[go: up one dir, main page]

US3860596A - 2-aryl-4-substituted-amino-5-pyrimidyl derivatives - Google Patents

2-aryl-4-substituted-amino-5-pyrimidyl derivatives Download PDF

Info

Publication number
US3860596A
US3860596A US285154A US28515472A US3860596A US 3860596 A US3860596 A US 3860596A US 285154 A US285154 A US 285154A US 28515472 A US28515472 A US 28515472A US 3860596 A US3860596 A US 3860596A
Authority
US
United States
Prior art keywords
compound
grams
lower alkyl
phenyl
milliliters
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US285154A
Inventor
Dong H Kim
Arthur A Santilli
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Wyeth LLC
Original Assignee
American Home Products Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by American Home Products Corp filed Critical American Home Products Corp
Priority to US285154A priority Critical patent/US3860596A/en
Application granted granted Critical
Publication of US3860596A publication Critical patent/US3860596A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

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
    • C07D239/30—Halogen atoms or nitro radicals
    • 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
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C07D239/36—One oxygen atom as doubly bound oxygen atom or as unsubstituted hydroxy radical
    • 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
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom

Definitions

  • ABSTRACT Compounds of the following formula possess central 7 nervous system depressant properties in warm blooded animals:
  • R,R and R are independently selected from the group consisting of H and lower alkyl radicals
  • X is a member selected from the group consisting of CH OI-I, CI-IO, CO R in which R is H or lower alkyl,
  • Y is a member selected from the group consisting of pharmaceutically acceptable acid addition salts thereof.
  • R, R and R are independently selected from the group consisting of -H and lower alkyl radicals;
  • X is a member selected from the group consisting of -CH OH, -CHO,
  • R is -H or lower alkyl
  • Y is a member selected from the group consisting of R and -(CH ),,-Z, in which R and R are independently -H, lower alkyl or perfluoro-lower alkyl radicals, with the proviso that when R and R are -H, R is lower alkyl, Z is -H or -OH, and
  • n is one of the integers 3 or 4; and pharmaceutically acceptable acid addition salts thereof.
  • lower alkyl used throughout the specification, is used to include straight and branched chain univalent hydrocarbon radicals containing from 1 to 7 carbon atoms, such as methyl, ethyl, ipropyl, n-propyl, n-butyl, n-hexyl, and the like.
  • pharmaceutically acceptable acid addition salts is used to include those non-toxic acid addition salts which may be formed with both organic and inorganic acids such as hydrochloric, hydrobromic, sulfuric, phosphoric, methane sulfonic, nitric, p-toluene sulfonic, acetic, citric, maleic, succinic, and the like.
  • the compounds of this invention are prepared by reacting an arylamidine hydrochloride with a dialkyl 2- alkoxymethylene alkanedioate NH 1 2 m0 CO Et c NH HCl+ c: c ⁇
  • amine reactants are desirably aniline, mtrifluoromethylaniline, 2,3-dimethylaniline, methylamine, ethylamine, propylaminc, 3-
  • An especially useful aliphatic amine is 3- hydroxypropylamine, which may be cyclized through the ortho carboxyl group in the presence of an acetylating agent such as acetic anhydride to form the lactone l,3-oxazino-[2,3-b]pyrimido[4,5-d][1,3]oxazin-5-one.
  • an acetylating agent such as acetic anhydride
  • the 5-carboalkoxy substituent of the pyrimidine nucleus may be reduced selectively by a reagent such as LiAlI-I, or (t-butoxy) -,LiAlI-I to afford the 5- hydroxymethyl compound, which undergoes mild oxidation with a reagent such as Mn0 to yield the 5- aldehydo compound.
  • a reagent such as LiAlI-I, or (t-butoxy) -,LiAlI-I to afford the 5- hydroxymethyl compound, which undergoes mild oxidation with a reagent such as Mn0 to yield the 5- aldehydo compound.
  • the compounds of this invention are physiologically active central nervous system depressants.
  • the compounds were evaluated in accordance with the following test procedures, the biological activity of the specifically exemplified compounds being presented in conjunction with the specific preparative procedure, infra:
  • PROCEDURE I The compounds were administered orally and intraperitoneally to-three mice (14 to 24 grams) at doses ranging from 0.04 to 400 milligrams per kilogram of host body weight. The animals were watched for a minimum of two hours during which time signs of general stimulation (i.e., increased spontaneous motor activity, hyperactivity on tactile stimulation, twitching), general depression (i.e., decreased spontaneous motor activity, decreased respiration) and autonomic activity (i.e., miosis, mydriasis, diarrhea) were noted.
  • general stimulation i.e., increased spontaneous motor activity, hyperactivity on tactile stimulation, twitching
  • general depression i.e., decreased spontaneous motor activity, decreased respiration
  • autonomic activity i.e., miosis, mydriasis, diarrhea
  • the compounds tested were found to be physiologically active compounds in experimental and comparative pharmacology and are of value in the treatment of mammals, e.g., mice, rats, etc., who are responsive to treatment with central nervous system depressant agents. Specifically the compounds may be administered for the purpose of inducing a calming effect in mammals.
  • the compounds of this invention are individually unique in their activity as anti-inflammatory agents.
  • the pertinent testing procedures by which antiinflammatory activity was evaluated are as follows:
  • PROCEDURE II From 1.0 to 100 milligrams of the compound tested per kilogram body weight was administered orally to six rats (120-l 60 grams in weight, averaged between groups) with a six rat control being administered aqueous vehicle with no active compound. 60 minutes after drug administration, edema was induced by injection of 0.05 milliliters of 1 per cent carrageenin solution into the subplantar tissue of the rats right hind paw. The paw volume was immediately volumetrically determined with a plethysmograph and again 3 hours later. The mean volume swelling for the control group was determined and compared to the test group. Swelling inhibition of 23 per cent or more was considered to be indicative of an active compound.
  • PROCEDURE III I This procedure is a modification of the procedure disclosed in Mizushima, Arch. In. Pharmacodyn., vol. 149, pp. 1-7 (1964).
  • Test solutions are prepared to contain 2.5 milliliters of buffered 1 per cent albumin (bovine serum Fraction V) and 2.5 milliliters of buffer or the solution being tested.
  • the buffer solvent consists of 0.05 molar tris(hydroxymethyl)amino methane, (pH6.5). Up to 2.5 per cent final solution concentration dimethylformamide may be employed to solubilize the compound being tested.
  • the control and test systems are heated at 69C for 4 minutes, cooled and their turbidities are read at 54 millimicrons. Test compounds that decrease the solution turbidity more than 20 per cent at a concentration up to 1 milligram per liter are deemed active.
  • PROCEDURE IV This procedure is a modification of the procedure of Gerber et al., Biochem. Pharmacol, vol. 16, pp. 115-123 (1967).
  • a mixture of 3 milliliters of 2.07 millimolar solution of the test compound, 3 milliliters of 4.1 per cent human serum albumin (Fraction V), and 0.2 milliliters of 2 millimolar 5,5-dithiobis(2-nitrobenzoic acid) in 0.1 molar aqueous potassium phosphate buffer solution (pH 7.4) is incubated at 30C.
  • the reaction rates are measured for 40 minutes by reading absorbance at 4l2 millimicrons.
  • the net per cent increase produced by the test compound is calculated for and 30 minute periods.
  • a minimum per cent acceleration denotes activity of the test compound at a maximum concentration of 1 milligram per liter.
  • the antiinflammatory agent accelerates the disulfidesulfhydryl interchange in serum albumen as is evidenced by an increase in the formation of pigmented 5-thio-2-nitro benzoic acid from serum albumin and 5,5-dithiobis(2- nitrobenzoic acid).
  • PROCEDURE V This test is a modification of the procedure of Skidmore et al., J. Pharm. Pharmacol, vol. 17, pp. 671-673 (1965).
  • a reaction mixture is prepared to contain 2.0 milliliters of 2.01 per cent bovine serum albumin (Fraction V), 2.0 milliliters of 0.15 millimolar 2,4,6- trinitrobenzaldehyde, and 2.0 milliliters of a 3.0 millimolar (or less) solution of the test compound, all in 0.1 molar sodium phosphate (pH 7.5). Dimethylformamide may be present up to 3 per cent of the final volume to facilitate solubilization. The rate of reaction is measured at room temperature by reading the absorbance at 425 and 525 millimicrons over a 40 minute period. The net per cent inhibition of color formation is calculated at 30 minutes for both wave lengths and averaged. A compound that decreases the color formation by more than 20 per cent at l milligram per liter is considered to be active.
  • Fraction V bovine serum albumin
  • Dimethylformamide may be present up to 3 per cent of the final volume to facilitate solubilization.
  • the rate of reaction is measured at room temperature by reading the absorbance at 425 and 5
  • the compounds of the invention When the compounds of the invention are employed as described above they may be administered alone or in combination with pharmacologically acceptable carriers, the proportion of which is determined by the chosen route of administration and standard pharmaceutical practice. For example, they may be administered orally in tablet or capsule form with conventional flavors, diluents, lubricants, disintegrators or binding agents as may be required. They may be administered orally in the form of a solution or they may be injected parenterally. For parenteral administration they may be used in the form of a sterile solution containing other solutes, for example, enough saline or glucose to make the solution isotonic. It is most advantageous to provide the compound as a dry powder in a suitable container so that it may be admixed with a suitable aqueous vehicle prior to administration.
  • Tablets containing the central nervous system depressants of this invention may be formulated by admixing a unit dosage amount of the active compound with microcrystalline cellulose N.F.; magnesium stearate U.S.P.; and a filler such as lactose U.S.P. to obtain any desired ultimate tablet weight.
  • the acid addition salt of the desired compound of compound mixture of this invention is combined with lactose U.S.P. to form a packageable (sealed glass ampoule, or the like) mix which, when combined with the injection vehicle, such as sterile water containing about 1 per cent benzyl alcohol and 0.6 per cent sodium acetate/acetic acid buffer, may be parenterally employed.
  • the injection vehicle such as sterile water containing about 1 per cent benzyl alcohol and 0.6 per cent sodium acetate/acetic acid buffer, may be parenterally employed.
  • the specific formulation, for tablets, capsules or injectables depends upon the host and formulation techniques employed.
  • Acetylate a,a,a-trifluoromethyl-m-toluidine (32 grams) by adding thereto in dropwise manner 22 grams of acetic anhydride while stirring the mixture. After the exothermic reaction subsides, heat the mixture on a steam bath for 20 minutes. Cool the mixture. Filter the product and wash it with water. Recrystallize the product from diethylether-petroleum ether to yield 29 grams of N-acetyl-a,a,a-trifluoro-m-toluidine melting at l01l03C.
  • N- lower alkyl-a.a,a-trifluoro-m-toluidine derivatives such as the N-propyl and N-butyl compounds may be prepared.
  • This carboxylic acid is a central nervous system depressant, demonstrating activity at a dosage level of 127 milligrams per kilogram body weight and above.
  • anti-inflammatory activity was observed in vivo and in vitro in accordance with the Test Procedures No. II, III at 0.09 millimolar concentration and V at 0.3 millimolar concentration supra.
  • EXAMPLE 1V Ethyl 4-(N-ethyl-a,a,a-Trifluoro-m-to1uidino)-2- phenyl-S-pyrimidinecarboxylate Reflux a mixture of 5-carbethoxy-4-chloro-2- phenylpyrimidine (6.5 grams), N-ethyl-a.a,a-trifluorom-toluidine (5 grams), sodium carbonate (2.7 grams) and N.N-dimethyl formamide (45 milliliters) for 3.5 hours. Pour the reaction mixture into cold water to separate the product as an oil. Wash the oil several times with water and cool to cause solidification. Filter and wash with diethyl ether to obtain 4.0 grams of product which upon recrystallization from petroleum ether affords the title compound melting at 100102C.
  • the ester prepared in accordance with the preceding Example exhibited anti-inflammatory activity at a minimum concentration of 0.8 millimoles per liter in accordance with Test Procedure No. 111.
  • the free acid prepared by the method presented in the preceding paragraph produced a central nervous system depressant effect when administered orally and intraperitoneally at doses as low as 127 milligrams per kilogram host body weight, to mice, as evidenced by decreased motor activity, decreased respiration mydriasis and hyperemia. Furthermore, the free acid produced an anti-inflammatory effect when tested in accordance with Procedures III at 0.03 millimolar minimal effect and V at 0.08 millimolar concentration.
  • the product of the preceding example produces central nervous system depressant effects on mice when administered orally at a concentration as low as 127 milligrams per kilogram host body weight as evidenced by hyperactivity to touch decreased motor activity, sedation and decreased respiration.
  • EXAMPLE Vll 4-(3-Hydroxypropylamino)-2-phenyl-5'- pyrimidinecarboxylic acid Reflux a mixture of the ethyl ester of Example VI (15 grams), 15 per cent aqueous NaOH solution (45 milliliters), and ethanol (10 milliliters) for 0.5 hour. Adjust the pH of the solution to about 2 by adding HCl, thereby precipitating the free acid. Filter and wash with water to obtain 8.0 grams of product having a melting point of 223225C. Further purification of the title compound by dissolving in base followed by acidification yields a product melting at 228230C.
  • 4-(3-Hydroxypropylamino)-2-phenyl-5- pyrimidinecarboxylic acid produced central nervous system depressant effects in mice when oral doses as low as 127 milligrams per kilogram body weight are administered.
  • the observed effects are decreased motor activity, sedation, decreased respiration, augmented flexor, reflex, mydriasis and hyperemia.
  • the free acid produces an anti-inflammatory effect upon oral administration to rats in accordance with Test Procedure II.
  • lactone l,3-oxazino[2,3-b]pyrimido[4,5- d][1,3]-oxazin-5-one produces central nervous system depressant activity when administered intraperitoneally to mice in doses as low as 40 milligrams per kilogram body weight, as evidenced by decreased motor activity and decreased respiration.
  • the product of the preceding example produces central nervous system depressant effects in mice when administered intraperitoneally in doses as low as 40 milligrams per kilogram host body weight, evidenced by decreased motor activity, decreased respiration and ataxia at a dose as low as 400 milligrams per kilogram body weight.
  • Example X produces central nervous system depressant effects in mice when administered orally in doses as low as 400 milligrams per kilogram and intraperitoneally in doses as low as 127 milligrams per kilogram host body weight.
  • the depressant effects are observed in hyperactivity to touch, decreased motor activity, ataxia, decreased respiration and ptosis.
  • Example X produces central nervous system depressant effects in mice at oral doses as low as 12.7 milligrams per kilogram host body weight, evidenced by decreased motor activity sedation and decreased respiration.
  • R is -H or lower alkyl

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

AND -(CH2)n-Z, in which R3 and R4 are independently -H, lower alkyl or perfluoro-lower alkyl radicals, with the proviso that when R and R2 are -H, R3 is lower alkyl, Z is -H or -OH, and N IS ONE OF THE INTEGERS 3 OR 4; AND PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF.

IN WHICH R,R1 and R2 are independently selected from the group consisting of -H and lower alkyl radicals; X is a member selected from the group consisting of -CH2OH, CHO, -CO2R5, in which R5 is -H or lower alkyl, Y is a member selected from the group consisting of

Compounds of the following formula possess central nervous system depressant properties in warm blooded animals:

Description

United States Patent 11 1 Kim et al.
[ 1 Jan. 14,1975
I 54 l 2-ARYL-4-SUBSTITUTED-AMINO-5- PYRI MIDYL DERIVATIVES [75] Inventors: Dong H. Kim, Wayne; Arthur A.
Santilli, Havertown, both of Pa.
[73] Assignee: American Home Products Corporation, New York, NY.
22 Filed: Aug. 31, 1972 21 Appl. No.: 285,154
[52] US. Cl. 260/256.4 N, 260/244 R, 424/248,
424/251 [51] Int. Cl C07d 51/42 [58] Field of Search 260/256.4 N
[56] References Cited UNITED STATES PATENTS 3,563,984 2/l97l Kim et al. 260/244 OTHER PUBLICATIONS Juby et al, J. Med. Chem., 10, 954-956, (1967).
Primary ExaminerRaymond V. Rush Attorney, Agent, or Firm-Richard K. Jackson [57] ABSTRACT Compounds of the following formula possess central 7 nervous system depressant properties in warm blooded animals:
X l N i R in which R,R and R are independently selected from the group consisting of H and lower alkyl radicals;
X is a member selected from the group consisting of CH OI-I, CI-IO, CO R in which R is H or lower alkyl,
Y is a member selected from the group consisting of pharmaceutically acceptable acid addition salts thereof.
8 Claims, No Drawings 2-ARYL-4-SUBSTITUTED-AMINO -PYRIM IDYL DERIV ATIVES BACKGROUND OF THE INVENTION BRIEF DESCRIPTION OF THE INVENTION In accordance with this invention, there is provided a group of chemical compounds which produce central nervous system depressant effects when administered to warm blooded animals, processes for their production, methods for their administration and administrable compositions.
The compounds of this invention may be depicted by the structural formula:
in which R, R and R are independently selected from the group consisting of -H and lower alkyl radicals; X is a member selected from the group consisting of -CH OH, -CHO,
-CO R in which R is -H or lower alkyl, Y is a member selected from the group consisting of R and -(CH ),,-Z, in which R and R are independently -H, lower alkyl or perfluoro-lower alkyl radicals, with the proviso that when R and R are -H, R is lower alkyl, Z is -H or -OH, and
n is one of the integers 3 or 4; and pharmaceutically acceptable acid addition salts thereof.
The expression lower alkyl used throughout the specification, is used to include straight and branched chain univalent hydrocarbon radicals containing from 1 to 7 carbon atoms, such as methyl, ethyl, ipropyl, n-propyl, n-butyl, n-hexyl, and the like. The expression pharmaceutically acceptable acid addition salts is used to include those non-toxic acid addition salts which may be formed with both organic and inorganic acids such as hydrochloric, hydrobromic, sulfuric, phosphoric, methane sulfonic, nitric, p-toluene sulfonic, acetic, citric, maleic, succinic, and the like..
The compounds of this invention are prepared by reacting an arylamidine hydrochloride with a dialkyl 2- alkoxymethylene alkanedioate NH 1 2 m0 CO Et c NH HCl+ c: c\
1 CO Et 1 N (30 m I followed by displacement of the 4-hydroxyl group with chlorine by reaction of PCI PCI SOCI POCl and the like, and dechloroamination with either an aromatic amine of the formula 3 /R #E N an aliphatic amine of the formula H N(CH ),,Z, where the groups R, R ,,R R, R and Z and the value of n are hereinabove defined. Thus, the
amine reactants are desirably aniline, mtrifluoromethylaniline, 2,3-dimethylaniline, methylamine, ethylamine, propylaminc, 3-
hydroxypropylamine, butylaminc, N-cthylanilinc, N-
methyl-3-trifluoromethylaniline, N-ethyl-3- trifluoroaniline, and the like.
An especially useful aliphatic amine is 3- hydroxypropylamine, which may be cyclized through the ortho carboxyl group in the presence of an acetylating agent such as acetic anhydride to form the lactone l,3-oxazino-[2,3-b]pyrimido[4,5-d][1,3]oxazin-5-one.
The 5-carboalkoxy substituent of the pyrimidine nucleus may be reduced selectively by a reagent such as LiAlI-I, or (t-butoxy) -,LiAlI-I to afford the 5- hydroxymethyl compound, which undergoes mild oxidation with a reagent such as Mn0 to yield the 5- aldehydo compound.
The compounds of this invention are physiologically active central nervous system depressants. The compounds were evaluated in accordance with the following test procedures, the biological activity of the specifically exemplified compounds being presented in conjunction with the specific preparative procedure, infra:
PROCEDURE I The compounds were administered orally and intraperitoneally to-three mice (14 to 24 grams) at doses ranging from 0.04 to 400 milligrams per kilogram of host body weight. The animals were watched for a minimum of two hours during which time signs of general stimulation (i.e., increased spontaneous motor activity, hyperactivity on tactile stimulation, twitching), general depression (i.e., decreased spontaneous motor activity, decreased respiration) and autonomic activity (i.e., miosis, mydriasis, diarrhea) were noted.
The compounds tested were found to be physiologically active compounds in experimental and comparative pharmacology and are of value in the treatment of mammals, e.g., mice, rats, etc., who are responsive to treatment with central nervous system depressant agents. Specifically the compounds may be administered for the purpose of inducing a calming effect in mammals.
The compounds of this invention are individually unique in their activity as anti-inflammatory agents. The pertinent testing procedures by which antiinflammatory activity was evaluated are as follows:
PROCEDURE II From 1.0 to 100 milligrams of the compound tested per kilogram body weight was administered orally to six rats (120-l 60 grams in weight, averaged between groups) with a six rat control being administered aqueous vehicle with no active compound. 60 minutes after drug administration, edema was induced by injection of 0.05 milliliters of 1 per cent carrageenin solution into the subplantar tissue of the rats right hind paw. The paw volume was immediately volumetrically determined with a plethysmograph and again 3 hours later. The mean volume swelling for the control group was determined and compared to the test group. Swelling inhibition of 23 per cent or more was considered to be indicative of an active compound.
PROCEDURE III I This procedure is a modification of the procedure disclosed in Mizushima, Arch. In. Pharmacodyn., vol. 149, pp. 1-7 (1964).
Test solutions are prepared to contain 2.5 milliliters of buffered 1 per cent albumin (bovine serum Fraction V) and 2.5 milliliters of buffer or the solution being tested. The buffer solvent consists of 0.05 molar tris(hydroxymethyl)amino methane, (pH6.5). Up to 2.5 per cent final solution concentration dimethylformamide may be employed to solubilize the compound being tested. The control and test systems are heated at 69C for 4 minutes, cooled and their turbidities are read at 54 millimicrons. Test compounds that decrease the solution turbidity more than 20 per cent at a concentration up to 1 milligram per liter are deemed active.
PROCEDURE IV This procedure is a modification of the procedure of Gerber et al., Biochem. Pharmacol, vol. 16, pp. 115-123 (1967).
A mixture of 3 milliliters of 2.07 millimolar solution of the test compound, 3 milliliters of 4.1 per cent human serum albumin (Fraction V), and 0.2 milliliters of 2 millimolar 5,5-dithiobis(2-nitrobenzoic acid) in 0.1 molar aqueous potassium phosphate buffer solution (pH 7.4) is incubated at 30C. The reaction rates are measured for 40 minutes by reading absorbance at 4l2 millimicrons. The net per cent increase produced by the test compound is calculated for and 30 minute periods. A minimum per cent acceleration denotes activity of the test compound at a maximum concentration of 1 milligram per liter. In theory, the antiinflammatory agent accelerates the disulfidesulfhydryl interchange in serum albumen as is evidenced by an increase in the formation of pigmented 5-thio-2-nitro benzoic acid from serum albumin and 5,5-dithiobis(2- nitrobenzoic acid).
PROCEDURE V This test is a modification of the procedure of Skidmore et al., J. Pharm. Pharmacol, vol. 17, pp. 671-673 (1965).
A reaction mixture is prepared to contain 2.0 milliliters of 2.01 per cent bovine serum albumin (Fraction V), 2.0 milliliters of 0.15 millimolar 2,4,6- trinitrobenzaldehyde, and 2.0 milliliters of a 3.0 millimolar (or less) solution of the test compound, all in 0.1 molar sodium phosphate (pH 7.5). Dimethylformamide may be present up to 3 per cent of the final volume to facilitate solubilization. The rate of reaction is measured at room temperature by reading the absorbance at 425 and 525 millimicrons over a 40 minute period. The net per cent inhibition of color formation is calculated at 30 minutes for both wave lengths and averaged. A compound that decreases the color formation by more than 20 per cent at l milligram per liter is considered to be active.
When the compounds of the invention are employed as described above they may be administered alone or in combination with pharmacologically acceptable carriers, the proportion of which is determined by the chosen route of administration and standard pharmaceutical practice. For example, they may be administered orally in tablet or capsule form with conventional flavors, diluents, lubricants, disintegrators or binding agents as may be required. They may be administered orally in the form of a solution or they may be injected parenterally. For parenteral administration they may be used in the form of a sterile solution containing other solutes, for example, enough saline or glucose to make the solution isotonic. It is most advantageous to provide the compound as a dry powder in a suitable container so that it may be admixed with a suitable aqueous vehicle prior to administration.
Tablets containing the central nervous system depressants of this invention may be formulated by admixing a unit dosage amount of the active compound with microcrystalline cellulose N.F.; magnesium stearate U.S.P.; and a filler such as lactose U.S.P. to obtain any desired ultimate tablet weight. Furthermore, to prepare injectable formulations, the acid addition salt of the desired compound of compound mixture of this invention is combined with lactose U.S.P. to form a packageable (sealed glass ampoule, or the like) mix which, when combined with the injection vehicle, such as sterile water containing about 1 per cent benzyl alcohol and 0.6 per cent sodium acetate/acetic acid buffer, may be parenterally employed. The specific formulation, for tablets, capsules or injectables depends upon the host and formulation techniques employed.
DETAILED DESCRIPTION OF THE INVENTION The following Preparations 1-3 illustrate the technique employed to prepare the intermediates from which the biologically active compounds of this invention, presented in Examples 1 11, were prepared.
PREPARATION l Ethyl 4-chloro-6-methyl-2-phenyl-5- pyrimidinecarboxylate.
With vigorous stirring, add 7.8 grams of benzamidine hydrochloride to a freshly prepared solution of sodium ethoxide (2.3 grams sodium in milliliters absolute ethanol). Add 1 1.5 grams diethyl ethoxyethylidenemalonate to the mixture and reflux for 1% hour. Chill the reaction mixture and filter to remove inorganic salts. Evaporate the filtrate to dryness under reduced pressure. Dissolve the residue in water and acidify the solution with hydrochloric acid. Collect the precipitate and recrystallize from ethyl acetate to obtain 3.6 grams of the title compound which exhibits an uncorrected melting point of 174176C.
Elemental Analysis: C H N O Calculated: C, 65.10; H. 5.46; N. 10.85. Found: C, 65.25; H. 5.45; N. 10.88.
Reflux a mixture of the product of the preceding paragraph (5.7 grams) and phosphorus oxychloride (6O milliliters) for 3.5 hours. Remove the unreacted phosphorus oxychloride under reduced pressure. Treat the residual oil with crushed ice to obtain 5.2 grams of ethyl 4-chloro-6-methyl-2-phenyl-5- pyrimidinecarboxylate as a yellow solid.
PREPARATION II Ethyl 4-chloro-2-phenyl-5-pyrimidinecarboxylate By following the instruction of Procedure I, with the exception that diethyl ethoxymethylenemalonate is used as the reactant in lieu of diethyl ethoxyethylidenemalonate, yields 5-carbethoxy-4-hydroxy-2- phenylpyrimidine which may be dehydroxychlorinated to the 4-chloro derivative (Kim & Santilli, J. Heterocycl. Chem, vol. 6. pp. 819-828 (1969).
PREPARATION III N-lower alkyl-a,a,a-trifluoro-m-toluidine.
Acetylate a,a,a-trifluoromethyl-m-toluidine (32 grams) by adding thereto in dropwise manner 22 grams of acetic anhydride while stirring the mixture. After the exothermic reaction subsides, heat the mixture on a steam bath for 20 minutes. Cool the mixture. Filter the product and wash it with water. Recrystallize the product from diethylether-petroleum ether to yield 29 grams of N-acetyl-a,a,a-trifluoro-m-toluidine melting at l01l03C.
Elemental Analysis: C H F NO Calculated: C. 53.20; H, 3.9
7'. N. 6.89 Found: C. 52.96; H, 4.06; N. 6.85
Reduce 30.5 grams of the product of the preceding paragraph with 5.7 grams of lithium aluminum hydride in tetrahydrofuran to give 17 grams of N-ethyl-a,a,a' trifluoro-m-toluidine which has a boiling point of 40C. at 0.75 millimeters mercury pressure.
Elemental Analysis: C H F N Calculated: C. 57.74; H, 5.38; N. 7.48 Found: C. 57.09; H. 5.26; N. 7.51
Following the above detailed procedure, various N- lower alkyl-a.a,a-trifluoro-m-toluidine derivatives such as the N-propyl and N-butyl compounds may be prepared.
The following examples present specific instructions in accordance with which the compound aspects ofthis invention were prepared.
EXAMPLE I Ethyl 4-methyl-2-phenyl 6-(a,a,a-trifluoro-mtoluidino)-5-pyrimidinecarboxylate.
Reflux a mixture of ethyl 4-chloro-6-methyl-2 phenyl-S-pyrimidinecarboxylate (2.6 grams), a.a,a-trifluoro-m-toluidine (10 milliliters) and ethanol 15 milliliters) for 2 hours. Cool the reaction mixture, filter the precipitate and wash the product with water. Crystallize the product from ethanol to obtain 2.5 grams of the title compound which has a melting point of -123C.
Elemental Analysis: C H F N O Calculated: C. 62.84; H. 4.52; N. 10.47 Found: C. 62.93; H. 4.53. N. 10.52
EXAMPLE II Elemental Analysis: C H F N O Calculated: C. 61.13. H. 3. .N.
8 11.29 Found: C. 61.00; H. 3.88; 11.41
This carboxylic acid is a central nervous system depressant, demonstrating activity at a dosage level of 127 milligrams per kilogram body weight and above. The activity noted in mice, upon oral administration in accordance with Test Procedure No. 1, supra, decreased motor activity, sedation, decreased respiration and hyperemia. In addition, anti-inflammatory activity was observed in vivo and in vitro in accordance with the Test Procedures No. II, III at 0.09 millimolar concentration and V at 0.3 millimolar concentration supra.
EXAMPLE III 2-Phenyl-4-(2,3-xylidino)-5-pyrimidinecarboxylic acid and the ethyl ester thereof Following the technique of Example I react 2,3- xylidine and ethyl 4-chloro-2-pheny1-5- pyrimidinecarboxylate to yield the ethyl ester which is hydrolyzed to afford the free acid.
EXAMPLE 1V Ethyl 4-(N-ethyl-a,a,a-Trifluoro-m-to1uidino)-2- phenyl-S-pyrimidinecarboxylate Reflux a mixture of 5-carbethoxy-4-chloro-2- phenylpyrimidine (6.5 grams), N-ethyl-a.a,a-trifluorom-toluidine (5 grams), sodium carbonate (2.7 grams) and N.N-dimethyl formamide (45 milliliters) for 3.5 hours. Pour the reaction mixture into cold water to separate the product as an oil. Wash the oil several times with water and cool to cause solidification. Filter and wash with diethyl ether to obtain 4.0 grams of product which upon recrystallization from petroleum ether affords the title compound melting at 100102C.
Elemental Analysis: c n F n o Calculated: C, 63.61; H. 4.85; N, 10.12 Found: C, 63.27; H, 514; N, 10.22
The ester prepared in accordance with the preceding Example exhibited anti-inflammatory activity at a minimum concentration of 0.8 millimoles per liter in accordance with Test Procedure No. 111.
EXAMPLE V 4-(ethyl-0 1,a-trifluoro-metoluidine)-2-phenyl-5- pyrimidinecarboxylic acid Heat a mixture of the ethyl ester of Example IV (1.5
grams), 50 per cent aqueous dimethylsulfoxide (75 milliliters), 15 per cent aqueous sodium hydroxide solution (4.5 milliliters) and milliliters of dimethylsulfoxide on a steam bath for 6 hours. Allow the temperature of the mixture to fall to room temperature and acidify with 3N HCl to precipitate the free acid. Filter and wash with water to yield 1.4 grams of the title compound. An analytically pure compound melting at 180-l 82C. is obtained by recrystallization from aqueous ethanol.
Elemental Analysis: C H F N O Calculated: C, 62.01; H, 4.16; N, 10.80 Found: C, 61.59; H, 4.07; N, 10.85
The free acid prepared by the method presented in the preceding paragraph produced a central nervous system depressant effect when administered orally and intraperitoneally at doses as low as 127 milligrams per kilogram host body weight, to mice, as evidenced by decreased motor activity, decreased respiration mydriasis and hyperemia. Furthermore, the free acid produced an anti-inflammatory effect when tested in accordance with Procedures III at 0.03 millimolar minimal effect and V at 0.08 millimolar concentration.
EXAMPLE VI Elemental Analysis: C H N O Calculated: C, 63.77; H, 6.36; N, 13.95 Found: C, 63.65; H, 6.49; N, 13.99
The product of the preceding example produces central nervous system depressant effects on mice when administered orally at a concentration as low as 127 milligrams per kilogram host body weight as evidenced by hyperactivity to touch decreased motor activity, sedation and decreased respiration.
EXAMPLE Vll 4-(3-Hydroxypropylamino)-2-phenyl-5'- pyrimidinecarboxylic acid Reflux a mixture of the ethyl ester of Example VI (15 grams), 15 per cent aqueous NaOH solution (45 milliliters), and ethanol (10 milliliters) for 0.5 hour. Adjust the pH of the solution to about 2 by adding HCl, thereby precipitating the free acid. Filter and wash with water to obtain 8.0 grams of product having a melting point of 223225C. Further purification of the title compound by dissolving in base followed by acidification yields a product melting at 228230C.
Elemental Analysis: C, H, N -,O
Calculated: C. 61.53; H, 5.53; N. 15.38 Found: C, 61.33; H, 5.66; N. 15.61
4-(3-Hydroxypropylamino)-2-phenyl-5- pyrimidinecarboxylic acid produced central nervous system depressant effects in mice when oral doses as low as 127 milligrams per kilogram body weight are administered. The observed effects are decreased motor activity, sedation, decreased respiration, augmented flexor, reflex, mydriasis and hyperemia. In addition, the free acid produces an anti-inflammatory effect upon oral administration to rats in accordance with Test Procedure II.
EXAMPLE VIII 9,10-Dihydro-6a-methyl-2-phenyl-5H,6aH,8H- [1,3]oxazino[-2,3b]-pyrimido[4,5-d][1,3]oxazin-5-one Reflux a mixture of 4-(3-hydroxypropylamino)-2- phenyl-5-pyrimidinecarboxylic acid (3 grams) with acetic anhydride (40 milliliters) for about 30 minutes to obtain a clear solution. Remove the acetic anhydride in vacuo to leave a resinous material which crystallized from ethyl acetate after several washings with anhydrous diethyl ether to afford the title compound melting at l53155C.
Elemental Analysis: C H N o Calculated: C, 64.63; H, 509; N, 14.14 Found: C, 64.66; H, 5.06; N, 13.95
The lactone l,3-oxazino[2,3-b]pyrimido[4,5- d][1,3]-oxazin-5-one produces central nervous system depressant activity when administered intraperitoneally to mice in doses as low as 40 milligrams per kilogram body weight, as evidenced by decreased motor activity and decreased respiration.
EXAMPLE 1X 2-Phenyl-4-(a,a,a-trifluoro-m-toluidino)-5- pyrimidinemethanol.
Reduce 15.3 grams of ethyl 2-phenyl-4-(a,a,atrifluoro-m-toluidino)-5-pyrimidinecarboxylate with 1.6 grams of LiAlH; using tetrahydrofuran as the reaction solvent. After hours reaction time, the crude product weighed 13.8 grams. Crystallization from ethanol yielded an analytically pure sample melting at 174-177C.
Elemental Analysis: C,,,H,,F,N,0
Calculated: C. 62.61; H. 4.09; N, 12.17 Found: C, 62.61; H, 4.12; N, 12.10
The product of the preceding example produces central nervous system depressant effects in mice when administered intraperitoneally in doses as low as 40 milligrams per kilogram host body weight, evidenced by decreased motor activity, decreased respiration and ataxia at a dose as low as 400 milligrams per kilogram body weight.
EXAMPLE X 2-Phenyl-4-(2,3-xylidino)-5-pyrimidinemethanol Following the procedure of Example lX, reduce 13.5 grams of ethyl 2-phenyl-4-(2,3-xylidino)-5- pyrimidinecarboxylate with 2.0 grams of LiAll-L, in 250 milliliters of tetrahydrofuran to obtain 1 1 grams of the title compound which melts at l70l 74C. Recrystallization from ethanol yields the compound melting at l72l74.5C.
Elemental Analysis: C H N O Calculated: C. 74.73; H. Found: C. 74.49; H.
The product of Example X produces central nervous system depressant effects in mice when administered orally in doses as low as 400 milligrams per kilogram and intraperitoneally in doses as low as 127 milligrams per kilogram host body weight. Thus, the depressant effects are observed in hyperactivity to touch, decreased motor activity, ataxia, decreased respiration and ptosis.
EXAMPLE XI Elemental Analysis: C H F N O Calculated: C. 62.67; H. 3.53; N. I224 Found: C. 62.63; H. 3.42; N, ll.97
The product of Example X produces central nervous system depressant effects in mice at oral doses as low as 12.7 milligrams per kilogram host body weight, evidenced by decreased motor activity sedation and decreased respiration.
What is claimed is:
1. A compound of the formula:
in which R is -H or lower alkyl.
2. The compound of claim -1 which is 4-methyl-2- phenyl-6-(a,a,a-trifluoro-m-toluidino)-5- pyrimidinecarboxylic acid.
3. A compound of the formula 5 N CO2R CF C2H5 s in which R is -H or lower alkyl.
4. The compound of claim 3 which is 4-(N-ethyla,a,ot-trifluoro-m-toluidino)-2-phenyl-5- pyrimidinecarboxylic acid.
5. A compound of the formula:
N ECX in which X is -CH OH or -CHO; R is -H or alkyl of l to 7 carbon atoms; and R is -H, alkyl of l to 7 carbon atoms or perfluoroalkyl of 1 to 7 carbon atoms.
6. The compound of claim 5 which is 2-phenyl-4- (a,a,a-trifluoro-m-toluidino)-5-pyrimidinemethanol.
7. the compound of claim 5 which is 2-phenyl-4-(2,3-
xylidino)-5-pyrimidinemethanol.
8. The compound of claim 5 which is 2-phenyl-4- (a,a,a-trifluoro-m-toluidino)-5- pyrimidinecarboxaldehyde.

Claims (7)

  1. 2. The compound of claim 1 which is 4-methyl-2-phenyl-6-( Alpha , Alpha , Alpha -trifluoro-m-toluidino)-5-pyrimidinecarboxylic acid.
  2. 3. A compound of the formula
  3. 4. The compound of claim 3 which is 4-(N-ethyl- Alpha , Alpha , Alpha -trifluoro-m-toluidino)-2-phenyl-5-pyrimidinecarboxylic acid.
  4. 5. A compound of the formula:
  5. 6. The compound of claim 5 which is 2-phenyl-4-( Alpha , Alpha , Alpha -trifluoro-m-toluidino)-5-pyrimidinemethanol.
  6. 7. the compound of claim 5 which is 2-phenyl-4-(2,3-xylidino)-5-pyrimidinemethanol.
  7. 8. The compound of claim 5 which is 2-phenyl-4-( Alpha , Alpha , Alpha -trifluoro-m-toluidino)-5-pyrimidinecarboxaldehyde.
US285154A 1972-08-31 1972-08-31 2-aryl-4-substituted-amino-5-pyrimidyl derivatives Expired - Lifetime US3860596A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US285154A US3860596A (en) 1972-08-31 1972-08-31 2-aryl-4-substituted-amino-5-pyrimidyl derivatives

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US285154A US3860596A (en) 1972-08-31 1972-08-31 2-aryl-4-substituted-amino-5-pyrimidyl derivatives

Publications (1)

Publication Number Publication Date
US3860596A true US3860596A (en) 1975-01-14

Family

ID=23092977

Family Applications (1)

Application Number Title Priority Date Filing Date
US285154A Expired - Lifetime US3860596A (en) 1972-08-31 1972-08-31 2-aryl-4-substituted-amino-5-pyrimidyl derivatives

Country Status (1)

Country Link
US (1) US3860596A (en)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3979408A (en) * 1973-05-25 1976-09-07 Gruppo Lepetit S.P.A. 2-(Pyrrol-1-yl)amino-4,5-dihydro-1H-imidazole derivatives
EP0606011A1 (en) * 1992-12-28 1994-07-13 SHIONOGI SEIYAKU KABUSHIKI KAISHA trading under the name of SHIONOGI & CO. LTD. Aminopyrimidine derivatives and their production and use
US20050049247A1 (en) * 2003-07-02 2005-03-03 Wilson Dean Mitchell Pyrimidines useful as modulators of voltage-gated ion channels
US20070293464A1 (en) * 2003-11-10 2007-12-20 X-Ceptor Therapeutics, Inc. Substituted Pyrimidine Compositions and Methods of Use
EP1549316A4 (en) * 2002-09-10 2008-04-09 Scios Inc INHIBITORS OF TFGbeta
CN116496252A (en) * 2022-04-29 2023-07-28 江苏亚虹医药科技股份有限公司 Pyrimidine compound, preparation method and medical application thereof

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3563984A (en) * 1968-12-20 1971-02-16 American Home Prod Oxazolo(2,3-b)pyrimido(4,5-d)(1,3)oxazinones

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3563984A (en) * 1968-12-20 1971-02-16 American Home Prod Oxazolo(2,3-b)pyrimido(4,5-d)(1,3)oxazinones

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3979408A (en) * 1973-05-25 1976-09-07 Gruppo Lepetit S.P.A. 2-(Pyrrol-1-yl)amino-4,5-dihydro-1H-imidazole derivatives
EP0606011A1 (en) * 1992-12-28 1994-07-13 SHIONOGI SEIYAKU KABUSHIKI KAISHA trading under the name of SHIONOGI & CO. LTD. Aminopyrimidine derivatives and their production and use
US5439911A (en) * 1992-12-28 1995-08-08 Shionogi & Co., Ltd. Aminopyrimidine derivatives and their production and use
US5519139A (en) * 1992-12-28 1996-05-21 Shionogi & Co., Ltd. Aminopyrimidine derivatives and their production and use
EP1549316A4 (en) * 2002-09-10 2008-04-09 Scios Inc INHIBITORS OF TFGbeta
US20050049247A1 (en) * 2003-07-02 2005-03-03 Wilson Dean Mitchell Pyrimidines useful as modulators of voltage-gated ion channels
US7816529B2 (en) 2003-07-02 2010-10-19 Vertex Pharmaceuticals Incorporated Pyrimidines useful as modulators of voltage-gated ion channels
US20110003814A1 (en) * 2003-07-02 2011-01-06 Vertex Pharmaceuticals Incorporated Pyrimidines useful as modulators of voltage-gated ion channels
US8324220B2 (en) 2003-07-02 2012-12-04 Vertex Pharmaceuticals Incorporated Pyrimidines useful as modulators of voltage-gated ion channels
US20070293464A1 (en) * 2003-11-10 2007-12-20 X-Ceptor Therapeutics, Inc. Substituted Pyrimidine Compositions and Methods of Use
US8455489B2 (en) * 2003-11-10 2013-06-04 Exelixis, Inc. Substituted pyrimidine compositions and methods of use
CN116496252A (en) * 2022-04-29 2023-07-28 江苏亚虹医药科技股份有限公司 Pyrimidine compound, preparation method and medical application thereof

Similar Documents

Publication Publication Date Title
KR102746900B1 (en) Tetrahydropyranyl amino-pyrrolopyrimidinone and methods of use thereof
US4886807A (en) Novel pyrimidopyrimidine derivative, process for producing it and pharmaceutical composition
JP2004520285A (en) New lactam-substituted pyrazolopyridine derivatives
US10933065B2 (en) Tetrahydropyranyl amino-pyrrolopyrimidinone and methods of use thereof
ES2730942T3 (en) Triazolopyridine derivatives as modulators of TNF activity
CA2760766A1 (en) Novel pyrimidine derivatives and their use in the treatment of cancer and further diseases
EP0617020A1 (en) Carboxylic acid derivatives having retinoic acid-like activity
NZ236385A (en) Pyrrolo (2,3-d) pyrimidinylethyl substituted glutamic acid derivatives, preparatory processes and pharmaceutical compositions thereof
ES2743190T3 (en) Imidazotizol derivatives as modulators of TNF activity
US4349549A (en) Anti-hypertensive 1-substituted spiro(piperidine-oxobenzoxazine)s
WO2022060951A1 (en) Compositions for modulating splicing
US3860596A (en) 2-aryl-4-substituted-amino-5-pyrimidyl derivatives
EP0335979A1 (en) Thienopyrimidine derivatives
WO2022084741A1 (en) Cftr modulator compounds, compositions, and uses thereof
EP0102175A1 (en) 5-Oxo-5H-(1)benzopyrano(2,3-b)pyridine derivatives, their production and use
EP0244352B1 (en) Pyrido[4,3-d]pyrimidine derivatives
US3816423A (en) 2-aryl-4-amino-5-cyano pyrimidine derivatives
US3575979A (en) 7-alkyl - 5 - methoxy - 7h-pyrrolo(2,3-d) pyrimidine-6-carboxamides and related compounds
RU2747991C1 (en) Tetrahydropyranyl amino-pyrrolopyrimidinone and methods of its use
US3835144A (en) Amino derivatives of (4,3-c pyrazolopyridine cabroxylic acids and esters
US3563984A (en) Oxazolo(2,3-b)pyrimido(4,5-d)(1,3)oxazinones
US4010159A (en) Pyrrolo[3,4-d]pyrimidines and methods for their preparation
US4070362A (en) Amino derivatives of triazolo(4,5-B)pyridines
CN115925718A (en) A tetracyclic lactam derivative and its application
HK40059782B (en) Tetrahydropyranyl amino-pyrrolopyrimidinone for use in treating btk-mediated disorders