents and may be administered for this purpose as the free base or pharmaceutically-acceptable acid addition salt, either alone or with a pharmaceutically-acceptable carrier.
  • Treating said 4-aminoquinazolines with alkyl isocyanate R3-NCO results in the formation of the desired compound of Formula I or II wherein R is alkyl containing up to 6 carbon atoms.
  • R is alkyl containing up to 6 carbon atoms.
  • a substantial excess of the alkyl isocyanate should be used.
  • the reaction is preferably conducted in a pressure vessel when the alkylisocyanate has a low boiling point, for example methyl isocyanate, in order to prevent loss of this reagents. With higher boiling isocyanates, the need for a pressure vessel is not as urgent and it may be dispensed with entirely where the boiling point is sufiiciently high.
  • reaction-inert organic solvents such as benzene, toluene, pyridine and triethylamine.
  • basic solvents such as pyridine and triethylamine are preferred.
  • reaction time nor temperature is critical. When using a pressure vessel, temperatures between room temperature and about C. are efiective; when a pressure vessel is not used, with higher alkyl isocyanates, temperatures between room temperature and reflux are appropriate. Reaction times up to about 24 hours are adequate; of course a higher reaction temperature will permit the use of shorter times Without a loss of product. With methyl isocyanate, for example, running the reaction for about 4-10 hours at about 100 C. has typically resulted in satisfactory yields.
  • the products are isolated from the reaction mixture by standard procedures familiar to those skilled in the art, for example, precipitation, removal of solvent, extraction and the like.
  • the reaction with alkyl isocyanate is conducted under the same conditions of time, temperature, pressure and substrate ratio as aforesaid treatment of 4-aminoquinazolines with alkyl isocyanate.
  • the resulting 1-(2- chloro-4-quinazolinyD-3aalkylurea is most easily converted to the various 1-(2-arnino-4-quinazolinyl)-3-alkylureas by heating a solution or suspension of the chloro material with the appropriate amine, e.g. heating with ethylamine results in the formation of a Z-ethylarrfino-quinazoline.
  • An ethanolic solution of the amine may conveniently be used for suspending the chloro material and temperatures between about 100 C. and 180 C. are adequate. Heating for up to about 24 hours is usually sufficient. The final material is easily isolated by evaporating the excess solvent .and amine and recrystallizing the product.
  • Preparation of compounds of Formulae I and II wherein R is hydrogen is accomplished by reacting a 2-amino-4- (unsubstituted amino)quinazoline with an inorganic cyanate and hydrochloric acid.
  • Ammonium cyanate, sodium cyanate and potassium cyanate are suited for this purpose.
  • At least equimolar amounts, with respect to the quinazoline, of cyanate and hydrochloric acid are preferably used, and more preferably, at least a molar excess of each Will be used.
  • reaction is conveniently conducted by adding the reagents to an aqueous suspension of the quinazoline. Neither reaction time nor temperature is critical, and the reaction may be conducted between about room temperature and reflux, with the necessary time to obtain satisfactory yields being dependent upon the temperature. It has been found that warming the aqueous reaction mixture on a steam bath for one hour afiords a satisfactory yield of the product, which may then be isolated and purified by standard techniques such as solvent removal, crystallization, extraction and the like.
  • Preferred agents are those wherein R and R are each methoxy, in particular 1-[2 (4- ⁇ 2-furoyl ⁇ -1- piperazinyl)-6,7-dimethoxy 4 quinazolinyl1-3 methylurea, l-[2-(dimethylamino)-6,7 dimethoxy 4 -quinazolinyl] 3 methylurea,l-[Z-(4-allyl-l-piperazinyl)6,7- dimethoxy 4 quinazolinyl]-3-methylurea and 1-[2-(4- carboisobutoxy-l-piperazinyl)-6,7-dimethoxy-4 quinazolinyl] -3-methylurea.
  • the instant compounds may be conveniently administered in the form of pharmaceutically-acceptable salts.
  • pharmaceutically-acceptable is meant those salts which do not have substantially greater toxicity than the free compound.
  • the pharmaceutically acceptable acid ad-- dition salts inlude salts of mineral acids such as hydrochloric, hydrobromic, hydriodic, phosphoric, metaphosphoric, nitric and sulfuric acids, as well as salts of organic acids such as tartaric, citric, maleic, glycollic, gluconic, gulonic, succinic, .arylsulfonic, e.g. p-toluenesulfonic acid and the like.
  • the pharmaceutically-unacceptable salts while not useful for therapy, are valuable for use in the isolation and purification of these newly discovered compounds. Furthermore, they are useful for the preparation of the therapeutically valuable pharmaceutically-acceptable salts.
  • the more common salts include those formed with hydrofluoric and perchloric acids. Hydrofluon'de salts are particularly useful for the preparation of the pharmaceutically-acceptable salts.
  • the hydrochloride salts for example, may be prepared by the solution of the hydrofluoride salts in hydrochloric acid and crystallization of the hydrochloride salt thereby formed.
  • compositions with less than 0.005% by weight of active ingredient might be used, it is preferred to use com positions containing not less than 0.005% of the active ingredient; otherwise the amount of carrier becomes excessively large.
  • Activity increases with the concentration of the active ingredient.
  • the composition may contain 10, 50, 75 or an even higher percentage by weight of the active.
  • the person who administers the instant agents will determine the dosage which will be most suitable, and it will vary with the age, weight and response of the particular subject as well as with the nature and extent of the symptoms and the pharmacological characteristics of the particular agent to be administered. Generally, small doses will be administered initially, with a gradual increase in the dosage until the optimum level is determined. -It will often be found that when the composition is administered orally, larger quantities of the active ingredient will be required to produce the same level as produced by a small quantity administered parenterally. In general, a dosage level within the range of from about 0.2 to about 50 mg. of active ingredient per kilogram of body weight, administered in single or multiple dose units, will efiectively lower blood pressure.
  • EXAMPLE III age levels are desirable, and such are within the scope of 5 Alkyl iscyaates are i .With z'dimethylamino'lt' this invention amino 6,7 dimethoxyquinazohne and 2-[4-(2-furoyl) The following examples are given to more fully illus prperaz1n-l-yl]-4-amino-6,7-d1methoxyqu1naz0l1ne accordtrate the persent invention.
  • quinazolinyl]-3-ethylurea of pyridine was added methyl isocyanate (20.6 g., 0.36 1-[2-(4-[Z-fiuroyl]-l-piperazinyl)-6,7-dirnethoXy-4- mole).
  • the mixture was heated in a pressure vessel at quinazolinyl]-3-isopropylurea 80 C. for 4 hours and then cooled in an ice bath.
  • Example V The following 1 (6,7 d1meth0xy-4-qu1nazohnyl)-3- 002C113 methylureas are prepared by the procedure of Example V; CH3O N I NHYJNHCH; N 01130- N NY 0 EXAMPLE VIII CH3O 1-[2-(4-ally1-1-piperazinyl)-6,7-dimethoxy-4- I quinazolinyl]-3-methylurea NHfiNHOm The procedure of Example V was repeated using an 0 equivalent amount of 2-[4-ally1-1-piperazinyl]-4-amino- 6,7-d1methoxyquinazoline. The reaction was conducted Y at 100 C.
  • the resulting mixture of crude product and ammonium Z R; R4 R5 chloride is powdered finely and iusplended7 30 mil. gg g gl fii 8g g g of water.
  • the mixture is warmed s ow y to wit v roxye y- -p r; a y stime--. ame.
  • Example X The procedure of Example X is repeated using an equivalent amount of appropriate quinazoline t0 atford the following products EXAMPLE XIV (2-ethylamino-6,7-dimethoxy-4- quinazolinyl) urea
  • 2 chloro-4-amino-6,7-dimethoxy quinazoline 6.2 g., 0.03 mole
  • 30 ml. of warm water is added, with stirring, 2.75 ml. (0.33 mole) of concentrated hydrochloric acid (12 N).
  • the resulting solution is placed in a porcelain evaporating dish, 1.98 g. (0.33 mole) of ammonium cyanate is added, and the mixture is heated on a steam bath for one hour.
  • the liquid is allowed to cool, set aside at room temperature for one hour, and then slowly evaporated to dryness over a period of 2-3 hours.
  • the crystalline material is crushed finely, 30 ml. of water is added, and again the mixture is evaporated slowly.
  • the residual powder is heated on a steam bath for an additional 4-5 hours, after which time it is finely powdered and again suspended in 30 ml. of water.
  • the mixture is warmed slowly to 70 C. with stirring, then allowed to cool to 35 C.
  • the resulting (2- chloro-6,7-dimethoxy-4-quinazolinyl)urea is collected by filtration.
  • Additional acid addition salts of each of these porducts are similarly prepared by using aqueous solutions of the following acids in place of said hydrochloric acid: hydrobromic acid, hydriodic acid, nitric acid, sulfuric acid, citric acid, phosphoric acid, maleic acid, tartaric acid and lactic acid.
  • the systolic blood pressure was determined on the coccygeal artery according to the method of Prioli and Wynbury, J. Appl. Physiol. 15, 323 (1960) prior to drug administration and 2, 6 and 24 hours thereafter.
  • the drugs were administered orally in the form of capsules, except as indicated.
  • R and R are each selected from the group consisting of hydrogen, alkyl having from 1 to 5 carbon atoms, alkenyl having from 3 to 5 carbon atoms, hydroxyalkyl having from 2 to 5 carbon atoms, phenyl, benzyl, phenylethyl, Z-furfuryl, 2,2,2-trifluoroethyl and cyclo alkyl having from 3 to 8 carbon atoms;
  • R is H or alkyl having from 1 to 6 carbon atoms
  • R and R are each selected from hydrogen and alkoxy having from 1 to 3 carbon atoms, at least one of R and R being alkoxy;
  • Z is selected from the group consisting of morpholino
  • Y is selected from the group consisting of hydrogen, alkyl having from 1 t o 5 carbon atoms, hydroxyalkyl where alkyl has from 2 to 5 carbon atoms, alkanoyl having from 2 to 7 carbon atoms, allyl ,propargyl, Z-methylallyl, phenyl, benzyl, benzoyl, halobenzoyl and halophenyl where halo is chloro or bromo, trifluoromethylphenyl, methoxyphenyl, methylphenyl, methylbenzoyl, methoxybenzoyl, trifluoromethylbenzoyl, furoyl, benzofuroyl, thenoyl, pyridinecarbonyl, 3,4, S-trimethoxybenzoyl, carboxylic acid alkyl ester Where alkyl has from 1 to 6 carbon atoms, carboxylic acid alkenyl ester Where alkenyl has from 3 to 6 carbon atoms; piperidino
  • X is hydrogen or phenyl
  • X is selected from the group consisting of hydrogen, alkyl having from 1 to 5 carbon atoms, al-koxy having from 1 to 4 carbon atoms, hydroxy, hydroxyalkyl where alkyl has from 2 to 5 carbon atoms, phenyl, and benzyl when X is hydrogen, and X is carboxylic acid alkyl ester where alkyl has from 1 to 6 carbon atoms when X- is phenyl; and the hydrofluoric acid and prechloric acid addition salts thereof, and the pharmaceutically acceptable mineral acid and organic acid addition salts thereof.

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US702534A 1968-02-02 1968-02-02 Quinazolinylureas Expired - Lifetime US3574212A (en)

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3723434A (en) * 1970-07-17 1973-03-27 Pfizer Piperazino isoquinoline bronchodilators
US3920636A (en) * 1972-10-30 1975-11-18 Eisai Co Ltd Quinazoline compounds
US3980650A (en) * 1972-05-05 1976-09-14 N.V. Koninklijke Pharmaceutische Fabrieken V/H Brocades-Stheeman En Pharmacia 4-Amino-pyrimidine derivatives
US4495188A (en) * 1980-11-26 1985-01-22 Sankyo Company Limited Acylaminoquinazoline derivatives and a pharmaceutical composition containing them
US4749705A (en) * 1986-03-13 1988-06-07 Kotobuki Seiyaku Co., Ltd. Quinazoline derivative and anti-hypertensive agents
US4775673A (en) * 1983-06-01 1988-10-04 Spofa, Spojene Podniky Pro Zdravotnickou Vyrobu Substituted acylpiperazinoquinazolines and pharmaceutical compositions containing same
EP1018879A4 (en) * 1996-02-02 2002-07-24 Nitromed Inc NITROSIZED AND NITROSYLATED ALPHA ADRENO RECEPTORE ANTAGONISTS, PREPARATIONS AND THEIR USE
US20020143007A1 (en) * 1996-02-02 2002-10-03 Garvey David S. Nitrosated and nitrosylated alpha-adrenergic receptor antagonists, compositions and methods of use
US20050065161A1 (en) * 1996-02-02 2005-03-24 Nitromed, Inc. Nitrosated and nitrosylated alpha-adrenergic receptor antagonist compounds, compositions and their uses

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3723434A (en) * 1970-07-17 1973-03-27 Pfizer Piperazino isoquinoline bronchodilators
US3980650A (en) * 1972-05-05 1976-09-14 N.V. Koninklijke Pharmaceutische Fabrieken V/H Brocades-Stheeman En Pharmacia 4-Amino-pyrimidine derivatives
US3920636A (en) * 1972-10-30 1975-11-18 Eisai Co Ltd Quinazoline compounds
US4495188A (en) * 1980-11-26 1985-01-22 Sankyo Company Limited Acylaminoquinazoline derivatives and a pharmaceutical composition containing them
US4775673A (en) * 1983-06-01 1988-10-04 Spofa, Spojene Podniky Pro Zdravotnickou Vyrobu Substituted acylpiperazinoquinazolines and pharmaceutical compositions containing same
US4749705A (en) * 1986-03-13 1988-06-07 Kotobuki Seiyaku Co., Ltd. Quinazoline derivative and anti-hypertensive agents
EP1018879A4 (en) * 1996-02-02 2002-07-24 Nitromed Inc NITROSIZED AND NITROSYLATED ALPHA ADRENO RECEPTORE ANTAGONISTS, PREPARATIONS AND THEIR USE
US20020143007A1 (en) * 1996-02-02 2002-10-03 Garvey David S. Nitrosated and nitrosylated alpha-adrenergic receptor antagonists, compositions and methods of use
US20050065161A1 (en) * 1996-02-02 2005-03-24 Nitromed, Inc. Nitrosated and nitrosylated alpha-adrenergic receptor antagonist compounds, compositions and their uses
US20050187222A1 (en) * 1996-02-02 2005-08-25 Nitromed, Inc. Nitrosated and nitrosylated alpha-adrenergic receptor antagonist compounds

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BE726984A (en)) 1969-07-16
FR2001171A1 (en)) 1969-09-26
GB1195932A (en) 1970-06-24
SE358166B (en)) 1973-07-23

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