WO1994026721A1 - Derive de pyrimidine et composition pharmaceutique - Google Patents

Derive de pyrimidine et composition pharmaceutique Download PDF

Info

Publication number
WO1994026721A1
WO1994026721A1 PCT/JP1994/000764 JP9400764W WO9426721A1 WO 1994026721 A1 WO1994026721 A1 WO 1994026721A1 JP 9400764 W JP9400764 W JP 9400764W WO 9426721 A1 WO9426721 A1 WO 9426721A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
general formula
tetrazolyl
carbon atoms
integer
Prior art date
Application number
PCT/JP1994/000764
Other languages
English (en)
Japanese (ja)
Inventor
Torataro Minegishi
Akihiro Ohkubo
Izumi Shimoyama
Hideki Nagano
Shigeo Iida
Hiroaki Sato
Yoshiko Shirakami
Tadashi Mizuta
Original Assignee
Nkk Corporation
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 Nkk Corporation filed Critical Nkk Corporation
Priority to DE4493151T priority Critical patent/DE4493151T1/de
Publication of WO1994026721A1 publication Critical patent/WO1994026721A1/fr
Priority to GB9500538A priority patent/GB2284419A/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings

Definitions

  • the present invention relates to a novel pyrimidine derivative and a pharmaceutical composition containing the pyrimidine derivative as an active ingredient, particularly to an angiotensin II antagonist. Since the novel pyrimidine derivative according to the present invention has angiotensin II antagonistic activity, it is useful for various circulatory diseases, such as hypertension, heart disease, stroke or arteriosclerosis.
  • the renin-angiotensin system is known as a major pressor factor in living organisms. That is, active renin (proteolytic enzyme) secreted from the kidney specifically acts on a renin substrate (angiotensinogen) produced in the liver to produce angiotensin I (AI). This AI is converted to angiotensin II (All) by angiotensin-converting enzyme (ACE) produced in the lung, and it is thought that this All exhibits strong pressor activity. Therefore, the antagonist of ⁇ can be used for treating cardiovascular diseases such as hypertension caused by ⁇ .
  • pyrimidine derivatives are also described in EP-0407342, JP-A-3-133964, JP-A-3-197466, JP-A-4-120072, JP-A-4-230370 and JP-A-4-1261. And JP-A-4-330073 and EP-0445811.
  • the present invention provides a compound of the general formula (I):
  • R 1 and R 2 may be the same or different and each represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a lower alkoxy group, a lower alkylthio group, a halogen atom, a phenyl group, or R 3 and R 4 may be the same or different, and each represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom, a nitro group, a sulfone group, a carboxyl group, or a lower group.
  • X is indicates 0, NH or S (0) P, p is an integer of 0 to 2, m is an integer of 1-2)
  • B is a carboxyl group, a lower alkoxycarbonyl group, a tetrazolyl group, or a protected tetrazolyl group, and n is an integer of 1-2.
  • the present invention may be referred to as the compound (I) of the present invention] or a salt thereof.
  • the present invention provides a pharmaceutical composition, particularly an angiotensin, comprising a pyrimidine derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient. It also relates to the agent.
  • a lower alkyl group means, for example, a linear or branched alkyl group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, and an isobutyl group.
  • the lower alkenyl group means, for example, a linear or branched alkenyl group having 2 to 6 (particularly 2 to 4) carbon atoms, such as a vinyl group, an aryl group, a 1-propenyl group and an isopropyl group.
  • lower alkynyl group examples include a linear or branched alkynyl group having 2 to 6 (particularly 2 to 4) carbon atoms, such as an ethynyl group, 1-propynyl group, 2-propynyl group,
  • Examples include a 1-hexynyl group, a 2-hexynyl group, a 3-hexynyl group, a 4-hexynyl group, and a 5-hexynyl group.
  • the lower alkoxy group for example, a linear or branched alkoxy group having 1 to 6 (particularly 1 to 4) carbon atoms, for example, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group Groups, isobutoxy group, t-butoxy group, n-pentyloxy group, n-hexanoxy group and the like.
  • the lower alkylthio group include linear or branched alkylthio groups having 1 to 6 (particularly 1 to 4) carbon atoms, such as methylthio, ethylthio, n-propylthio, isopropylthio, and n-butyl.
  • Examples include a tylthio group, an isobutylthio group, a sec-butylthio group, a t-butylthio group, an n-pentylthio group, and an n-hexylthio group.
  • Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • Examples of the substituent of the substituted phenyl group include a lower alkyl group having 1 to 6 (particularly 1 to 4) carbon atoms, a lower alkoxy group having 1 to 6 (particularly 1 to 4) carbon atoms, a halogen atom, and a nitro group.
  • an alkoxycarbonyl group having 2 to 6 (particularly 2 to 4) carbon atoms for example, a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, an isopropoxycarbonyl group, an n-butoxy group
  • Examples include a rubonyl group, an isobutoxycarbonyl group, a sec-butoxycarbonyl group, a t-butoxycarbonyl group, and an n-pentyloxycarbonyl group.
  • Examples of the cycloalkoxycarbonyloxyalkoxycarbonyl group include a cycloalkoxycarbonyloxyalkoxycarbonyl group having a cycloalkoxy portion having 5 to 7 carbon atoms and an alkoxy portion having 1 to 2 carbon atoms, for example, 1- (cyclo Hexyloxycarbonyloxy) ethoxycarbonyl group and the like.
  • Low Al Examples of the canyloxyalkoxycarbonyl group include a lower alkanoloxyalkoxycarbonyl group in which the lower alkanoyl moiety has 2 to 6 carbon atoms, such as a bivaloyloxymethoxycarbonyl group.
  • Examples of the protecting group for the protected tetrazolyl group include a trityl group, a p-nitrobenzyl group, a 1-ethoxyshetyl group, and a t-butoxycarbonyl group.
  • a nitrogen-containing heterocyclic ring for example, a triazole ring, an imidazole ring, a pyrrolyl ring , A pyridine ring, a pyrimidine ring, a pyrazine ring, and the like, and a condensed ring thereof is formed by a protecting group such as a trityl group, a p-nitrobenzyl group, a 1-ethoxyshethyl group, and a t-butoxycarbonyl group. It may be substituted.
  • R 1 represents a hydrogen atom, a lower alkyl group having 1 to 6 carbon atoms or a phenyl group
  • R 2 represents a lower alkyl group having 1 to 4 carbon atoms
  • R 3 represents a hydrogen atom
  • R 4 represents a lower alkyl group having 1 to 2 carbon atoms, a lower alkoxy group having 1 to 2 carbon atoms, a halogen atom, a nitro group, a carboxyl group, and a lower alkoxy moiety having 1 carbon atom.
  • Noi Ruo alkoxyalkoxy group or tetrazolyl group is 1-2 carbon atoms, together with the ring carbon atom to which R 3 and R 4 which are attached X is 0, m is 1,
  • B is a carboxyl group, and the lower alkoxy moiety is a carbon atom having 1 to 2 carbon atoms.
  • a lower alkoxycarbonyl group, a tetrazolyl group, or a protected tetrazolyl group, and n is 1 is preferable.
  • R 1 represents a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an n-butyl group, an n-pentyl group or a phenyl group
  • 2 represents a methyl group, ethyl group, n-propyl group or II-butyl group
  • R 3 represents a hydrogen atom
  • R 4 represents a methyl group, a methoxy group, a chlorine atom, a nitro group, a carboxyl group, a methoxy group.
  • a carbonyl group, a cyclohexyloxycarbonyloxyethoxycarbonyl group, a pivaloyloxymethoxycarbonyl group or a tetrazolyl group, or R 3 and R 4 are taken together with the ring carbon atom to which they are bonded.
  • Condensed 1, 2, 3-tria Forming a condensed 1,2,3-triazolyl ring substituted with a sol ring or a trityl group, X represents 0, m represents 1, B represents a carboxyl group, a methoxycarbonyl group, Compounds that represent a tetrazolyl group or a trityltetrazolyl group, and n represents 1 are more preferred.
  • Examples of the salt of the compound (I) of the present invention include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, and organic amines such as methylamine salt, ethylamine salt, triethylamine salt and pyridine salt. Salts, basic amino acid salts such as lysine and arginine, and ammonium salts.
  • the compound (I) of the present invention may have a geometric isomer, an optical isomer or a tautomer, and any single isomer thereof or any mixture thereof is also included in the present invention. Is done.
  • the compound (I) of the present invention can be prepared, for example, by the following method. That is, the general formula ( ⁇ )
  • the compound of the present invention (I) is obtained by reacting the compound represented by the formula with a base.
  • Bases that can be used in the reaction include alkali metal compounds such as sodium hydroxide, potassium hydroxide, sodium hydride, sodium methoxide, sodium ethoxide, potassium t-butoxide, sodium carbonate, potassium carbonate, and sodium hydrogen carbonate.
  • Alkali metal carbonates such as thorium and potassium hydrogen carbonate, triethylamine, Organic amines such as isopropylethylamine, pyridine and N, N-dimethylaminopyridine.
  • Any solvent may be used as long as it does not take part in the reaction.
  • organic solvents such as N, N-dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone, dioxane, tetrahydrofuran, acetone, alcohol, or a mixture of these solvents
  • a mixed solvent with water is exemplified.
  • the reaction temperature is in the range of 120 to 200 ° C, preferably 0 to 100 ° C, and the reaction is usually completed in 1 to 48 hours.
  • the compound (I) of the present invention has the general formula (IV)
  • R 1 R 2 , R 3 , R 4 and m have the same meaning as described above, and Z is a halogen atom
  • V is a hydroxyl group, an amino group, or a sulfhydryl group.
  • Compound (I) of the present invention can be obtained by reacting the compound represented by the above formula in the same manner as described above.
  • Compound (I) of the present invention having a carboxyl group as a substituent can also be produced by hydrolyzing compound (I) of the present invention having a corresponding lower alkoxycarbonyl group in the presence of an acid or a base.
  • Acids used in this reaction include hydrochloric acid and sulfuric acid, and bases include sodium hydroxide and potassium hydroxide.
  • As the solvent a mixed solvent of water and an alcohol (eg, methanol, ethanol, etc.) is preferable, and usually completes in a temperature range from room temperature to reflux under 10 minutes to 10 hours.
  • the compound (I) of the present invention having a lower alkoxycarbonyl group as a substituent can also be produced by esterifying the compound (I) of the present invention having a corresponding carboxyl group in the presence of an acid.
  • Acids used in this reaction include hydrochloric acid, sulfuric acid, Arylsulfonic acid and the like.
  • the reaction is usually carried out using the alcohol to be reacted, for example, methanol, ethanol, propanol, butanol, etc.
  • Compound (I) of the present invention having a tetrazolyl group as a substituent can also be produced by removing the protective group of compound (I) of the present invention having a corresponding protected tetrazolyl group, Further, it can be produced by reacting the corresponding cyano compound with various azides.
  • the compound of the present invention (I) having a sulfoxide group or a sulfone group as a substituent can also be produced by oxidizing the compound of the present invention (I) having a corresponding sulfido group.
  • the oxidizing agent used for this reaction include hydrogen peroxide, peracetic acid, trifluoroperoxy acid, metabenzo-perbenzoic acid, and manganese diacid.
  • the solvent include methylene chloride, chloroform, benzene, methanol, ethanol, formic acid, acetic acid, water or a mixture thereof.
  • TC ⁇ P at a temperature of 40 to 60 ° C for 5 minutes to 6 hours "5.
  • the compound (I) of the present invention has excellent angiotensin ⁇ ⁇ antagonist activity and high safety, it can be used as a pharmaceutical composition, particularly as an angiotensin ⁇ antagonist for the treatment of various cardiovascular diseases.
  • the circulatory system disease include hypertension, heart disease, stroke and arterial sclerosis, and are also useful as a therapeutic agent for ocular hypertension.
  • compositions containing the compound (I) of the present invention or a pharmacologically acceptable salt thereof as an active ingredient, particularly an angiotensin II antagonist, are orally or parenterally administered (for example, intramuscular injection, intravenous injection). , Subcutaneous injection, rectal administration, transdermal administration, etc.) and pharmaceutically acceptable adjuvants, and tablets, capsules, granules, powders, pills, fine granules, injections, Enteral preparations, suppositories and the like can be used.
  • auxiliaries include excipients, binders, disintegrants, lubricants, buffers, preservatives, solubilizers, preservatives, flavoring agents, soothing agents, stabilizers, coloring agents These can be used in an appropriate combination according to a conventional method.
  • Excipients include lactose, sucrose, glucose, sorbitol, corn starch, crystal cells Loose, etc .; Binders: cellulose derivatives, gum arabic, gelatin, polyvinyl alcohol, polyvinyl ether, etc .; Disintegrators: carboxymethyl cellulose calcium, etc .; Lubricants: talc, magnesium stearate, polyethylene glycol Preservatives include methyl paraoxybenzoate, paraethyl benzoate, sorbic acid, phenol, cresol, chlorocresol, etc., and dissolution aids include polyoxyethylene coconut oil castor oil and polysorbate 80.
  • Nicotinic acid amide polyoxyethylene sorbitan monolaurate, maglogol, etc .
  • flavoring agents such as cocoa powder, coconut oil, and cinnamon powder
  • stabilizing agents such as sodium sulfite and metasulfite.
  • Sodium d
  • the dose required for angiotensin ⁇ antagonistic action varies depending on age, body weight, gender, symptoms, administration method, administration period, therapeutic effect, etc.For oral administration, usually 1 to 100 mg per adult per day It is preferably 5 to 200 mg, which is usually administered in 1 to 3 divided doses.
  • Reference Examples 2 to 42 were prepared according to the method of Reference Example 1.
  • Reference Example 2 2-ethyl-1-5- (4-methoxycarboxy-benzyl) -6-methylbilimidine-1-4 (3H) -one [Yield: 56%.
  • i-% i ⁇ m) z% 'L ⁇ )% LL-% VL ⁇ m) Z'L- ⁇ VL i ⁇
  • ⁇ 8 ⁇ ' ⁇ :) 6 ⁇ / (' ⁇ ⁇ £ 0n'(s'HZ)(s'HZ) 90 '( s ' H £) Z8 '£' (zH ⁇ 7 ''-i'b 'HZ) 08'Z
  • Vp96 OM size 9 00 / size £ / ⁇ s ⁇ size) size ⁇ 9) ⁇ ) H ⁇ 9 sc>-
  • Extract the receptor preparation after total protein content was diluted thick Si buffer one such that the 250 gm 1 (see Table 2 below), 0.5 of 5 nM [3 H] - Anjio Tianjin II and Various concentrations of the test compound were added and incubated at 25 ° C for 1 hour.
  • the reaction mixture is stopped the reaction by suction filtration through a glass fiber filter one (Wh a tma n GF / B filter), and receptor-bound [3 H] one Angi O Tianjin ⁇ and free [ [ 3H] Angiotensin II was isolated.
  • Y is the binding radiation dose in the presence of the test compound
  • T is the binding radiation dose in the absence of the test compound
  • S is the specific binding radiation dose in the absence of the test compound
  • D is the dose of the test compound.
  • the concentration, K is the IC 5 of the test compound. Indicates a value. Table 3 shows the test results.
  • Example 82 The compound of Example 82 1. 6X 10- 8 Compound of Example 84 2.4X10-8 Compound of Example 88 3.6X10-18 Compound of Example 90 3.0X10-8 Compound of Example 92 1.7X10-8 Compound of Example 94 1-8
  • Example 1 05 Compound 1.9X10-18 Compound of Example 107 2.8X10-18 Compound of Example 22 22 3.18
  • the usefulness of the compound of the present invention was confirmed by its inhibitory effect on angiotensin ⁇ ⁇ -induced contraction of rat aorta.
  • the compound (I) of the present invention was superior in vasoconstriction inhibitory activity to the compound described in EF-0407342 and the pyrimidine derivative having a benzyl group at the 5-position used as reference compounds.
  • the components of the above composition were uniformly mixed to give a tablet of 20 Omg per tablet.
  • the mixture was granulated and filled into a gelatin capsule to give a capsule having a capsule content of 20 Omg per capsule.
  • the components of the above composition were dissolved in distilled water for injection to make a total volume of 1000 ml, and sealed in an ampoule to give an injection of 1 ampoule and 1 ml.
  • the compound (I) of the present invention has excellent angiotensin II antagonistic activity and high safety, and thus is useful as an excellent cardiovascular agent. Therefore, the compound of the present invention is useful as an agent for treating cardiovascular diseases such as hypertension, heart disease, stroke, and atherosclerosis.
  • cardiovascular diseases such as hypertension, heart disease, stroke, and atherosclerosis.
  • the structural formulas of the compounds described in Examples 1 to 159 are shown below. In the following structural formula, Me is a methyl group, Et is an ethyl group, n—Pr is an n-propyl group, n—Bu is an n-butyl group, n—Pen is an n-pentyl group, and P h is a phenyl group.
  • Example 65 (Example 66) (Example 67) (Example 68)
  • Example 119 (Example 120) (Example 121) (Example 122)
  • Example 137 Example 137
  • Example 138 Example 139
  • Example 140 Example 140

Landscapes

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

Abstract

Dérivé de pyrimidine présentant un antagonisme de l'angiotensine (II) et représenté par la formule générale (I) dans laquelle A représente (I-1) ou bien (I-2), R1 et R2 représentent chacun hydrogène, alkyle, alcényle, alcynyle, alcoxy, alkylthio, halogène ou phényle éventuellement substitué; R3 et R4 représentent chacun hydrogène, alkyle, alcoxy, halogène, nitro, sulfone, carboxy, alkoxycarbonyle, cycloalcoxycarbonyloxyalcoxycarbonyle, alcanoyloxy alcoxycarbonyle ou éventuellement tétrazolyle protégé, ou bien R3 et R4 peuvent être combinés pour former un composé cyclique condensé pentagonal ou hexagonal pouvant être substitué; X représente O, NH ou bien S(O)¿p?; p représente un entier compris entre 0 et 2; m vaut 1 ou 2; B représente carboxy, alcoxycarbonyle ou bien éventuellement tétrazolyle protégé; et n vaut 1 ou 2.
PCT/JP1994/000764 1993-05-13 1994-05-12 Derive de pyrimidine et composition pharmaceutique WO1994026721A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
DE4493151T DE4493151T1 (de) 1993-05-13 1994-05-12 Pyrimidinderivate und Arzneimittel
GB9500538A GB2284419A (en) 1993-05-13 1995-01-11 Pyrimidine derivative and pharmaceutical composition

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP13544393 1993-05-13
JP5/135443 1993-05-13
JP7398294 1994-03-17
JP6/73982 1994-03-17

Publications (1)

Publication Number Publication Date
WO1994026721A1 true WO1994026721A1 (fr) 1994-11-24

Family

ID=26415125

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1994/000764 WO1994026721A1 (fr) 1993-05-13 1994-05-12 Derive de pyrimidine et composition pharmaceutique

Country Status (4)

Country Link
CN (1) CN1109687A (fr)
DE (1) DE4493151T1 (fr)
GB (1) GB2284419A (fr)
WO (1) WO1994026721A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0685467A1 (fr) * 1993-12-16 1995-12-06 Nkk Corporation Nouveau derive de pyrimidine et composition medicinale
US7229993B2 (en) 2002-03-13 2007-06-12 Euro-Celtique S.A. Aryl substituted pyrimidines and the use thereof

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015036563A1 (fr) 2013-09-16 2015-03-19 Bayer Pharma Aktiengesellschaft Trifluorométhylpyrimidones disubstituées et leur utilisation comme antagonistes du ccr2

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
J. MED. CHEM., Vol. 35, No. 20, (1992), B. DE et al., "Discovery of a Novel Class of Orally Active, Non-Peptide Angiotensin II Antagonists", p. 3714-3717. *
J. MED. CHEM., Vol. 35, No. 25, (1992), KARNAIL S. ATWAL et al., "Dihydropyrimidine Angiotensin II Receptor Antagonists", p. 4751-4763. *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0685467A1 (fr) * 1993-12-16 1995-12-06 Nkk Corporation Nouveau derive de pyrimidine et composition medicinale
EP0685467A4 (fr) * 1993-12-16 1996-04-17 Nippon Kokan Kk Nouveau derive de pyrimidine et composition medicinale.
US7229993B2 (en) 2002-03-13 2007-06-12 Euro-Celtique S.A. Aryl substituted pyrimidines and the use thereof

Also Published As

Publication number Publication date
DE4493151T1 (de) 1995-07-20
GB9500538D0 (en) 1995-03-08
CN1109687A (zh) 1995-10-04
GB2284419A (en) 1995-06-07

Similar Documents

Publication Publication Date Title
US9655904B2 (en) Substituted benzoazepines as toll-like receptor modulators
ES2811119T3 (es) Derivados de naftiridina como antagonistas de integrina alfa v beta 6 para el tratamiento de, por ejemplo, enfermedades fibróticas
CN101362764B (zh) 具有PDE-5抑制活性的5,7-二氨基吡唑并[4,3-d]嘧啶
RU2317296C2 (ru) Изетионатная соль селективного ингибитора cdk4
JP5806417B2 (ja) Ｍｇａｔ２阻害剤としてのアリールジヒドロピリジノンおよびピペリジノン
CN104884454A (zh) 用作IL-12、IL-23和/或IFNα应答调节剂的酰胺取代的杂环化合物
TWI481604B (zh) Novel 5-fluorouracil derivatives
TW200418832A (en) Indole derivatives or benzimidazole derivatives for modulating IκB kinase
AU2010284241A1 (en) Substituted benzoazepines as Toll-like receptor modulators
CN102203101A (zh) 作为p38激酶抑制剂的吡咯并[2,3-c]吡啶衍生物
CN101203519A (zh) 用于治疗癌症和病毒感染如丙型肝炎的用作Toll样受体调节剂的2－酰氨基－6－氨基－8－氧代嘌呤衍生物
JP2024016225A (ja) がんおよび糖尿病の治療に有用な６－アリール－４－モルホリン－１－イルピリドン化合物
ES2814126T3 (es) Derivado de urea o sal farmacológicamente aceptable del mismo
JP2022521825A (ja) アンドロゲン受容体モジュレーター及びタンパク質分解誘導キメラリガンドとして使用するための方法
JP7187575B2 (ja) Ｒｈｏキナーゼ阻害剤としてのベンゾピラゾール系化合物
US11952366B2 (en) Substituted 1,3,5-triazines as inhibitors for a rho family of GTP-ases
WO2016127916A1 (fr) Corps gras hétérocyclique saturé à six chaînons amino substitué utilisé comme inhibiteur de la dpp-iv, à action prolongée
TWI818538B (zh) Ｌｐａ受體拮抗劑及其用途
AU2022240688A1 (en) Furan fused ring-substituted glutarimide compound
WO2005030773A1 (fr) Nouveaux derives pyrazolopyrimidine
JP2590797B2 (ja) イミダゾインドリジン誘導体及びその製法
WO1994026721A1 (fr) Derive de pyrimidine et composition pharmaceutique
JPWO2011024468A1 (ja) 新規なスルホンアミド誘導体及びこれを含有する医薬
JPH10147575A (ja) ヒドロキノン誘導体及びその医薬用途
JP2564784B2 (ja) イミダゾピリジン誘導体及びその製法

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): CN DE GB JP US

ENP Entry into the national phase

Ref document number: 1995 367222

Country of ref document: US

Date of ref document: 19950523

Kind code of ref document: A

RET De translation (de og part 6b)

Ref document number: 4493151

Country of ref document: DE

Date of ref document: 19950720

WWE Wipo information: entry into national phase

Ref document number: 4493151

Country of ref document: DE