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WO1992012979A1 - ACIDES ACETIQUES 2,4-DIOXO-PYRIDO [2,3-d] PYRIMIDINE-3- AINSI QUE LEURS ESTERS ET LEURS SELS - Google Patents

ACIDES ACETIQUES 2,4-DIOXO-PYRIDO [2,3-d] PYRIMIDINE-3- AINSI QUE LEURS ESTERS ET LEURS SELS Download PDF

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Publication number
WO1992012979A1
WO1992012979A1 PCT/US1991/007943 US9107943W WO9212979A1 WO 1992012979 A1 WO1992012979 A1 WO 1992012979A1 US 9107943 W US9107943 W US 9107943W WO 9212979 A1 WO9212979 A1 WO 9212979A1
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WO
WIPO (PCT)
Prior art keywords
compound
alkyl
chlorine
trifluoromethyl
hydrogen
Prior art date
Application number
PCT/US1991/007943
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English (en)
Inventor
Harry R. Howard
Original Assignee
Pfizer Inc.
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 Pfizer Inc. filed Critical Pfizer Inc.
Publication of WO1992012979A1 publication Critical patent/WO1992012979A1/fr
Priority to FI933244A priority Critical patent/FI933244L/fi

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • This invention relates to 2,4-dioxo-pyrido[2,3- d]pyrimidine-3-acetic acids.
  • the compounds are useful for the control of certain chronic complications arising from diabetes mellitus (e.g., diabetic cataracts, retinopathy and neuropathy .
  • the present invention also relates to pharmaceutical compositions comprising such compounds and to the use of such compounds in treating complications arising from diabetes mellitus.
  • Past attempts to obtain new and better oral antidiabetic agents have, for the most part, involved an endeavor to synthesize new compounds that lower blood sugar levels.
  • K. Sestanj et al. in U.S. Patent No. 3,821,383 disclose that certain aldose reductase inhibitors like l,3-dioxo-lH-benz[d,e]isoquinoline-2(3H)- acetic acid and some closely-related derivatives thereof are useful for these purposes even though they are not known to be hypoglycemic.
  • aldose reductase which is primarily responsible for catalyzing the reduction of aldoses (like glucose and galactose) to the corresponding polyols (such as sorbitol and galactitol) in the human body.
  • aldose reductase primarily responsible for catalyzing the reduction of aldoses (like glucose and galactose) to the corresponding polyols (such as sorbitol and galactitol) in the human body.
  • polyols such as sorbitol and galactitol
  • these compounds control certain chronic diabetic complications, including those of an ocular nature, since it is already known in the art that the presence of polyols in the lens of the eye leads to cataract formation and concomitant loss of lens clarity.
  • 1,2,3,4-tetrahydro-2,4-dioxo-3-quinazoline-alkanoic acids and their use as plant growth regulators, fungicides and anti-allergenic agents are described by Akademie derticianen der DDR in Ger. (East) DD 250,118.
  • the present invention relates to compounds of the formula
  • X is hydrogen, fluorine, chlorine, bromine, trifluoromethyl, Cj-Q, alkyl, C 1 -C 4 alkoxy or C ⁇ C 4 alkylthio;
  • Q is a divalent alkylene radical having from one to three carbon atoms; and R 1 is phenyl, thiazolophenyl, trifluoromethyl- thiazolophenyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, phenyloxadiazolyl, thiazolopyridinyl, oxazolopyridinyl, imidazopyridinyl, triazolopyridinyl or indolyl, wherein said phenyl, benzothiophenyl, benzoxazolyl, benzothiazolyl and phenyloxadiozolyl groups are each optionally substituted with up to two identical or non- identical substituents on the benzene ring, said identical substituents being
  • R 2 is hydrogen or C,-C 6 alkyl; and the pharmaceutically acceptable base addition salts thereof.
  • R 1 is phenyl or benzothiazol-2-yl or a ring-substituted derivative of phenyl or benzothiazol-2-yl. More preferably, R 1 is 3,4- dichlorophenyl or 4-bromo-2-fluorophenyl.
  • Preferred compounds of the invention are:
  • the present invention also relates to a pharmaceutical composition for the treatment of chronic complications associated with diabetes comprising a compound of the formula I or a pharmaceutically acceptable base addition salt thereof in an amount effective to prevent or alleviate such chronic complications and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for the treatment of chronic complications associated with diabetes comprising a compound of the formula I or a pharmaceutically acceptable base addition salt thereof in an amount effective to prevent or alleviate such chronic complications and a pharmaceutically acceptable carrier.
  • Specific and preferred compositions of the present invention comprise the foregoing specific and preferred compounds.
  • the present invention also relates to a method for treating a diabetic subject to prevent or alleviate chronic complications arising in said subject, which comprises administering to said diabetic subject an amount of a compound of the formula I or a pharmaceutically acceptable base addition salt thereof effective to prevent or alleviate such complications.
  • the present invention also relates to compounds of the following formulae IV, V and VI:
  • an appropriately substituted carboxylic acid ester of formula VI is converted by means of a suitable reagent or reagents into the title compounds of formula I.
  • a suitable reagent or reagents which may be useful for this transformation are those which are often employed by those skilled in the art for converting carboxylic acid esters to the corresponding carboxylic acids and may include sodium or potassium hydroxides, hydrochloric acid, trifluoroacetic acid and the like.
  • These reagents may be used in the presence or absence of a reaction-inert solvent such as water, lower alcohol, lower ether or cyclic ether, or an organic acid (such as acetic acid) .
  • a solution of sodium hydroxide in water is preferred for this step.
  • these reactions may be carried out at a temperature that is in the range of about 0°C up to the boiling point of the solvent employed, and is preferably conducted in the range of about 20°C to about 40°C.
  • Isolation of the desired products of formula I may be effected by adjusting the pH of the reaction mixture to within the range of about 1 to about 7, followed by filtration of the precipitated acidic product I or by extraction of the crude product into a water-immiscible solvent which may be subsequently dried and evaporated to obtain product acid I. Further purification may then be accomplished by crystallization/recrystallization of the crude product I from a suitable solvent system or by chromatographic methods.
  • the intermediates of formula V which possess a removable hydrogen atom at the 1-position of the pyrido[2,3-d]pyrimidineacetate may be alkylated with a variety of activated arylalkyl or heteroarylalkyl compounds of general formula Z-Q-R 1 , where Q and R 1 are as previously defined and Z is a leaving group such as halogen or lower alkane-sulfonate.
  • This particular reaction is normally carried out in the presence of a base condensing agent, such as an alkali metal hydride, alkanoate or amide, or an alkali metal-alky1 or metal-aryl compound, as the case may be.
  • reaction is usually conducted in a reaction-inert organic solvent, preferably using N,N-di- (lower alkyl) lower alkanoamide for the best results; preferred agents in this connection would include sodium hydride as the base condensing agent and N,N- dimethylformamide as the solvent.
  • a reaction-inert organic solvent preferably using N,N-di- (lower alkyl) lower alkanoamide for the best results; preferred agents in this connection would include sodium hydride as the base condensing agent and N,N- dimethylformamide as the solvent.
  • substantially equimolar quantities of the reactants are employed.
  • the preferred temperature range is from about 0°C up to about the boiling point of the solvent employed for a period of about 0.5 hours to about 48 hours.
  • the reaction is usually conducted at room temperature for a period of time which is often less than 24 hours.
  • reaction may be conducted at pressures up to 5 atmospheres, in practice it is adequate to perform this step at atmospheric pressure, usually under an inert atmosphere such as nitrogen or argon gas and with suitable exclusion of moisture which could decrease the yield of intermediate product VI.
  • an inert atmosphere such as nitrogen or argon gas
  • the desired N-l substituted esters of formula VI are recovered from the reaction mixture by the use of any number of standard techniques known to those skilled in the art.
  • reaction mixture is first diluted with water and the crude reaction product is then filtered (in the case of a precipitated solid product) or extracted into a suitable, water-immiscible solvent from which the crude intermediate of formula VI may be isolated by evaporation of the solvent to dryness. Further purification of these compounds may best be accomplished as in the case of the final acid products of formula I, i.e., by crystallization /recrystallization from a suitable solvent system, or by chromatography of the crude reaction product.
  • N-l unsubstituted esters of formula V are themselves novel compounds and they may be prepared by one of several methods reported in the scientific literature. For example, E. Papadopoulos (Journal of Heterocvclic Chemistry. 1981, vol. 18, 515) has described a procedure for the conversion of a ureido ester into a 2,4- quinazolinedione-3-acetic acid by treating the former with concentrated ammonium hydroxide in ethanol at 25°C. In the examples described within the present invention, the novel ureido esters of formula IV are similarly best converted to the compounds of formula V by the action of concentrated ammonium hydroxide in ethanol at 50°C.
  • ureido esters of formula IV are prepared by the condensation of the appropriate methyl nicotinate III with an ester of isocyanoacetic acid, this condensation taking place with equimolar amounts of the two components in the presence or absence of a reaction-inert solvent.
  • the compounds of formula III, the starting materials for the preparation of the ureido esters of formula IV are either commercially available or are readily prepared using methods and procedures found in the scientific literature.
  • Esters of the general structural type VI may be isolated prior to conversion to the acids of structure I. In instances when a different ester is desired, the acid I may be esterified using any variety of procedures known to those skilled in the art of organic chemistry.
  • the acid I may be suspended in the appropriate C,-C 6 alcohol and treated with a suitable inorganic acid (e.g., hydrochloric acid or sulfuric acid) and then stirred under an inert atmosphere with the exclusion of moisture at a temperature within the range of room temperature to about the boiling point of the alcohol employed.
  • a suitable inorganic acid e.g., hydrochloric acid or sulfuric acid
  • the crude ester VI so obtained may be isolated by removal of the solvent alcohol and purification by recrystallization, chromatography, distillation or other suitable technique.
  • the chemical bases which are used in this invention to prepare the aforementioned pharmaceutically acceptable base addition salts are those which form non-toxic base salts with the herein described 1-substituted 2,4-dioxo- pyrido[2,3-d]pyrimidine-3-acetic acids, such as l-(4-bromo- 2-flurophenylmethyl)-6-chloro-l,4-dihydro-2,4-dioxo-3(2H)- pyrido[2,3-d]pyrimidineacetic acid.
  • These particular non- toxic base salts include those derived from such pharmacologically acceptable cations as sodium, potassium, calcium, magnesium, etc.
  • salts can be easily prepared by treating the aforementioned acid compounds with an aqueous solution of the pharmacologically acceptable cation and then evaporating the resulting solution to dryness, preferably under reduced pressure.
  • they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as above. In either case, stoichiometric quantities of the reagents must be employed to ensure completeness of the reaction and maximum production of yields of the desired final base addition salts.
  • salts of the title compounds may be prepared using pharmacologically acceptable organic bases to form the salts, these organic bases including compounds such as diethanolamine, meglumine, cyclohexylamine, dicyclo- hexylamine and the like.
  • the salts derived from these organic bases may be prepared by combining the two reagents in essentially equimolar amounts in a suitable solvent from which the derived base addition salt can be isolated by virtue of its reduced solubility in the solvent system, or by concentration of the solvent system to dryness followed by crystallization/recrystallization of the crude salt in a suitable solvent system.
  • the starting materials required for preparing the compounds of formula I are either known compounds which are readily available commercially or they are described in the literature or else they can easily be synthesized by those skilled in the art starting from common chemical reagents and using conventional methods of organic synthesis.
  • 2-aminonicotinic acid is readily prepared from the known 2-aminonicotinonitrile (Beilstein, 22., 542).
  • the compounds of the formula I and the pharmaceutically acceptable salts thereof are readily adapted to therapeutic use as aldose reductase inhibitors for the control of certain chronic diabetic complications, in view of their ability to reduce lens and peripheral nerve (e.g., the sciatic nerve) sorbitol levels in diabetic subjects.
  • the active compounds of the present invention can be administered to affected mammals (including humans) by either the oral, topical or parenteral routes of administration. In general, these compounds are ordinarily administered in dosages ranging from about 0.50 mg to about 50 mg per kg of body weight per day, although variations will necessarily occur depending upon the weight and condition of the subject being treated and the particular route of administration chosen.
  • the active compounds of this invention can be administered in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically-acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, aqueous suspensions, injectable solutions, elixirs, syrups, and the like.
  • Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents.
  • the active compounds of the invention will be present in such dosage forms at concentration levels ranging from about 0.5% to about 90% by weight of the total composition to provide the desired unit dosage.
  • tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate may be employed along with various disintegrants such as starch and preferably potato or tapioca starch, alginic acid and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, gelatin and acacia.
  • disintegrants such as starch and preferably potato or tapioca starch, alginic acid and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, gelatin and acacia.
  • lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules; preferred materials in this connection also include the high molecular weight polyethylene glycols.
  • the essential active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes, and if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof.
  • solutions of the active compounds of the present invention may be prepared, taking into account the solubility of the compound or salt to be utilized.
  • solutions in sesame or peanut oil or in aqueous propylene glycol or N,N-dimethyIformamide as well as sterile aqueous solutions may be employed.
  • Such aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • sterile aqueous media employed are all readily obtainable by standard techniques well-known to those skilled in the art.
  • the utility of the compounds of the present invention may be predicted by measuring their ability to (1) inhibit the enzyme activity of isolated aldose reductase; (2) reduce or inhibit sorbitol accumulation in the sciatic nerve and lens of acutely streptozotocinized (i.e. diabetic) rats; (3) reverse already-elevated sorbitol levels in the sciatic nerve and/or lens of chronic streptozotocin-induced diabetic rats; (4) prevent or inhibit galactitol formation in the lens of acutely galactosemic rats, and/or (5) delay cataract formation and reduce the severity of lens opacities in chronic galactosemic rats.
  • Methyl 2-amino-5-chloronicotinate A mixture of 6.2 g (36 mmol) of the title compound of Example 1A and 70 ml methanol was treated with HC1 gas for 2 hours, refluxed for 16 hours (a homogeneous solution resulted) and then treated with HC1 gas for an additional 2 hours. TLC (90 CHC1 3 :10 methanol) then showed completion of reaction (RF 0.70 vs 0.10 for the title compound of Example 1A) . The solvent was removed in vacuo, the solids were washed with 5% NaHC0 3 , and then with water, and were then dried overnight under vacuum to yield the title compound, 6.21 g (93%), m.p. 260-263°C, m/e: 186 (p + ) , 188.
  • Example 4 The compounds of Examples 2 and 3 were tested for their ability to reduce or inhibit aldose reductase enzyme activity via the procedure of S. Hayman et al. , as described in the Journal of Biological Chemistry. Vol. 240, p.877 (1965) and as modified by K. Sestanj et al. in U.S. Patent No. 3,821,383. In each case, the substrate employed was partially purified aldose reductase enzyme obtained from human placenta. At a concentration of 10" the compounds showed a percent inhibition greater than 70%.
  • Example 5 The compounds of Examples 2 and 3 were tested for their ability to reduce or inhibit sorbitol accumulation in the sciatic nerve and lens of streptozotocinized (i.e., diabetic) rats by the procedure described in U.S. Patent No. 3,821,383. In the present study, the amount of sorbitol accumulation in the sciatic nerve and lens of each test animal was measured 27 hours after the induction of diabetes. The compounds were the administered orally at 25 mg/kg at intervals of 4, 8 and 24 hours after the administration of streptozotocin.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Diabetes (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)

Abstract

Cette invention concerne une série de nouveaux acides acétiques 2,4-dioxo-pyrido 2,3-d pyrimidine-3- ainsi que leurs esters et leurs sels d'addition basiques pharmaceutiquement acceptables. Ces composés sont utiles dans le domaine de la thérapie en tant qu'inhibiteurs de l'aldose réductase, afin de maîtriser certaines complications chroniques du diabète sucré. Sont également présentés des procédés permettant de préparer ces composés à partir de substances de départ déjà connues.
PCT/US1991/007943 1991-01-17 1991-11-05 ACIDES ACETIQUES 2,4-DIOXO-PYRIDO [2,3-d] PYRIMIDINE-3- AINSI QUE LEURS ESTERS ET LEURS SELS WO1992012979A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
FI933244A FI933244L (fi) 1991-01-17 1993-07-16 2,4-dioxopyrido(2,3-d)pyrimidin-3-aettikssyror samt deras estrar och salter

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US64260091A 1991-01-17 1991-01-17
US642,600 1991-01-17

Publications (1)

Publication Number Publication Date
WO1992012979A1 true WO1992012979A1 (fr) 1992-08-06

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PCT/US1991/007943 WO1992012979A1 (fr) 1991-01-17 1991-11-05 ACIDES ACETIQUES 2,4-DIOXO-PYRIDO [2,3-d] PYRIMIDINE-3- AINSI QUE LEURS ESTERS ET LEURS SELS

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EP (1) EP0568540A1 (fr)
JP (1) JPH05509108A (fr)
CA (1) CA2100164A1 (fr)
FI (1) FI933244L (fr)
IE (1) IE920120A1 (fr)
PT (1) PT100013A (fr)
WO (1) WO1992012979A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5654309A (en) * 1992-12-29 1997-08-05 Takeda Chemical Industries, Ltd. Pyridopyrimidine derivatives, their production and use
CN104725376A (zh) * 2015-03-31 2015-06-24 山东友帮生化科技有限公司 6-氯-8-羧基咪唑并[1,2-a]吡啶的合成方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1401549A (en) * 1972-07-07 1975-07-16 Hisamitsu Pharmaceutical Co Pyrido-2,3-d-pyrimidine-2,4-1h,3h- diones and methods of preparing them

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1401549A (en) * 1972-07-07 1975-07-16 Hisamitsu Pharmaceutical Co Pyrido-2,3-d-pyrimidine-2,4-1h,3h- diones and methods of preparing them

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Chemical Abstracts, vol. 114, 1991, (Columbus, Ohio, US), see page 756, abstract no. 102035e, & JP,A,02225485 (TAIHO PHARMACEUTICAL CO., LTD) 7 September 1990, see abstract *
European Journal of Medicinal Chemistry, vol. 25, 1990 (Paris, FR), F. BILLON et al.: "Aldose reductase inhibition by 2,4-oxo and thioxo derivatives of 1,2,3,4-tetrahydroquinazoline", pages 121-126, see page 123, compound V9 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5654309A (en) * 1992-12-29 1997-08-05 Takeda Chemical Industries, Ltd. Pyridopyrimidine derivatives, their production and use
CN104725376A (zh) * 2015-03-31 2015-06-24 山东友帮生化科技有限公司 6-氯-8-羧基咪唑并[1,2-a]吡啶的合成方法

Also Published As

Publication number Publication date
CA2100164A1 (fr) 1992-07-18
FI933244A0 (fi) 1993-07-16
IE920120A1 (en) 1992-07-29
JPH05509108A (ja) 1993-12-16
FI933244L (fi) 1993-07-16
PT100013A (pt) 1993-01-29
EP0568540A1 (fr) 1993-11-10

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