WO1997020822A1 - Quinazolin-2,4-diazirines en tant qu'antagoniste du recepteur du neuropeptide y - Google Patents

Quinazolin-2,4-diazirines en tant qu'antagoniste du recepteur du neuropeptide y Download PDF

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Publication number
WO1997020822A1
WO1997020822A1 PCT/EP1996/005066 EP9605066W WO9720822A1 WO 1997020822 A1 WO1997020822 A1 WO 1997020822A1 EP 9605066 W EP9605066 W EP 9605066W WO 9720822 A1 WO9720822 A1 WO 9720822A1
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Prior art keywords
phenylamino
substituted
methoxy
quinazoline
lower alkyl
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PCT/EP1996/005066
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English (en)
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Heinrich RÜEGER
Tibur Schmidlin
Pascal Rigollier
Yasuchika Yamaguchi
Marina Tintelnot-Blomley
Walter Schilling
Leoluca Criscione
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Novartis Ag
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Priority to AU76928/96A priority Critical patent/AU7692896A/en
Publication of WO1997020822A1 publication Critical patent/WO1997020822A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4

Definitions

  • aromatic radicals including ring A
  • aromatic radicals are radicals which may be monosubstituted or polysubstituted, for example di- or trisubstituted, for example by identical or different radicals, for example selected from the group as given above.
  • Preferred substituents of corresponding aryl radicals are, for example, halogen, lower alkyl, halo- lower alkyl, lower alkoxy, oxy-lower alkylene-oxy, hydroxy, hydroxy-lower alkoxy, and lower alkoxy-lower alkoxy.
  • Lower alkanoyloxy is in particular C 2 -C ⁇ -alkanoyloxy, such as acetyloxy, propionyloxy, butyryloxy, isobutyryloxy or pivaloyloxy.
  • C 2 -C 5 -alkanoyloxy is preferred.
  • Amino which is di-substituted by lower alkylene is in particular C 3 -C ⁇ -alkyleneamino, preferably 1 -azidino, 1 -pyrrolidino or 1 -piperidino.
  • Phenyl-, naphthyl-, furyl-, thienyl-, or pyridyl-lower alkoxy is in particular phenyl-, naphthyl- or pyridyl-d-C -alkoxy, such as phenyl-methoxy, 2-phenyl-ethoxy, 1- or 2-naphthyl- methoxy, or 2-, 3-, or 4-pyridyl-methoxy.
  • C 3 -C 8 -Cycloalkyl-am ⁇ no is in particular C 3 -C 6 -cycloalkyl-am ⁇ no and is, for example, cyclopropyl-, cyclopentyl- and cyclohexyl-amino.
  • C 3 -C 8 -Cycloalkyl-lower alkylamino is in particular C 3 -C 8 -cycloalkyl-d-C ⁇ - alkylamino and is, for example, cyclopropylmethyl-amino or cyclohexylmethyl- amino C 3 -C 8 -Cycloalkyl-C ⁇ -C 4 -alkylam ⁇ no is preferred
  • Phenyl-, naphthyl-, furyl-, thienyl-, or pyridyl-lower alkyl-amino is in particular phenyl-, naphthyl-, furyl-, thienyl-, or py ⁇ dyl-d-C 4 -alkyl-am ⁇ no, preferably benzyl-ammo, 2-phenethyl- amino, 1- or 2-naphthylmethyl-am ⁇ no, or 2-, 3-, or 4-pyr ⁇ dylmethyl-am ⁇ no.
  • Di-(C 3 -C 8 -cycloalkyl-lower alkyl)-am ⁇ no is in particular d ⁇ -(C 3 -C 6 -cycloalkyl-C ⁇ -C 4 -alkyl)-am ⁇ no, preferably cyclopropylmethyl-amino, cyclopentylmethyl-amino or cyclohexylmethyl-amino
  • Lower alkyl-(phenyl-, naphthyl-, furyl-, thienyl-, or pyridyl)- amino is in particular d-C -alkyl- (phenyl-, naphthyl-, furyl-, thienyl-, or pyridyl)- amino, such as (m)ethyl-phenyl-amino.
  • Carboxy-lower alkyl is in particular carboxy-C ⁇ -C 4 -alkyl, such as carboxy-methyl, 2-carboxy- ethyl, or 3-carboxy-propyl.
  • Carboxy-lower alkoxy is in particular carboxy-d-C 4 -alkoxy, such as carboxy-methoxy, 2- carboxy-ethoxy, or 3-carboxy-propyloxy.
  • Lower alkoxy-carbonyl-lower alkoxy is in particular C 2 -C 5 -alkoxycarbonyl-d-C 4 -alkoxy, such as (m)ethoxycarbonyl-methoxy, 2-methoxycarbonyl-ethyl, or 2-(2-ethoxycarbonyl)-ethyl.
  • Lower alkoxy-lower alkoxy-carbonyl-lower alkoxy is in particular d-C 4 -alkoxy-C 2 -C 5 - alkoxycarbonyl-d-C -alkoxy, such as (m)ethoxymethoxycarbonyl-methoxy, 2-ethoxy- methoxycarbo ⁇ yl-ethyl, or 2-[(2-ethoxy-ethoxycarbonyl)]-ethyl.
  • (Phenyl-, naphthyl-, furyl-, thienyl-, or pyridyl) -lower alkoxycarbonyl-lower alkoxy is in particular (phenyl-, naphthyl-, furyl-, thienyl-, or pyridyl)-C 2 -C 5 -alkoxycarbonyl-d-C 4 -alkoxy, such as benzyloxycarbonyl-methoxy, phenethyloxycarbonyl-methoxy, 2- (benzyloxycarbonyl)-ethoxy, or 2-(2-phenethyloxycarbonyl)-ethoxy.
  • Carbamoyl-lower alkoxy is in particular carbamoyl-C ⁇ -C 4 -alkoxy, such as carbamoyl- methoxy, 2-carbamoyl-ethoxy, or 3-carbamoyl-propyloxy.
  • Phenylene is 1 ,2-, 1 ,3 or preferably 1 ,4-phenylene; naphthylene is in particular 1 ,2-, 1 -3-, 1 ,4-, 2,4-, 1 ,5-, or 2,7-naphthylene, furylene is in particular 2,3-, 2,4- or 3,4-furylene, thienylene is in particular 2,3-, 2,4- or 3,4-thienylene, pyridylene is in particular 2,3- or 2,4- pyridylene.
  • Obesity for example, is a wide-spread phenomena which e.g. causes a variety of pathological symptoms or influences the overall state of health. Also associated therewith are considerable socio-economic investments and a heavy financial burden for managed health care organisations.
  • the problem to be solved is to present an approach to systemically treat obesity or related diseases or disorders. Surprisingly, it has been manifested that the modulation of the NPY receptor subtype Y5 leads to a control of the eating behavior.
  • NPY neuropeptide Y1 receptor
  • This receptor is unique in that its classification is based solely on feeding behavior data, rather than radioligand binding data, unlike the Y1 , Y2, Y3, and Y4 (or PP) receptors, each of which are described previously in both radioligand binding and functional assays.
  • 125 I-PYY- based expression cloning technique may be used to isolate a rat hypothalamic cDNA encoding an "atypical Y1 " receptor referred to herein as the Y5 subtype.
  • Y5 homolog may be isolated and characterized of from human hippocampus.
  • NPY The peptide neurotransmitter neuropeptide Y
  • NPY is a 36 amino acid member of the pancreatic polypeptide family with widespread distribution throughout the mammalian nervous system. NPY is considered to be the most powerful stimulant of feeding behavior yet described (Clark, J.T., Kalra, P.S., Crowley, W.R., and Kalra, S.P. (1984).
  • Neuropeptide Y and human pancreatic polypeptide stimulate feeding behavior in rats. Endocrinology 1 15: 427-429, 1984; Levine, A.S., and Morley, J.E. (1984).
  • Neuropeptide Y A potent inducer of consummatory behavior in rats.
  • Direct injection into the hypothalamus of satiated rats, for example, can increase food intake up to 10-fold over a 4-hour period (Stanley, B G , Magdahn, W , Seirafi, A , Nguyen, M.M., and Leibowitz, S F (1992) Evidence for neuropeptide Y mediation of eating produced by food deprivation and for a variant of the Yi receptor mediating this peptide's effect Peptides 13.
  • NPY neuropeptide Y and energy balance: one way ahead for the treatment of obesity? Eur. J. Clin.
  • NPY neuropeptide Y and neuropeptide Y receptor subtypes in brain and peripheral tissues Progress in Neurobioloqy 38 125-167) It is therefore vital that knowledge of the molecular biology and structural diversity of the individual receptor subtypes be understood as part of a rational drug design approach to develop subtype selective compounds
  • Table 1 A brief review of NPY receptor pharmacology is summarized below and also in Table 1
  • Rank orders of affinity for key peptides are based on previously reported binding and functional data (Schwartz, T.W , J Fuhlendorff, L.L.Kjems, M.S. Knstensen, M. Vervelde, M O'Hare, J.L. Krstenansky, and B.
  • NPY receptor pharmacology has historically been based on structure/activity relationships within the pancreatic polypeptide family.
  • the entire family includes the namesake pancreatic polypeptide (PP), synthesized primarily by endocrine cells in the pancreas; peptide YY (PYY), synthesized primarily by endocrine cells in the gut; and NPY, synthesized primarily in neurons (Michel, M.C. (1991).
  • Receptors for neuropeptide Y multiple subtypes and multiple second messengers.
  • Trends Pharmacol.: 12: 389-394 Dumont et al., 1992; Wahlestedt and Reis, 1993).
  • pancreatic polypeptide family members share a compact structure involving a "PP-fold” and a conserved C-terminal hexapeptide ending in Tyr 36 (or Y 36 in the single letter code).
  • the striking conservation of Y 36 has prompted the reference to the pancreatic polypeptides' receptors as "Y-type" receptors (Wahlestedt, C, L. Edvinsson, E. Ekblad, and R. Hakanson. Effects of neuropeptide Y at sympathetic neuroeffector junctions: Existence of Yi and Y 2 receptors. In: Neuronal messengers in vascular function, Fernstrom Symp. No 10., pp. 231-242. Eds A. Nobin and CH. Owman. Elsevier: Amsterdam (1987)), all of which are proposed to function as seven transmembrane-spanning G protein-coupled receptors (Dumont et al., 1992).
  • the receptor requires both the N- and the C-terminal regions of the peptides for optimal recognition.
  • the Y1 receptor has been cloned from a variety of species including human, rat and mouse (Larhammar, D., A.G. Blomqvist, F. Yee, E. Jazin, H. Yoo, and C. Wahlestedt. (1992). Cloning and functional expression of a human neuropeptide Y/peptide YY receptor of the Y1 type. J. Biol.
  • the Y2 receptor recognizes PYY - NPY » PP and is relatively tolerant of N-terminal deletion (Gêtmar, L. and Rl Hakanson (1994). Neuropeptide Y effector systems: perspectives for drug development. Trends. Pharmacol. 15:153-159).
  • the receptor has a strict requirement for structure in the C-terminus (Arg 33 -Gln 34 -Arg 35 -Tyr 36 -NH 2 ); exchange of Gin 34 with Pro 34 , as in PP, is not well tolerated.
  • the Y2 receptor has recently been cloned.
  • [D-Trp ⁇ Neuropeptide Y A competitive antagonist of NPY in rat hypothalamus. J. Med. Chem. 37: 311-815 showed that feeding can be regulated by [D-Trp 32 ]NPY. While this peptide is presented as an NPY antagonist, the published data at least in part support a stimulatory effect of [D-Trp 3z ]NPY on feeding. [D- Trp 32 ]NPY thereby represents another diagnostic tool for receptor identification.
  • This plasmid (pcEXV-rY5) was deposited on November 4, 1994 with the American Type Culture Collection (ATCC), 12301 Parklawn Drive, Rockville, Maryland 20852, U.S.A. under the provisions of the Budapest Treaty for the International Recognition of the Deposit of Microorgansims for the Purposes of Patent Procedure and was accorded ATCC Accession No. CRL 75944.
  • a method for determining whether a ligand is a Y5 receptor antagonist comprises contacting a cell transfected with and expressing DNA encoding a Y5 receptor with the ligand in the presence of a known Y5 receptor agonist, such as PYY or NPY, under conditions permitting the activation of a functional Y5 receptor response, detecting a decrease in Y5 receptor activity, and thereby determining whether the ligand is a Y5 receptor antagonist.
  • a known Y5 receptor agonist such as PYY or NPY
  • the cell lines are transfected with a vector which is adapted for expression in a mammalian cell which comprises the regulatory elements necessary for expression of the DNA in the mammalian cell operatively linked to the DNA encoding the mammalian Y5 receptor as to permit expression thereof.
  • the cells were seeded one day before transfection at a density of 30,000 cells/cm 2 on Lab-Tek chamber slides (1 chamber, Permanox slide from Nunc Inc., Naperville, IL). On the next day, cells were washed twice with PBS, 735 ml of transfection cocktail was added containing 1/10 of the DNA from each pool and DEAE-dextran (500 mg/ml) in Opti-MEM I serum free media (G ⁇ bco®BRL LifeTechnologies Inc.
  • a human hippocampal cDNA library has been screened using the polymerase chain reaction.
  • 1 ⁇ l (4 x 10 6 bacteria) of each of 450 amplified pools containing each »5000 independent clones and representing a total of 2.2 x 10 6 was subjected directly to 40 cycles of PCR and the resulting products analyzed by agarose gel electrophoresis.
  • One of three positive pools was analyzed further and by sib selection a single cDNA clone was isolated and characterized. This cDNA turned out to be full length and in the correct orientation for expression.
  • DS ⁇ DNA was sequenced with a sequenase kit (US Biochemical, Cleveland, OH) according to the manufacturer.
  • Binding data reflect competitive displacement of 125 I-PYY and 125 I-PYY 3 . 36 from rat hypothalamic membranes. Peptides were tested at concentrations ranging from 0.001 nM to 100 nM unless noted. The IC 50 value corresponding to 50% displacement, and the percentage of displacement relative to that produced by 300 nM human NPY, were determined by nonlinear regression analysis. Data shown are representative of at least two independent experiments.
  • Pools # 147, 246, 254 and 312 turned out to contain cDNAs encoding a Y1 receptor, pool # 290 turned out to encode a Y2 subtype, but pools # 81 and 92 were negative by PCR analysis for Y1 , Y2 and Y4 and therefore likely contained a cDNA encoding a new rat hypothalamic NPY receptor (Y5). Pools # 81 and 92 later turned out to contain an identical NPY receptor cDNA. Pool 92 was subjected to sib selection as described until a single clone was isolated (designated CG-18). The isolated clone carries a 2.8 kb cDNA.
  • the hydrophobicity plot displayed seven hydrophobic, putative membrane spanning regions which makes the rat hypothalamic Y5 receptor a member of the G-protein coupled superfamily.
  • the nucleotide and deduced amino acid sequences are shown in SEQ ID NOS: 1 and 2, respectively.
  • the compounds according to the present invention and their pharmaceutically acceptable salts have proven to exhibit pronounced and selective affinity to the Y5 receptor subtype (shown in Y5 binding test) and in vitro and in vivo antagonistic properties These properties are shown in vitro by their ability to inhibit NPY-induced calcium increase in stable transfected cells expressing the Y5 receptor and in vivo by their ability to inhibit food intake induced by intracerebrovent ⁇ cular application of NPY or 24 h food deprivation in conscious rats
  • buffer 1 homoogenisation buffer, pH 7 7 at 4°C
  • buffer 2 saliva buffer, pH: 7.4 at room temperature
  • HEPES N-2-hydroxyethylp ⁇ peraz ⁇ ne-N'-2-ethanesulfonic acid
  • Cells are washed in phosphate buffered saline and harvested using a rubber policeman The cells are homogenised using a Polytron homogeniser (3 bursts of 8 seconds) in ice- cold hypotonic buffer (buffer 1 , pH 7.7 at 4°C ).
  • R 2 represents (i) hydrogen, halogen, cyano, nitro, lower alkyl, or phenyl, (II) ammo which is mono-substituted by lower alkyl, phenyl or pyridyl, or which is disubstituted by lower alkyl or by C 2 -C 6 -alkylene;
  • the invention most preferably relates to a method of treatment and prophylaxis of disorders and diseases associated with NPY receptor subtype Y5 comprising administering to a warm-blooded animal in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in which
  • alk ! and alk 2 both represent a single bond; and R 2 is hydrogen, 1 -piperidino or C ⁇ -C - alkoxy, especially methoxy; the benzo ring A is unsubstituted or substituted in position 8 of the quinazoline ring by d-C -alkoxy, especially methoxy, or
  • the invention most preferably relates to a method of treatment and prophylaxis of disorders and diseases associated with NPY receptor subtype Y5 comprising administering to a warm-blooded animal in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in which alki and alk 2 both represent a single bond;
  • halogen hydroxy, lower alkoxy, hydroxy-lower alkoxy, lower alkoxy-lower alkoxy, ammo, substituted ammo, carboxy, lower alkoxy-carbonyl, lower alkoxy-lower alkoxy-carbonyl, (carbocyclic or heterocyclic) aryl-lower alkoxy-carbonyl, carbamoyl, N-substituted carbamoyl, and -S(O) n -R, R 3 and R together represent lower alkylene [which may be interrupted by O, S(O) n , NRo] or represent lower alkylene which is condensed at two adjacent carbon atoms with a benzene ring;
  • lower alkoxy which is substituted by a substituent selected from the group consisting of: halogen, hydroxy, lower alkoxy, C 3 -C 8 -cycloalkyl, (carbocyclic or heterocyclic) aryloxy, (carbocyclic or heterocyclic) aryl, amino, substituted amino, carboxy, lower alkoxy-carbonyl, lower alkoxy-lower alkoxy-carbonyl, (carbocyclic or heterocyclic) aryl-lower alkoxy-carbonyl, carbamoyl, and N-substituted carbamoyl; (iv) amino, substituted amino;
  • Ri represents hydrogen, lower alkyl, lower alkenyl, halo-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, or (carbocyclic or heterocyclic) aryl-lower alkyl;
  • R 2 represents (vi) a group selected from -CH(OH)-R, -CO-R, -NRrCO-O-R, -NR CO-R, -NR CO-NR ⁇ -R, - NR 1 -SO 2 -R, -NR!-SO 2 -NR R, -SO 2 -R, -SO 2 -NR R, or -SOrNR CO-R, [R being as defined below and Ri being as defined above, or the group -N(R)(R ⁇ ) represents amino which is di ⁇ substituted by lower alkylene ⁇ which may be interrupted by O, S(O) n or NR 0 ⁇ or which is di ⁇ substituted by lower alkylene which is condensed at two adjacent carbon atoms with a benzene ring]; or
  • lower alkyl which is substituted by a substituent selected from the group consisting of: halogen, hydroxy, lower alkoxy, amino, substituted amino, carboxy, lower alkoxy-carbonyl, lower alkoxy-lower alkoxy-carbonyl, (carbocyclic or heterocyclic) aryl-lower alkoxy-carbonyl, carbamoyl, and N-substituted carbamoyl;
  • lower alkoxy which is substituted by a substituent selected from the group consisting of: halogen, hydroxy, lower alkoxy, C 3 -C 8 -cycloalkyl, (carbocyclic or heterocyclic) aryloxy, amino, substituted amino, lower alkoxy-carbonyl, lower alkoxy-lower alkoxy-carbonyl, (carbocyclic or heterocyclic) aryl-lower alkoxy-carbonyl, carbamoyl, and N-substituted carbamoyl;
  • Ri represents hydrogen, lower alkyl, lower alkenyl, or lower alkoxy-lower alkyl
  • R 3 and R 4 independently of one another, represent (i) hydrogen, lower alkyl, lower alkenyl, (carbocyclic or heterocyclic) aryl, or (carbocyclic or heterocyclic) aryl-lower alkyl;
  • lower alkyl which is substituted by a substituent selected from the group consisting of: lower alkoxy, substituted amino, lower alkoxy-carbonyl, lower alkoxy-lower alkoxy-carbonyl, and substituted carbamoyl;
  • R 3 represents hydrogen, lower alkyl which is unsubstituted or substituted by C 3 -d- cycloalkyl, by phenyl, or by di-lower alkylamino, or represents C 3 -C 7 -cycloalkyl, phenyl which is unsubstituted or is substituted by a substituent selected from the group consisting of: halogen, cyano, lower alkyl, lower alkoxy, hydroxy, and carbamoyl, or represents indazolyl;
  • R 3 and R 4 together represent lower alkylene which is condensed at two adjacent carbon atoms with a benzene ring;
  • X represents phenylene which is unsubstituted or substituted by halogen, lower alkyl, halo-lower alkyl, lower alkoxy, or oxy-lower alkylene-oxy, or represents nahthylene; wherein the benzo ring A is unsubstituted or substituted a substituent selected from the group consisting of' halogen, nitro, ammo, di-lower alkylamino, lower alkyl, lower alkoxy, lower alkoxy-lower alkoxy, lower alkoxy-lower alkyl, di-(lower alkyl)-amino-lower alkyl, phenyl, and lower alkanoyl.
  • R 3 represents phenyl which is unsubstituted or is substituted by a substituent selected from the group consisting of: halogen, cyano, lower alkyl, lower alkoxy, and oxy-lower alkylene-oxy;
  • X represents phenylene which is unsubstituted or substituted by halogen, lower alkyl, halo-lower alkyl, or lower alkoxy; wherein the benzo ring A is unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, lower alkyl, halo-lower alkyl, lower alkoxy, hydroxy, hydroxy-lower alkoxy, and lower alkoxy-lower alkoxy.
  • Ri represents hydrogen or lower alkyl
  • R 4 represents (i) hydrogen
  • the invention relates especially to a new compound of formula (I) or a salt thereof in which alki represents a single bond; alk 2 represents a single bond or d-C 3 -alkylene;
  • R 4 represents hydrogen
  • X represents 1 ,4-phenylene or 1 ,3-phenylene which is di-substituted by oxy- methyiene-oxy; wherein the benzo ring A is unsubstituted or substituted by C ⁇ -C 4 -alkoxy, especially, methoxy, preferably in position 8 of the quinazoline ring.
  • the invention relates especially to a new compound of formula (I) or a salt thereof in which alki and alk 2 both represent a single bond;
  • R 2 is d-C 4 -alkoxy, especially methoxy, and R 3 is phenyl which is substituted by hydroxy, especially 3-hydroxy-phenyl; or
  • R 2 is C ⁇ -C 4 -alkoxy-d-C 4 -alkoxy, especially 2-methoxy-ethoxy, or 1 -piperidino;
  • the invention relates especially to a new compound of formula (I) or a salt thereof in which alk, represents a single bond; alk 2 represents C C 3 -alkylene; and
  • R 3 represents phenyl which is unsubstituted or is substituted by a substituent selected from the group consisting of: halogen, cyano, d-C 4 -alkyl, C ⁇ -C -alkoxy, and oxy- d-C 4 - alkylene-oxy; and
  • X represents phenylene which is unsubstituted or substituted by halogen, C ⁇ -C 4 -alkyl, C ⁇ -C -alkoxy, lower alkoxy-lower alkyl; wherein the benzo ring A is unsubstituted or substituted by C ⁇ -C 4 -alkoxy.
  • Reactive esterified hydroxyl Z4 is in particular hydroxyl esterified with a strong inorganic acid or organic sulfonic acid, for example halogen, such as fluorine, chlorine, or bromine, sulfonyloxy, such as hydroxysulfonyloxy, halosulfonyloxy, for example fluorosulfonyloxy, Ci-Cralkane-sulfonyloxy which is unsubstituted or substituted, for example by halogen, for example methane- or trifluoromethanesulfonyloxy, C ⁇ -C ⁇ ycloalkanesulfonyloxy, for example cyclohexanesulfonyloxy, or benzenesulfonyloxy which is unsubstituted or substituted, for example by Ci-d-alkyl or halogen, for example p-bromobenzene- or p-toluenesulfonyloxy.
  • Preferred Z 1 or Z 2 is chloro, bromo or iodo, methanesulfonyloxy or trifluoromethanesulfonyloxy, or p-toluenesulfonyloxy, or methylthio or methoxy.
  • Suitable bases are, for example, alkali metal hydroxides, hydrides, amides, alkanolates, carbonates, triphenylmethylides, di-lower alkylamides, aminoalkylamides or lower alkylsilylamides, naphthaleneamines, lower alkylamines, basic heterocycles, ammonium hydroxides, and carbocyclic amines.
  • Examples which may be mentioned are sodium hydroxide, sodium hydride, sodium amide, sodium methoxide, sodium ethoxide, potassium tert- butoxide, potassium carbonate, lithium triphenylmethylide, lithium diisopropylamide, potassium 3-(aminopropyl)amide, potassium bis(trimethylsilyl)amide, dimethylaminonaphthalene, di- or triethylamine, or ethyldiisopropylamine, N-methylpiperidine, pyridine, benzyltrimethylammonium hydroxide, 1 ,5-diazabicyclo[4.3.0]non-5-ene (DBN) and 1 ,8-diaza- bicyclo[5.4.0]undec-7-ene (DBU).
  • the starting material of fomulae (Ila), (lib), (Ilia), and (lllb) is essentially known or is accessible analogously to preparation processes known per se.
  • a compound according to the invention containing hydroxyl can be etherified by methods known per se.
  • the etherification can be carried out, for example, using an alcohol, such as a substituted or unsubstituted lower alkanol, or a reactive ester thereof.
  • Suitable reactive esters of the desired alcohols are, for example, those with strong inorganic or organic acids, such as corresponding halides, sulfates, lower alkanesulfonates or substituted or unsubstituted benzenesulfonates, for example chlorides, bromides, iodides, methane-, benzene- or p-toluenesulfonates.
  • the etherification can be carried out, for example, in the presence of a base, an alkali metal hydride, hydroxide or carbonate, or of an amine.
  • corresponding ethers such as lower alkoxy compounds, can be cleaved, for example, by means of strong acids, such as mineral acids, for example the hydrohalic acids hydrobromic or hydriodic acid, which may advantageously be present in the form of pyridinium halides, or by means of Lewis acids, for example halides of elements of main group III or the corresponding sub-groups.
  • Compounds according to the invention containing hydroxymethyl groups can be prepared, for example, starting from compounds containing corresponding carboxyl or esterified carboxyl, corresponding compounds being reduced in a manner known per se, for example by reduction with a hydride which, if desired, may be complex, such as a hydride formed from an element of the 1st and 3rd main groups of the periodic table of the elements, for example borohydride or aluminohydride, for example lithium borohydride, lithium aluminium hydride, diisobutylaluminium hydride (an additional reduction step using alkali metal cyanoborohydride, such as sodium cyanoborohydride, may be necessary), and also diborane.
  • a hydride which, if desired, may be complex, such as a hydride formed from an element of the 1st and 3rd main groups of the periodic table of the elements, for example borohydride or aluminohydride, for example lithium borohydride, lithium aluminium
  • Suitable oxidising agents for the oxidation to the sulfoxide step are, for example, inorganic peracids, such as peracids of mineral acids, for example periodic acid or persulfuric acid, organic peracids, such as appropriate percarboxylic or persulfonic acids, for example performic, peracetic, trifluoroperacetic or perbenzoic acid or p-toluenepersulfonic acid, or mixtures of hydrogen peroxide and acids, for example a mixture of hydrogen peroxide with acetic acid.
  • inorganic peracids such as peracids of mineral acids, for example periodic acid or persulfuric acid
  • organic peracids such as appropriate percarboxylic or persulfonic acids, for example performic, peracetic, trifluoroperacetic or perbenzoic acid or p-toluenepersulfonic acid
  • mixtures of hydrogen peroxide and acids for example a mixture of hydrogen peroxide with acetic acid.
  • the oxidation to the sulfone step may also be carried out appropriately at low temperatures using dinitrogen tetroxide as the catalyst in the presence of oxygen, just like the direct oxidation of (lower) alkylthio to (lower) alkanesulfonyl.
  • the oxidising agent is customarily employed in an excess.
  • this can be converted into an esterified carboxyl group, for example, by treating with an alcohol, such as a lower alkanol, in the presence of a suitable esterifying agent, such as an acid reagent, for example an inorganic or organic acid or a Lewis acid, for example zinc chloride, or a condensing agent which binds water, for example a carbodiimide, such as N,N'-dicyclohexylcarbodiimide, or by treating with a diazo reagent, such as with a diazo-lower alkane, for example diazomethane.
  • an alcohol such as a lower alkanol
  • a suitable esterifying agent such as an acid reagent, for example an inorganic or organic acid or a Lewis acid, for example zinc chloride
  • a condensing agent which binds water
  • a carbodiimide such as N,N'-dicyclohexylcarbodiimide
  • a diazo reagent such
  • Compounds of the formula (I) which contain an esterified carboxyl group as a substituent can be transesterified into other ester compounds of the formula (I) by transesterification, for example by treating with an alcohol, customarily a higher approp ⁇ ate alcohol than that of the esterified carboxyl group in the starting material, in the presence of a suitable transesterifying agent, such as a basic agent, for example an alkali metal (C- j -C7)alkanoate, (C-
  • a suitable transesterifying agent such as a basic agent, for example an alkali metal (C- j -C7)alkanoate, (C-
  • this can also first be converted into a reactive derivative, such as an anhydride, including a mixed anhydride, such as an acid halide, for example an acid chloride (for example by treating with a thionyl halide, for example thionyl chloride), or an anhydride using a formic acid ester, for example a (C- ⁇ -C ⁇ )a ⁇ ky ⁇ ester (for example by treating a salt, such as an ammonium or alkali metal salt, with a haloformic acid ester, such as a chloroformic acid ester, such as a (C-
  • esters such as (C-
  • an aromatic ring contains a hydrogen atom as a substituent
  • the latter can be replaced by a halogen atom with the aid of a halogenating agent in a customary manner, for example brominated with bromine, hypobromic acid, acyl hypobromites or other organic bromine compounds, for example N- bromosuccinimide, N-bromoacetamide, N-bromophthalimide, pyridinium perbromide, dioxane dibromide, 1 ,3-dibromo-5,5-dimethylhydantoin or 2,4,4,6- tetrabromo-2,5-cyclohexanedien-1-one, or chlorinated with elemental chlorine, for example in
  • an aromatic ring in the compounds according to the invention contains an amino group
  • this can be diazotized in a customary manner, for example by treating with a nitrite, for example sodium nitrite, in the presence of a suitable protonic acid, for example a mineral acid, the reaction temperature advantageously being kept below about 5°O
  • a suitable protonic acid for example a mineral acid
  • the diazonium group present in the salt form and obtainable in this way can be substituted by analogous processes, for example as follows: by the hydroxyl group analogously to the boiling-out of phenol in the presence of water; by an alkoxy group by treating with an appropriate alcohol, energy having to be added; by the fluorine atom analogously to the Schiemann reaction in the thermolysis of corresponding diazonium tetrafluoroborates; by the halogen atoms chlorine, bromine or iodine and also the cyano group analogously to the Sandmeyer reaction in the reaction with corresponding Cu(l) salts, initially with cooling
  • the hydrogenation may preferably be carried out at pressures between 1 and about 100 at and at room temperature between about -80° to about 200°C, in particular between room temperature and about 100°O
  • the reaction is advantageously carried out in a solvent, such as water, a lower alkanol, for example ethanol, isopropanol or n-butanol, an ether, for example dioxane, or a lower alkanecarboxylic acid, for example acetic acid.
  • a solvent such as water, a lower alkanol, for example ethanol, isopropanol or n-butanol, an ether, for example dioxane, or a lower alkanecarboxylic acid, for example acetic acid.
  • the invention relates in particular to the processes described in the examples.
  • Salts of compounds of the formula (I) can be prepared in a manner known per se.
  • acid addition salts of compounds of the formula (I) are obtained by treating with an acid or a suitable ion exchange reagent. Salts can be converted into the free compounds in a customary manner, and acid addition salts can be converted, for example, by treating with a suitable basic agent.
  • the compounds according to the invention having salt-forming, in particular basic properties can be obtained in free form or preferably in the form of salts.
  • novel compounds including their salts of salt-forming compounds can also be obtained in the form of their hydrates or can include other solvents used for crystallization.
  • the novel compounds can be present in the form of one of the possible isomers or as mixtures thereof, for example as pure optical isomers, such as antipodes, or as isomer mixtures, such as racemates, diastereoisomer mixtures or racemate mixtures, depending on the number of asymmetric carbon atoms.
  • the invention also relates to those embodiments of the process, according to which a compound obtainable as an intermediate in any step of the process is used as a starting material and the missing steps are carried out or a starting material in the form of a derivative or salt and/or its racemates or antipodes is used or, in particular, formed under the reaction conditions.
  • the invention likewise relates to novel starting materials which have been specifically developed for the preparation of the compounds according to the invention, to their use and to processes for their preparation, the variables alki, alk 2 , R-) , R2, R3, R 4 , and X having the meanings indicated for the preferred compound groups of the formula (I) in each case.
  • the invention likewise relates to pharmaceutical preparations which contain the compounds according to the invention or pharmaceutically acceptable salts thereof as active ingredients, and to processes for their preparation.
  • compositions according to the invention which contain the compound according to the invention or pharmaceutically acceptable salts thereof are those for enteral, such as oral, furthermore rectal, and parenteral administration to (a) warm-blooded animal(s), the pharmacological active ingredient being present on its own or together with a pharmaceutically acceptable carrier.
  • enteral such as oral, furthermore rectal, and parenteral administration to (a) warm-blooded animal(s), the pharmacological active ingredient being present on its own or together with a pharmaceutically acceptable carrier.
  • the daily dose of the active ingredient depends on the age and the individual condition and also on the manner of administration.
  • novel pharmaceutical preparations contain, for example, from about 10 % to about 80%, preferably from about 20 % to about 60 %, of the active ingredient.
  • Pharmaceutical preparations according to the invention for enteral or parenteral administration are, for example, those in unit dose forms, such as sugar-coated tablets, tablets, capsules or suppositories, and furthermore ampoules. These are prepared in a manner known per se, for example by means of conventional mixing, granulating, sugar-coating, dissolving or lyophilizing processes.
  • compositions for oral use can be obtained by combining the active ingredient with solid carriers, if desired granulating a mixture obtained, and processing the mixture or granules, if desired or necessary, after addition of suitable excipients to give tablets or sugar-coated tablet cores.
  • Suitable carriers are, in particular, fillers, such as sugars, for example lactose, sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, furthermore binders, such as starch paste, using, for example, corn, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose and/or polyvinylpyrrolidone, if desired, disintegrants, such as the abovementioned starches, furthermore carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate; auxiliaries are primarily glidants, flow-regulators and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol.
  • fillers such as sugars, for example lactos
  • Sugar-coated tablet cores are provided with suitable coatings which, if desired, are resistant to gastric juice, using, inter alia, concentrated sugar solutions which, if desired, contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, coating solutions in suitable organic solvents or solvent mixtures or, for the preparation of gastric juice-resistant coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Colorants or pigments, for example to identify or to indicate different doses of active ingredient, may be added to the tablets or sugar-coated tablet coatings.
  • hard gelatin capsules and also soft closed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the hard gelatin capsules may contain the active ingredient in the form of granules, for example in a mixture with fillers, such as lactose, binders, such as starches, and/or lubricants, such as talc or magnesium stearate, and, if desired, stabilizers.
  • the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, it also being possible to add stabilizers.
  • Suitable rectally utilizable pharmaceutical preparations are, for example, suppositories, which consist of a combination of the active ingredient with a suppository base.
  • Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols.
  • gelatin rectal capsules which contain a combination of the active ingredient with a base substance may also be used.
  • Suitable base substances are, for example, liquid triglycerides, polyethylene glycols or paraffin hydrocarbons.
  • Suitable preparations for parenteral administration are primarily aqueous solutions of an active ingredient in water-soluble form, for example a water-soluble salt, and furthermore suspensions of the active ingredient, such as appropriate oily injection suspensions, using suitable lipophilic solvents or vehicles, such as fatty oils, for example sesame oil, or synthetic fatty acid esters, for example ethyl oleate or triglycerides, or aqueous injection suspensions which contain viscosity-increasing substances, for example sodium carboxymethylcellulose, sorbitol and/or dextran, and, if necessary, also stabilizers.
  • suitable lipophilic solvents or vehicles such as fatty oils, for example sesame oil, or synthetic fatty acid esters, for example ethyl oleate or triglycerides
  • viscosity-increasing substances for example sodium carboxymethylcellulose, sorbitol and/or dextran, and, if necessary, also stabilizers.
  • the starting material can be prepared, for example, as follows:
  • N,N-D ⁇ methylaniline (114.0 g) is added slowly to a solution of 1 H,3H-quinazolin-2,4-dione (146.0 g) in phosphorousoxychloride (535.4 ml) while this mixture is heated up to 140°C. After completion of the addition reflux is continued for 20 h . The reaction mixture is filtered and evaporated to give a residue which is added to ice and water. The product is extracted with dichloromethane and crystallized from diethylether and petroleum diethylether to yield 2,4-dichloro-qu ⁇ nazol ⁇ ne, m.p. 115 - 1 16°C.
  • Example 2 2-(4-Methoxy-phenylam ⁇ no)-4-phenylam ⁇ no-qu ⁇ nazol ⁇ ne hydrochloride
  • the starting material can be prepared, for example, as follows
  • the starting material can be prepared, for example, as follows.
  • Example 15 2-[3-(Aminomethyl)-phenylamino]-4-phenylamino-quinazoline dihydrochloride
  • a solution of 2-(3-cyano-phenylam ⁇ no)-4-phenylam ⁇ no-qu ⁇ nazol ⁇ ne hydrochloride (0.939 g) m ethanol (40 ml) is hydrogenated in the presence of Raney nickel (0.5 g) at ambient temperature and pressure. The catalyst is removed by filtration and the filtrate is concentrated in vacuo.
  • the starting material can be prepared, for example, as follows
  • Example 17 2-f4-(3-Cvclohexyl-propyloxy)-phenylam ⁇ no]-4-phenylam ⁇ no-qu ⁇ nazol ⁇ ne hydrochloride
  • a suspension of 2-(4-hydroxy-phenylamino)-4-phenylamino-quinazoline hydrochloride (292 g), 3-iodopropyl-cyclohexane (EP 518,426) (0.212 g), and potassium carbonate (0.221 g) in acetonitrile (20 ml) is heated to reflux for 5 h.
  • the raction mixture is filtered and the filtrate concentrated in vacuo.
  • the residue is added to 2N NaOH and extracted with ethylacetate.
  • the crude product is treated with 4N HCl in dioxane and crystallized from isopropanol and acetonitrile to yield
  • the starting material can be prepared, for example, as follows:
  • the precipitate is recrystallized from isopropanol and diethylether to yield 2-[4-(N,N-diethylam ⁇ no)-phenylam ⁇ no]-4-(3-methoxy- phenylam ⁇ no)-qu ⁇ nazoi ⁇ ne dihydrochloride, m.p. 239 - 241 °C.
  • Example 26 2-(4-Cvclohexy!-phenylamino)-4-(4-methoxy-phenylamino)-guinazoline hydrochloride A mixture of 2-chloro-4-(4-methoxy-phenylam ⁇ no)-qumazol ⁇ ne (0.343 g) and 4-cyclohexyl- anilme (0.274 g) is heated for 3 mm to produce a melt which is dissolved in isopropanol (4 ml) and 4N HCl in dioxane (0.1 ml).
  • Example 34 2-(4-Chloro-phenylamino)-4-phenylam ⁇ no-quinazoline hydrochloride M.p. 325 - 326°C.
  • Example 35 2-(4-Methyl-phenylamino)-4-phenylam ⁇ no-qu ⁇ nazoline hydrochloride M.p. 294 - 296°C.
  • Example 36 2-(3-Methoxy-phenylamino)-4-phenylamino-quinazol ⁇ ne hydrochloride M.p. 298 - 299°C.
  • Example 37 2-(2-Methoxy-phenylamino)-4-phenylamino-quinazoline hydrochloride M.p. 256 - 258°C.
  • Example 39 2,4-Di-(3-methoxy-phenylam ⁇ no)-gu ⁇ nazol ⁇ ne hydrochloride M.p. 232 - 233°C.
  • Example 40 2-[4-(Benzyloxy)-phenylam ⁇ no]-4-(4-methoxy-phenylam ⁇ no)-qu ⁇ nazoline hydrochloride M.p. 272 - 273°C.
  • Example 41 2-[4-(Aminomethyl)-phenylamino]-4-(4-methoxy-phenylamino)- quinazoline dihydrochloride M.p. 308 - 311 °C.
  • Example 58 2,4-D ⁇ phenylam ⁇ no-6-phenyl-qu ⁇ nazol ⁇ ne A solution of 2,4-d ⁇ chloro-6-phenyl-qu ⁇ nazol ⁇ ne (0.78 g) and aniline (0.54 ml) in 5 ml of ethanol is stirred under nitrogen at 60°C for 1 h. The crude product, which is crystallizing on cooling, is filtered off, redissolved in ethylacetate and aqueous 1 N NaOH solution and extracted with ethylacetate. The organic extracts are dried, evaporated and the oily residue is chromatographed on silica gel (elution with dichloromethane). Crystallization from methanol yields 2,4-d ⁇ phenylam ⁇ no-6-phenyl-quinazol ⁇ ne as colorless crystals melting at 145 - 147°C; Rf (A2) 0.59
  • the starting material can be prepared, for example, as follows:
  • the starting material can be prepared, for example, as follows:
  • Example 68 N- ⁇ 4-f8-Methoxy-4-(3-methoxy-phenylamino)-quinazolin-2-ylamino]-benzyl]l- methanesulfonamide hydrochloride Rf(A1) 0.52.
  • the starting material can be prepared, for example, as follows:
  • N,N-D ⁇ methylan ⁇ l ⁇ ne (0.36 ml) is added slowly to a solution of 8-methoxy-1 H,3H-qu ⁇ nazol ⁇ n- 2,4-d ⁇ one (J. Chem. Soc. 1921 ,1425) (1.20 g) in phosphorousoxychlonde (3.70 ml) while this mixture is heated up to 125°C. After the completion of the addition reflux g is continued for 10 h . Evaporation of the solvent in vacuo gives a residue which is added to ice and water Extraction with ethylacetate yields 2,4-d ⁇ chloro-8-methoxy-qu ⁇ nazol ⁇ ne, Rf(C4) 0.64
  • Example 73 Naphthalene-1 -sulfonic acid 4-f(4-am ⁇ no-qu ⁇ nazol ⁇ n-2-ylam ⁇ no)-methyn- benzylamide hydrochloride
  • the starting material can be prepared, for example, as follows a) ⁇ 4-f(Naphthalene-1-sulfonylamino)-methyll-benzyll-carbamic acid tert-butyl ester A solution of 3 g of naphthalene-1-sulfonylchloride and 4.53 ml of N,N-diisopropyl- ethylamine in acetonitrile (80 ml) is cooled to 0 °C and treated with a solution of 3.12 g of (4-amino methyl-benzyl)-carbamic acid tert-butyl ester (J. Med. Chem.
  • Example 74 Naphthalene-1 -sulfonic acid 3-f(4-amino-quinazolin-2-ylamino)-methyl]- benzylamide hydrochloride
  • the starting material can be prepared, for example, as follows:
  • Example 75 In a manner analogous to that described hereinbefore it is also possible to manufacture the following compounds:
  • the starting material can be prepared, for example, as follows:
  • the starting material can be prepared, for example, as follows:
  • Example 95 N(4)-Cvclohexyl-N(4)-ethyl-N(2)-[4-(methoxyethoxy)-phenyl-quinazoline-2,4- diamine hydrochloride
  • a mixture of 2-chloro-4-[(N-cyclohexyl-N-ethyi)-amino]-qu ⁇ nazol ⁇ ne (0.3 g) and 4- methoxyethoxy-aniline (0.225 g) is heated for 1 min to produce a melt which is dissolved in isopropanol (1 ml). The mixture is evaporated, and the residue is partioned between dichloromethane (20 ml) and water.
  • the aqueous phase is adjusted to pH 12 and extracted with methylenechloride, the combined organics are dried over magnesium sulfate and evaporated.
  • the crude product is purified by flash chromatography on silica gel (hexane/ethylacetate 1 :1) to give a foamy solid.
  • the product is dissolved in dioxane (4 ml), 4N HCl in dioxane (0.268 ml) is added and the mixture is evaporated.
  • the solid material is suspended in diethyl ether and filtered, followed by repeated washing with diethyl ether to yield N(4)-cyclohexyl-N(4)-ethyl-N(2)-[4-(methoxyethoxy)-phenyl-quinazoline-2,4-diamine hydrochloride as amorphous solid, Rf(A1) 0.48.
  • Example 98 2-f4-(Amino-carbonyl)-phenylaminol-4-phenylamino-quinazoline hydrochloride M.p. 334 - 337°C.
  • Example 103 2-f4-(2-Methoxy-ethyl)-phenylamino1-4-(4-amino-carbonyl-phenylamino ⁇ - quinazoline hydrochloride M.p. 288 - 290°C.
  • Example 105 2-[4-(3-Hvdroxy-propyl)-phenylaminol-8-methoxy-4-phenylamino-quinazoline hydrochloride
  • Example 106 2-f4-(3-Hvdroxy-propyl)-phenylaminol-4-phenylamino-quinazoline hydro ⁇ chloride M.p. 252 - 254°C.
  • Example 107 2-[4-(3-Hvdroxy-propyl)-phenylaminol-4-(3-methoxy-phenylamino)- quinazoline hydrochloride M.p. 213 - 214°C.
  • Example 109 2-r4-(2-Hvdroxy-ethoxy)-phenylamino1-4-phenylamino-quinazoline hydro ⁇ chloride M.p. 284 - 284°C.
  • Example 11 1 2-f4-(2-Hvdroxy-ethoxy)-phenylamino1-4-(4-methoxy-phenylamino)- quinazoline hydrochloride M.p. 245 - 246°C.
  • Example 112 2-f4-(2-Methoxy-ethyl)-phenylaminol-4-(4-methoxy-phenylamino)-quinazoline hydrochloride
  • Example 115 4-(4-Chloro-phenylamino)-2-[4-(methoxy-acetylamino-methyl)-phenylamino1- 8-methoxy-quinazoline hydrochloride M.p. 265 - 266°C.
  • Example 116 4-(4-Fluoro-phenylamino)-8-methoxy-2- r 4-(2-hvdroxyethyl)-phenylamino]- quinazoline hydrochloride M.p. 235 - 237°C.
  • Example 118 2-F4-(3-Hvdroxy-propyl)-phenylamino1-4-(3-hydroxyl-phenylamino)- quinazoline hydrochloride M.p. 260 - 262°C.
  • Example 1 19 6-Chloro-4-cvclohexylamino-2-r4-(3-hydroxy-propyl)-phenylaminol- quinazoline hydrochloride M.p. 248 - 249°C.
  • Example 120 6-Chloro-4-cyclohexylam ⁇ no-2-[4-(2-hvdroxy-ethoxy)-phenylam ⁇ nol- quinazolme hydrochloride M.p. 239 - 240°C
  • Example 125 2-[4-(2-Methoxy-ethoxy)-phenylam ⁇ nol-4-(4-methoxy-phenylam ⁇ no)- quinazoline hydrochloride M.p 257 - 259°C
  • Example 130 4-Cyclohexylamino-2-(4-hydroxy-phenylamino)-quinazoline hydrochloride M.p. 238 - 240°C.
  • Example 131 4-Cyclohexylamino-2-[4-(2-methoxy-ethoxy)-phenylamino]-8-methoxy- quinazoline hydrochloride M.p. 247 - 248°C.
  • Example 132 4-(4-Chloro-phenylamino)-2-[4-(2-methoxy-ethoxy)-phenylamino]-8-methoxy- quinazoline hydrochloride M.p. 268 - 269°C.
  • Example 133 4-(4-Fluoro-phenylamino)-2-f4-(2-methoxy-ethoxy)-phenylamino]-8-metho ⁇ y- quinazoline hydrochloride M.p. 257 - 258°C.
  • Example 135 4-N-Ethyl-cvclohexylamino-2-f4-(2-methoxy-ethoxy)-phenylamino1-8-methoxy- quinazoline hydrochloride
  • Example 136 4-(4-Chloro-phenylamino)-2-f4-(2-methoxyacetyl-aminomethy ⁇ -phenylaminol- 8-methoxy-quinazoline hydrochloride M.p. 267 - 277°C.
  • Example 137 4-Cvclohexylamino-8-methoxy-2-(4-phenylamino)-quinazoline hydrochloride M.p. 292 - 293°C.
  • Example 138 2,4-Di-(4-chloro-phenylamino)-quinazoline hydrochloride M.p. 360 - 362°C.
  • Example 139 2-[4-(2-Methoxyace I-aminomethvO-phenylamino]-8-methoxy-4- phenylamino-quinazoline hydrochloride M.p. 255 - 256°C.
  • Example 140 4-Cyclohexylamino-2-f4-(2-hvdroxyethyl)-phenylamino1-quinazoline hydrochloride
  • Example 142 2-[4-(3-Hydroxy-propoxy)-phenylaminol-4-(3-methyl-phenylamino)- quinazoline hydrochloride M.p. 246 - 248°C.
  • Example 144 2-[3,4-(Methylene-dioxo)-phenylamino1-8-methoxy-4-phenylamino- quinazoline hydrochloride M.p. 267 - 269°C.
  • Example 145 4-(4-Fluoro-phenylamino)-2-[3,4-(methylene-dioxo)-phenylamino1-8-methoxy- quinazoline hydrochloride M.p. 296 - 297°C.
  • Example 146 4-(3-Hvdroxy-phenylamino)-2-[4-(piperidin-1 -yl)-phenylamino]-quinazoline hydrochloride
  • Example 147 4-(3-Methyl-phenylamino)-2-[4-(3-benzyloxy-propoxy)-phenylamino]- quinazoline hydrochloride M.p. 138 - 140°C.
  • Example 157 Tablets, each containing 50 mg of active ingredient, for example, 2,4- diphenylamino-quinazoline hydrochloride, can be prepared as follows:
  • composition for 10,000 tablets
  • the active ingredient is mixed with the lactose and 292 g of potato starch, and the mixture is moistened using an alcoholic solution of the gelatin and granulated by means of a sieve. After drying, the remainder of the potato starch, the talc, the magnesium stearate and the highly disperse silica are admixed and the mixture is compressed to give tablets of weight 145.0 mg each and active ingredient content 50.0 mg which, if desired, can be provided with breaking notches for finer adjustment of the dose.
  • Example 158 Coated tablets, each containing 100 mg of active ingredient, for example, 2,4-diphenylamino-quinazoline hydrochloride, can be prepared as follows:
  • Composition (for 1000 tablets): Active ingredient 100.00 g
  • Example 159 Tablets and coated tablets containing another compound of the formula (I) or a pharmaceutically acceptable salt of a compound of the formula (I), for example as in one of Examples 1 to 56 , can also be prepared in an analogous manner to that described in Examples 157 and 158.
  • AGT AAG TTC ATA CCA GGG GTC CCC ACT TGC TTT GAG ATA AAA CCT GAA 1116 Ser Lys Phe Ile Pro Gly Val Pro Thr Cys Phe Glu Ile Lys Pro Glu 340 345 350

Abstract

L'invention concerne une méthode de traitement de troubles et maladies associés au sous-type Y5 du récepteur du neuropeptide Y, laquelle consiste à administrer à un animal à sang chaud nécessitant un tel traitement, et notamment à l'homme, une dose efficace sur le plan thérapeutique d'un composé de la formule (I) dans laquelle les variables sont telles que définies. L'invention concerne également des nouveaux composés de la formule (I) ou un sel de ceux-ci, des compositions pharmaceutiques ainsi que la fabrication de ces nouveaux composés et des sels de ceux-ci.
PCT/EP1996/005066 1995-12-01 1996-11-18 Quinazolin-2,4-diazirines en tant qu'antagoniste du recepteur du neuropeptide y WO1997020822A1 (fr)

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US08/566,027 1995-12-01

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