Quinoline and Quinazolin Compounds Useful for Treatment

专利摘要:
The present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof: Formula I Where R 1 is C 1-4 alkoxy optionally substituted with one or more fluorine atoms; R 2 is H; Or C 1-6 alkoxy optionally substituted with one or more fluorine atoms; R 3 is one or more groups independently selected from H, halogen, C 1-4 alkoxy and CF 3 ; In addition, the R 2 and one R 3 groups may together be —OCH 2 — wherein the methylene group is attached at the ortho-position of the pendant phenyl ring; R 4 is a 4-, 5- and 6-membered heterocyclic ring containing one or two heteroatoms selected from N, O and S, wherein the ring is optionally fused to a benzene ring, or N, O and A 5- or 6-membered heterocyclic ring containing 1 or 2 heteroatoms selected from S, wherein all ring systems are optionally substituted; X is CH or N; L is absent or is a ring group or an open chain group. Compounds of formula (I) are particularly useful for the treatment of benign hyperprostatitis.
公开号:KR19990076693A
申请号:KR1019980704806
申请日:1996-12-05
公开日:1999-10-15
发明作者:알란 존 콜리스；데이비드 나탄 아브라함 폭스；줄리 뉴만
申请人:디. 제이. 우드, 무어 제임스 더블유；화이자 리써치 앤드 디벨로프먼트 캄파니 엔.브이./에스.에이.；
IPC主号:

专利说明:

Quinoline and Quinazolin Compounds Useful for Treatment
International patent application WO 89/05297 discloses a number of substituted quinazoline compounds that act as gastric acid secretion inhibitors.
The present invention relates to novel compounds useful for the treatment, in particular for the treatment of benign hyperprostatitis.
According to the present invention there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof (collectively referred to herein as a "compound of the invention"):
Where
R ¹ is C _1-4 alkoxy optionally substituted with one or more fluorine atoms;
R ² is H, or C _1-6 alkoxy optionally substituted with one or more fluorine atoms;
R ³ is one or more groups independently selected from H, halogen, C _1-4 alkoxy and CF ₃ ;
In addition, the R ² and one R ³ groups may together be —OCH ₂ —, wherein the methylene group is attached to the ortho-position of the pendant phenyl ring;
R ⁴ is a 4-, 5- and 6-membered heterocyclic ring containing one or two heteroatoms selected from N, O and S, wherein the ring is optionally fused to a benzene ring, or N, O and 5- or 6-membered heterocyclic rings containing 1 or 2 heteroatoms selected from S, wherein the ring systems are all OH, C _1-4 alkyl, C _1-4 alkoxy, halogen, SO ₂ NR ⁸ R ⁹ And optionally substituted with one or more groups independently selected from NHSO ₂ (C _1-4 alkyl), wherein when S is a member of a ring system, it may be substituted with one or two oxygen atoms;
R ⁸ and R ⁹ are independently H or C _1-4 alkyl;
X is CH or N;
L is absent or is a vent of formula (Ia) or a chain of formula (Ib):
[Wherein,
N is attached to the 2-position of the quinoline or quinazoline ring;
A is absent or is CO or SO ₂ ;
Z is CH or N;
m is 1 or 2, and in addition, m may be 0 when Z is CH;
n is 1, 2 or 3, but the sum of m and n is 2, 3, 4 or 5.]
[Wherein,
N is attached to the 2-position of the quinoline or quinazoline ring;
A 'and Z' are the same as A and Z, respectively;
R ⁶ and R ⁷ are independently H or C _1-4 alkyl;
p is 1, 2 or 3, and in addition, p may be 0 when Z 'is CH.]
Pharmaceutically acceptable salts include hydrochloride and acid addition salts such as hydrobromide and phosphate.
Alkyl and alkoxy groups that R ^1-4 may represent or include may be straight chain, branched chain, cyclic, or a combination thereof.
The heterocyclic group represented by R ⁴ may be saturated or unsaturated.
Compounds of the invention can be optically active. Specifically, when the R ³ substituents are at the 2- or 3-position of the phenyl ring, they may exhibit atropisomerism with respect to the linkage connecting the pendant phenyl ring to the rest of the molecule. The present invention includes all optical isomers of the compounds of formula (I) and all diastereomers thereof.
Preferred groups of the abovementioned compounds are
(a) R ¹ is methoxy;
(b) R ² is methoxy;
(c) R ² and R ³ together are —OCH ₂ —;
(d) R ³ is H or 4-fluoro;
(e) groups of formula (II) are particularly preferred when R ⁴ is of formula (II), especially when Y is O), formula (III), formula (IV), formula (V) or formula (VI) Having a group;
(f) compounds wherein L is a group of formula (VII) or absent (particularly preferably L is absent when R ⁴ is a group of formula (V) or formula (VI)):

[Wherein,
Y is O, CH ₂ , SO ₂ , NR ⁵ or CHF;
R ⁵ is H or C _1-4 alkyl.]
According to the invention,
(a) when X is CH, cyclizes a compound of formula (X);
(b) when A or A 'is present and Z or Z' is N, reacting the appropriate compound of Formula (XIIIa) or Formula (XIIIb) with a compound of Formula (XIV);
(c) reacting a compound of formula (XVIII) with a compound of formula (XIX);
(d) when X is N, reacting a compound of formula (XXII) with a suitable compound of formula (XXIIIa) or formula (XXIIIb);
(e) when A or A 'is CO, reacting the appropriate compound of formula (XXVIIIa) or formula (XXVIIIb) with a compound of formula (XXIX);
(f) by the action of a strong base, a compound of formula (I), in which L is a ventilator of formula (Ia), wherein L is a chain of formula (Ib), wherein R ⁶ and R ⁷ are each H To the corresponding compound of
(g) when A or A 'is absent and Z or Z' is N, reacting a compound of Formula (XIIIa) or Formula (XIIIb) with a compound of Formula (XXX); or
(h) when R ² and one R ³ together are —OCH ₂ —, cyclize the compound of formula (XXXI),
Converting the resulting compound of formula (I) into a pharmaceutically acceptable salt or vice versa if desired or necessary,
Also provided are methods of making the compounds of the present invention.
[Wherein,
R ^1-4 and L are as defined above.]
[Wherein,
R ^1-3 , R ⁶ , R ⁷ , X, m, n and p are as defined above.]
[Wherein,
R ⁴ is as defined above, A 'is CO or SO ₂ and Lg is a leaving group.]
[Wherein,
R ¹ , R ² , R ⁴ , X, and L are as defined above.]
[Wherein,
R ³ is as defined above.]
[Wherein,
R ^1-3 is as defined above.]
[Wherein,
R ⁴ , R ⁶ , R ⁷ , A, A ', Z, Z', m, n and p are as defined above.]
[Wherein,
R ^1-3 , R ⁶ , R ⁷ , X, Z, Z ', m, n and p are as defined above and Lg is a leaving group.]
HR ^4a
[Wherein,
R ^4a is a group defined by R ⁴ containing a nucleophilic nitrogen atom in a ring attached to H.]
R ⁴ -Hal
[Wherein,
R ⁴ is as defined above and Hal is a halogen atom attached to the ring.]
[Wherein,
R ^1, R ^4, X and L are the same as defined above, R ^3a is R ² and R ^3a groups together -OCH ₂ - is the same as the R ³ except that it does not.
In process (a), it can be cyclized in the presence of strong bases (eg lithium diisopropylamide) and quenched with water in a solvent which does not adversely affect the reaction at temperatures near room temperature.
In process (b), suitable leaving groups are OH and Cl. When the compound of formula (XIV) is a carboxylic acid, conventional coupling agents such as 1-hydroxybenzotriazole mono in solvents such as CH ₂ Cl ₂ that do not adversely affect the reaction at or near room temperature Hydrate, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 4-methylmorpholine]. When the leaving group is Cl, the reaction may be performed in a solvent (eg, CH ₂ Cl ₂ ) that does not adversely affect the reaction at about 0 ° C.
In process (c), palladium catalysts such as tetrakis (triphenylphosphine) in solvents (e.g. mixtures of toluene, ethanol and 1N aqueous sodium carbonate) that do not adversely affect the reaction at elevated temperatures (e.g. reflux temperature of the solvent). ) Palladium] can be carried out in the presence of.
In process (d), the reaction can be carried out in a solvent (eg n-butanol) which does not adversely affect the reaction in the presence of a base (eg triethylamine) at elevated temperature (eg 100 ° C.).
In method (e), suitable leaving groups include Cl. The reaction can be carried out in a solvent (eg THF) that does not adversely affect the reaction in the presence of a base (eg triethylamine) at room temperature.
The reaction can also be carried out without isolating the compound of formula (XXVIIIa) or formula (XXVIIIb) by reacting a compound of formula (XIIIa) or (XIIIb) with a triphosgene and a compound of formula (XXIX). In this case the leaving group is -Cl. The reaction can be carried out in a solvent (eg CH ₂ Cl ₂ ) which does not adversely affect the reaction in the presence of a base (eg triethylamine) at or near room temperature.
In method (f), suitable strong bases comprise lithium diisopropylamide. The reaction can be carried out in a solvent (eg THF) that does not adversely affect the reaction.
In process (g), the reaction may be carried out in a solvent (eg a mixture of n-BuOH and dimethylacetamide) which does not adversely affect the reaction in the presence of a base (eg triethylamine) at elevated temperature (eg 80 ° C.). Can be.
In method (h), a suitable reagent is sodium carbonate with palladium acetate. The reaction may be carried out at an elevated temperature (eg 130 ° C.) in a solvent (eg dimethylacetamide) that does not adversely affect the reaction.
In the methods described above [e.g., method (c)], and in the methods set out below for the preparation of the starting materials used in the methods, when R ² and R ³ are present in different molecules they are —OCH ₂ —yl No number will be apparent to those skilled in the art.
Compounds of formula (X) [see method (a)] can be prepared by reacting a compound of formula (XI) with a combination of a compound of formula (XII) with phosphorus oxychloride in dichloromethane at the reflux temperature of the solvent .
Where
R ^1-4 and L are as defined above.
Compounds of formula (XIIIa) or (XIIIb) wherein X is CH (see method (b)) are suitably formulated by bubbling HCl gas through a solution of the compound in dichloromethane to formula (XVa) It can be prepared from the compound of (XVb).
Where
R ^1-3 , R ⁶ , R ⁷ , m, n and p are as defined above.
The compound of formula (XVa) or formula (XVb) is suitably cyclized with potassium hydroxide or lithium diisopropylamide and terminated with water at elevated temperature (eg 90 ° C.) in DMSO and terminated with water (XVIa) or formula (XVb) It can be prepared from the compound of XVIb).
Where
R ^1-3 , R ⁶ , R ⁷ , m, n and p are as defined above.
Compounds of formula (XVIa) or formula (XVIb) may be prepared by the process described above for the preparation of compounds of formula (X) as described above by It can be prepared by reacting with a compound of.
Where
R ⁶ , R ⁷ , m, n and p are as defined above.
Compounds of formula (XIIIa) or (XIIIb), wherein X is N, are prepared by reacting formula (XXII) with a compound of formula (XXIIa) or formula (XXIIb), suitably using the conditions of method (d) mentioned above. Can be.
Formula XXII

Where
R ^1-3 , R ⁶ , R ⁷ , m, n and p are as defined above.
Compounds of formula (XVIII) wherein X is CH [see method (c)] can be prepared by cyclizing the compound of formula (XX) using the above-mentioned method (a) reaction conditions.
Where
R ¹ , R ² , R ⁴ and L are as defined above.
Compounds of formula (XX) can be prepared by reacting a compound of formula (XXI) with a compound of formula (XII) as defined above, using the processes for the preparation of compounds of formula (X) mentioned above.
Where
R ¹ and R ² are as defined above.
Compounds of formula (XVIII) wherein X is N can be prepared by appropriately reacting compounds of formula (XXVII) with compounds of formula (XXIIIa) or formula (XXIIIb) using the reaction conditions of the above-mentioned method (d). have.
Where
R ¹ and R ² are as defined above.
Compounds of formula (XXII) [see method (d)] can be prepared from compounds of formula (XXIV) by reacting with saturated ammonia solution in methanol.
Where
R ^1-3 is as defined above.
The compound of formula (XXIV) is reacted with a compound of formula (XIX) as defined above using the above-mentioned method (c) reaction conditions, followed by reaction with POCl ₃ and N, N-dimethylaniline It can be prepared from a compound of).
Where
R ¹ and R ² are as defined above.
Compounds of formula (XXV) can be prepared from compounds of formula (XXVI) using conventional techniques.
Where
R ¹ and R ² are as defined above.
Compounds of formula (XXVIIIa) or formula (XXVIIIb) wherein Lg is Cl [see method (e)] can be prepared from compounds of formula (XIIIa) or (XIIIb) by appropriate reaction with triphosgene. The reaction can be carried out in a solvent (eg CH ₂ Cl ₂ ) that does not adversely affect the reaction in the presence of a base (eg triethylamine) at about −10 ° C.
Compounds of formula (XXXI) [see method (h)] can be prepared from compounds of formula (XXXII) by reacting with compounds of formula (XXXIII) in the presence of sodium hydride in DMF at room temperature.
Where
R^One, R^3a, R⁴, L and X are as defined above.
Compounds of formula (XXXII) are analogous to compounds of formula (I) and can be prepared using the same method. For example, when X is CH, this compound can be prepared by cyclizing a compound analogous to the compound of formula (X) using method (a). If X is N, this compound may be suitably prepared from compounds analogous to the compound of formula (XXII) and compounds of formula (XXIIIa) or formula (XXIIIb) using method (d).
Formula (XI), Formula (XII), Formula (XIV), Formula (XVIIa), Formula (XVIIb), Formula (XIX), Formula (XXI), Formula (XXIIa), Formula (XXIIb), Formula (XXIII), Compounds of formula (XXVI), formula (XXIX), formula (XXX) and formula (XXXIII) may also be used using known or known techniques.
Intermediate compounds of Formula (X), Formula (XIIIa), Formula (XIIIb), Formula (XVIII), Formula (XXII), Formula (XXVIIIa), Formula (XXVIIIb) and Formula (XXXI) form additional aspects of the present invention. do.
It will be apparent to those skilled in the art that sensitive functional groups are not required to be protected and deprotected during the synthesis of the compounds of the present invention. This can be done by conventional techniques as described by T W Greene and P G M Wuts ('Protective Groups in Organic Synthesis', John Wiley and Sons Inc., 1991).
The compounds of the present invention are useful because they have pharmacological activity in animals. In particular, the compounds are useful for treating a number of conditions including hypertension, myocardial infarction, male erectile dysfunction, hyperlipidemia, myocardial hepatosis and benign hyperprostatitis. Most preferably applied to the latter state. Thus, according to another embodiment of the present invention, there is provided a method of treating benign hyperprostatitis comprising administering to a patient suffering from such a disease a therapeutically effective amount of a compound of the present invention. Also provided is the use of a compound of the invention as a medicament and the use of a compound of the invention in the manufacture of a medicament suitable for the treatment of benign hyperprostatitis.
The compounds of the present invention can be administered by any convenient route, such as oral, parenteral (ie, intravenous, subcutaneous) or rectal. In addition, the required daily dosage will of course vary depending on the particular compound used in the particular condition being treated and the neutrality of that condition. However, in general, the total daily dosage administered 1 to 4 times / day is suitably about 0.01 to 10 mg, preferably about 0.05 to 1 mg per kg of body weight.
In general, the compounds of the present invention will be administered in the form of a suitable pharmaceutical formulation. Accordingly, according to another embodiment of the present invention, there is provided a pharmaceutical formulation comprising preferably less than 50% by weight of the compound of the present invention together with a pharmaceutically acceptable adjuvant, diluent or carrier. The pharmaceutical formulation is preferably in unit dosage form. Such forms include solid dosage forms such as tablets, pills, capsules, powders, granules and suppositories for oral, parenteral or rectal administration; And flavored emulsions with edible oils such as sterile parenteral solutions or suspensions, suitably flavored syrups, cottonseed oil, sesame oil, coconut oil and peanut oil, and liquid dosage forms such as elixirs and similar pharmaceutical vehicles.
Solid preparations may be prepared by the active ingredient in conventional tablets such as pharmaceutical carriers such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, gums and other diluents such as water. Prepared by mixing with preparative ingredients to form a formulation in the form of a homogeneous pre-formulation with a single dispersion of the active ingredient, which can be readily divided into effective unit dosage forms, which typically contain from 0.1 to about 500 mg of the active ingredient. Solid formulation forms may be coated or otherwise combined to prolong the action of the formulation.
The formulations of the invention may also comprise human 5-α reducing agent inhibiting compounds [see International Patent Application No. WO 95/28397], or the compounds of the invention may be mixed for simultaneous, separate or continuous use. As preparations may be provided in pharmaceutical packs which also contain human 5-α reducing agent inhibitory compounds.
Compounds of the invention can be tested against the following screen sets.
Contractile response of the human prostate
Prostate tissue was cut into longitudinal strips (about 3 × 2 × 10 mm) and suspended in an organ bath under 1 g of resting tension in Krebs Ringer bicarbonate of the following composition (mM): NaCl (119), KCl (4.7), CaCl ₂ (2.5), KH ₂ PO ₄ (1.2), MgSO ₄ (1.2), NaHCO ₃ (25), Glucose (11) and 95% O ₂ /5% Is filled with CO ₂ gas. The solution also contained 10 mM cocaine and 10 mM corticosterone. Tissues were added with a sensitive dose of (-)-noradrenaline (100 mM) and washed for at least 45 minutes. Isotonic shrinkage in response to cumulative addition of (-)-noradrenaline yielded a reference curve in all tissues. The curve is then further shown with or without antagonist (incubated for 2 hours). Antagonist affinity estimates (pA ₂ ) were measured using a single concentration of antagonist, where pA ₂ = -log [A] / (DR-1), where the dose rate (DR) for the corresponding control was And a single concentration of antagonist [A] under the assumption that the Schild regression is nearly single.
Prostate Pressure and Blood Pressure in Anesthetized Dog Models
Mature female beagle (12-15 kg body weight) was anesthetized with sodium pentobarbitone (intravenously injected at 30-50 mg / kg) and tracheal cannula was inserted. Pentobarbitone infusion was used to maintain anesthesia continuously. Bird Mk8 respirator (Bird Corp., Palm Springs, Calif., Calif.) adjusted to maintain blood gas in the range of pO ₂ 90-110 mmHg, pCO ₂ 35-45 mmHg, and pH 7.35-7.45. )] Was used to breathe the animals. Body temperature was maintained at 36 to 37.5 ° C. using a heated operating table. The catheter was placed into the left femoral artery for blood pressure measurement and also into the left femoral vein for compound administration. The heart rate was recorded via lead II ECG. Laparotomy was performed with cannula in both ureters to prevent changes in flow rate in the bladder. A 7F cardiac catheter (with a 1.5 mL balloon tip) was inserted through the urethra into the bladder. The instrument was filled with air and the catheter was removed until the instrument was gradually loaded in the prostate gland, which was confirmed by finger pressure. Instrument pressure was recorded via a Druck transducer. Prostate pressure and hemodynamic parameters were obtained on Grass Polygraph (Grass Instruments, Quincy, Mass.), And data were collected from Motorola 68000-based microcomputer systems (Temple, Arizona, USA). The measurement was carried out on a survey line using Motorola Inc. of the company. Compounds were prepared in PEG 300 and administered intravenously via femoral intravenous catheter. Reference dose-response curves (two reference curves for each experiment) were obtained by response to phenylephrine (administered 1-16 μg / kg in saline intravenously). Prior to the preparation of the phenylephrine curve (making up to a maximum dose of 128 μg / kg in the presence of the test compound), the compound was administered intravenously for 10 minutes at 10 to 300 μg / kg (relative to the compound base).
Due to the α ₁ -associated negative rhythm of phenylephrine, no perfect maximum response was obtained, but 10% higher than the baseline reaction obtained with 16 μg / kg of phenylephrine. Drug concentrations were calculated by shield analysis using dose ratios derived from metastasis in the phenylephrine dose-response curves based on the molar amount of compound / kg body weight yielding the "pseudo pA ₂ " calculation.
The compounds of the present invention are more potent, have a longer duration of action, have a broader range of activity, are more stable, have fewer side effects or are more selective (specifically, they are for example a-adrenoceptor pathways). Selective antagonism of star prostate receptors may have beneficial effects on benign hyperprostatitis without causing unnecessary cardiovascular effects), or may have the advantage of having properties that are more useful than prior art compounds.
The invention is illustrated by the following examples, where the abbreviations are used as follows:
DMA is dimethylacetamide,
DMF is dimethylformamide, DMPU is 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidone, EtOAc is ethyl acetate, EtOH is ethanol, h is time , MeOH is methanol, min is minute, n-BuOH is n-butanol, THF is tetrahydrofuran and tlc is thin layer chromatography.
Intermediate 1
1- (tert-butyloxycarbonyl) -1,4-diazepane
Di- (tert-butyl) in CH ₂ Cl ₂ (300 mL) in a solution of homopyrazine (100 g, 1.0 mole) and triethylamine (210 mL, 152 g, 1.5 mole) in CH ₂ Cl ₂ (500 mL) at 0 ° C. ) A solution of dicarbonate (195 g, 0.89 mol) was added. The mixture was allowed to warm to rt and stirred for 18 h, then CH ₂ Cl ₂ was evaporated under reduced pressure. The resulting residue was partitioned between ether and 2N citric acid and the aqueous layer was extracted four times with ether (200 mL). The aqueous layer was basified with 2N aqueous NaOH and then extracted four times with CH ₂ Cl ₂ (400 mL). The combined CH ₂ Cl ₂ extracts were washed twice with H ₂ O, once with saturated brine and dried over MgSO ₄ . After evaporation under reduced pressure, azeotroping four times with CH ₂ Cl ₂ gave the title compound (94.3 g, 53%) as a yellow waxy solid. R _f 0.25 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 90/10/1, v / v). MS m / z 201 (MH ⁺ ). Found: C, 58.86; H, 10.03; N, 13.58; C ₁₀ H ₂₀ N ₂ O ₂ 0.05CH ₂ Cl ₂ is C, 59.02; H, 9.91; N, 13.70% is required.
Intermediate 2
1- (tert-butyloxycarbonyl) -4- (4-morpholinecarbonyl) -1,4-diazepane
4-morpholine in CH ₂ Cl ₂ (100 mL) in a solution of Intermediate 1 (92.0 g, 0.46 mole) and triethylamine (96.0 mL, 69.7 g, 0.69 mole) in CH ₂ Cl ₂ (500 mL) at 0 ° C. A solution of carbonyl chloride (64.0 mL, 82.0 g, 0.55 mole) was added dropwise and the reaction was stirred at rt under N ₂ for 18 h. The reaction mixture is then diluted with CH ₂ Cl ₂ (400 mL), washed once with 2N citric acid (400 mL) three times with saturated brine (500 mL), dried over MgSO ₄ , and evaporated to yield the title compound as an off-white solid. 141.7 g, 98%) was obtained. R _f 0.80 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 90/10/1, v / v). MS m / z 314 (MH ⁺ ). Found: C, 57.50; H, 8.69; N, 13.41; C ₁₅ H ₂₇ N ₃ O ₄ is C, 57.50; H, 8.69; N, 13.41% is required.
Intermediate 3
1- (4-morpholinecarbonyl) -1,4-diazepane hydrochloride
The solution of Intermediate 2 (140.0 g, 0.44 mol) in CH ₂ Cl ₂ / MeOH (1/1, v / v, 600 mL) at 0 ° C. was saturated with HCl gas and the reaction mixture was allowed to warm under N ₂ for 18 h. After stirring at, the reaction mixture was evaporated under reduced pressure, slurried in EtOAc and filtered to give a white hygroscopic solid. It was slurried in acetone, filtered, washed with ether and purified by drying in vacuo at 60 ° C. to give the title compound (99.0 g, 90%) as a colorless solid. R _f 0.41 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 84/14/2, v / v). MS m / z 214 (MH ⁺ ). Found: C, 47.50; H, 8.10; N, 16.55; C ₁₀ H ₁₉ N ₃ O ₂ HCl 0.2 H ₂ O is C, 47.41; H, 8.12; N, 16.59% is required.
Intermediate 4
1-acetyl-4- (4-morpholinecarbonyl) -1,4-diazepane
To a solution of the intermediate 3 (50 g, 0.2 mole) and triethylamine (42 mL, 30.5 g, 0.3 mole) in CH ₂ Cl ₂ (400 mL) at 5 ° C. was added 15% acetic anhydride (23 mL, 24.9 g, 0.24 mole). After dropping over, the reaction was stirred for an additional 2 hours at room temperature under N ₂ . After dilution with CH ₂ Cl ₂ (600 mL), it was washed twice with saturated aqueous sodium bicarbonate (200 mL) and the mixed aqueous layers were extracted once with CH ₂ Cl ₂ (100 mL). The CH ₂ Cl ₂ layers are combined and washed with saturated brine, dried over MgSO ₄ , evaporated and a pale brown oil. It was dissolved in CH ₂ Cl ₂ (300 mL) and treated with triethylamine (8 mL, 5.8 g, 0.06 mol) and EtOH (5 mL), stirred at rt for 1 h, washed with saturated sodium bicarbonate and the aqueous layer was CH Extracted 5 times with ₂ Cl ₂ . The combined CH ₂ Cl ₂ layer was dried over MgSO ₄ and evaporated under reduced pressure to give a yellow oil which was then azeotroduced four times with CH ₂ Cl ₂ to give the title compound (47.1 g, 92%) as a yellow oil. R _f 0.45 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 90/10/1, v / v). MS m / z 256 (MH ⁺ ). Found: C, 52.62; H, 8.18; N, 15.02; C ₁₂ H ₂₁ N ₃ O ₃ 0.3CH ₂ Cl ₂ is C, 52.61; H, 7.75; N, 14.96% is required.
Example 1
4-amino-5- (2-chlorophenyl) -7-methoxy-2- [4- (4-morpholinecarbonyl) -1,4-diazepan-1-yl] quinoline
(a) 5- (2-chlorophenyl) -4-cyano-3-nitroanisole
5-bromo-4-cyano-3-nitroanisole (manufactured by Harrison et al. (J. Chem. Soc. C, 1769 (1966))) (250 mg, 0.86 mmol) and 2 Chlorophenylboronic acid (150 mg, 0.96 mmol) was dissolved in a mixture of toluene (10 mL), EtOH (5.6 mL) and 1N aqueous sodium carbonate (1.7 mL). The solution was left under nitrogen atmosphere and tetrakis (triphenylphosphine) palladium (30 mg, 0.03 mmol) was added. After refluxing for 3 hours, the solvent was removed from the reaction mixture under reduced pressure. The residue was partitioned between H ₂ O (50 mL) and EtOAc (50 mL) and the EtOAc layer was washed twice with H ₂ O (50 mL) and dried over MgSO ₄ . After removing the solvent, the crude material was purified on silica gel, eluting with hexane / ether (1/1, v / v). This resulted in the subtitle compound as a colorless gum (252 mg, 100%). R _f 0.38 (hexane / ether 1: 1, v / v). MS m / z 306 and 308 (MNH ₄ ⁺ ).
(b) 3-amino-5- (2-chlorophenyl) -4-cyanoanisole
The product of step (a) (300 mg, 1.0 mmol) was dissolved in DMF (3 mL) and a solution of sodium dithionite hydrate was added (500 mg in 6 mL H ₂ O, 2.9 mmol). The solution was warmed and any solid precipitated out of the solution. After stirring for 30 minutes, 15 mL of 2N HCl and H ₂ O were added. This mixture was extracted twice with EtOAc (30 mL), neutralized with 2N NaOH and reextracted twice with EtOAc (30 mL). The combined EtOAc extracts were dried over MgS0 ₄ and the solvent was removed to give crude product. It was purified on silica gel eluting with CH ₂ Cl ₂ / MeOH (98.2, v / v) to give the subtitle compound as a colorless gum (190 mg, 74%). R _f 0.29 (hexane / ether 1: 1, v / v). MS m / e 276 and 278 (MNH ₄ ⁺ ).
(c) 6- (2-chlorophenyl) -4-methoxy-2- {1- [4- (4-morpholinecarbonyl) -1,4-diazepan-1-yl] ethylideneamino} benzo Nitrile
The product of step (b) (190 mg, 0.74 mmol) was dissolved in CH ₂ Cl ₂ (5 mL) at room temperature and phosphorus oxychloride (0.082 mL, 0.86 mmol) was added in portions to the stirred solution. After 20 minutes, a solution of intermediate 4 (380 mg, 1.5 mmol) in CH ₂ Cl ₂ (5 mL) was added to the reaction mixture and the mixture was heated to reflux for 14 hours. After cooling to room temperature, additional 30 mL of additional CH ₂ Cl ₂ was added and the solution was washed twice with 2N aqueous NaOH (20 mL), dried over MgSO ₄ , and the solvent removed to give a colorless gum (155 mg, 43%). As a subtitle compound was obtained. R _f 0.26 (CH ₂ Cl ₂ / MeOH 95/5, v / v). MS m / z 496 (MH ⁺ ).
(d) 4-amino-5- (2-chlorophenyl) -7-methoxy-2- [4- (4-morpholinecarbonyl) -1,4-diazepane-1-
Quinoline
The product of step (c) (155 mg, 0.31 mmol) was dissolved in dry THF (5 mL) under anhydrous nitrogen atmosphere and the solution was cooled to -78 ° C. A solution of 1.5 M lithium diisopropylamide in THF (0.25 mL, 0.38 mmol) was added to the reaction and allowed to warm to room temperature. Thin film chromatography analysis indicated that since the starting material remained, the solution was recooled to -78 ° C and 0.25 mL of additional lithium diisopropylamide solution was added. After warming to room temperature, the mixture was again analyzed by thin layer chromatography and then quenched with H ₂ O (0.5 mL). EtOAc (30 mL) was added and the solution was washed twice with H ₂ O (20 mL), dried over MgSO ₄ and the solvent was removed under reduced pressure. The crude material was purified on silica gel eluting with CH ₂ Cl ₂ /MeOH/0.88NH ₃ (92/7/1, v / v) to afford the title compound as a colorless foam (50 mg, 31%). R _f 0.25 (CH ₂ Cl ₂ / MeOH 9/1, v / v). MS m / z 496 (M ⁺ ). ¹ H NMR (CDCl ₃ ) δ: 2.05 (2H, m), 3.14 (2H, m), 3.45 (2H, t), 3.60 (6H, m), 3.70 (2H, t), 2.83 (2H, bs) , 3.86 to 3.99 (5H, m), 5.75 (1H, s), 6.47 (1H, s), 7.0 (1H, s), 7.28 to 7.45 (3H, m), 7.45 to 7.51 (1H, m). Found C, 60.75; H, 6.02; M, 13.13; C ₂₆ H ₃₀ ClN ₅ O ₃ 0.25CH ₂ Cl ₂ is C, 60.96; H, 5.94; N, 13.54% is required.
Example 2
4-amino-7-methoxy-2- [4- (4-morpholincarbonyl) -1,4-diazepan-1-yl] -5-phenylquinoline
(a) 4-cyano-3-nitro-5-phenylanisole
A subtitle compound was prepared by the method of Example 1 (a) using phenylboronic acid. The crude material was titrated with 20 mL of ether and recrystallized from EtOAt to give a white crystalline solid (83%). Melting point 175 to 176 ° C. R_f0.44 (hexane / ether 1: 1, v / v). MS m / z 169 (M⁺Is Not observed).
(b) 3-amino-4-cyano-5-phenylanisole
The product of step (a) using the method of Example 1 (b) was reduced to yield the subtitle compound (41%) as a yellow gum. R _f 0.30 (hexane / ether 1: 1, v / v). MS m / z 242 (M ⁺ not observed).
(c) 4-methoxy-2- {1- [4-morpholin-4-carbonyl) -1,4-diazepane-1-yl] ethylideneamino} -6-phenylbenzonitrile
The subtitle compound was obtained as a white foam from the product of step (b) in a yield of 87% using the method described in Example 1 (c). R _f 0.66 (CH ₂ Cl ₂ / MeOH 9/1, v / v). MS m / z 462 (MH ⁺ ).
(d) 4-amino-7-methoxy-2- [4- (4-morpholinecarbonyl) -1,4-diazepan-1-yl] -5-phenylquinoline
The title compound (87%) was obtained as off-white powder from the product of step (c) using the method described in Example 1 (d). R _f 0.16 (CH ₂ Cl ₂ / MeOH 9/1, v / v). MS m / z 462 (MH ⁺ ). ¹ H NMR (CDCl ₃ ) δ: 2.05 (2H, m), 3.16 (4H, m), 3.48 (2H, t), 3.56 to 3.68 (6H, m), 3.71 (2H, t), 3.87 to 3.99 ( 7H, m), 5.73 (1H, s), 6.54 (1H, s), 7.01 (1H, bs), 7.41 (5H, s). Found C, 66.89; H, 6.78; M, 14.42; C ₂₆ H ₃₁ N ₅ O ₃ 0.1CH ₂ Cl ₂ is C, 66.69; H, 6.69; N, 14.90% is required.
Example 3
4-amino-6,7-dimethoxy-2- [4- (4-morpholinecarbonyl) -1,4-diazepan-1-yl] -5-phenylquinoline
(a) 2- (3,4-dimethoxyphenyl) -4,4-dimethyl-Δ ² -oxazoline
Subsidiary compounds are described in Meyers et al. Org. Chem., 39, 2787, (1974)] was prepared from 3,4-dimethoxybenzoic acid.
(b) 2- (3,4-dimethoxy-2-iodophenyl) -4,4-dimethyl-Δ ² -oxazoline
n-butyllithium (2.5M in hexane, 8.9 mL, 22.3 mmol) was added dropwise to the solution of the product of step (a) (4.2 g, 17.8 mmol) in dry ether (200 mL) at 0 ° C. and the reaction was carried out for 2 hours. Stir under N ₂ . To this was added iodine (5.46 g, 21.5 mmol) in ether (100 mL) dropwise and the reaction was allowed to warm to room temperature over 1 hour. The reaction mixture was poured into H ₂ O, the ether layer was separated and washed once with saturated aqueous sodium thiosulfate solution, then the saturated brine was dried over MgSO ₄ and evaporated under reduced pressure to give the subtitle compound as a yellow oil (5.2 g, 80%). ) Was obtained. R _f 0.60 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 90/10/1, v / v); MS m / z 362 (MH ⁺ ).
(c) 3,4-dimethoxy-2-iodobenzonitrile
POCl ₃ (2.7 mL, 4.4 g, 28.8 mmol) was added to a solution (5.2 g, 14.4 mmol) of the product of step (b) in pyridine (30 mL) and the reaction was heated to 85 ° C. for 18 h. The reaction mixture was cooled, partitioned between saturated aqueous sodium carbonate solution (300 mL) and then extracted twice with ether (100 mL). The ether layer was washed twice with 2N HCl (75 mL), then once with H ₂ O, then dried over MgSO ₄ and evaporated under reduced pressure to give a yellow oil. It was purified by slurrying with hexane and filtered to give the subtitle compound (2.82 g, 68%) as an off-white solid. R _f 0.80 (CH ₂ Cl ₂ / MeOH 95/5, v / v). MS m / z 307 (MH ⁺ ). Found C, 38.03; H, 2.88; N, 4.64; C ₉ H ₈ NO ₂ I 0.05hexane is C, 38.05; H, 2.97; N, 4.77% is required.
(d) 3,4-dimethoxy-2-iodo-6-nitrobenzonitrile
Nitronium tetrafluoroborate (1.73 g, 13.0 mmol) was added in portions to a solution (2.67 g, 9.2 mmol) of product of step (c) in acetonitrile (40 mL) at 0 ° C. The reaction was stirred under N _{2 for} 0.5 h, then added to saturated aqueous sodium bicarbonate solution and extracted once with EtOAc. The organic layer was washed once with saturated brine, dried over MgSO ₄ and evaporated under reduced pressure to give a residue, which was slurried in hexane and filtered to give the subtitle compound (2.51 g, 82%) as an off-white solid. . R _f 0.46 (EtOAc / hexanes 1/1, v / v). MS m / z 352 (MNH ₄ ⁺ ).
(e) 3,4-dimethoxy-6-nitro-2-phenylbenzonitrile
The subtitle compound was prepared from the product of step (d) by the method of Example 1 (a) using phenylboronic acid. Subtitle compound (81%) was obtained as a pale yellow solid. R _f 0.46 (EtOAc / hexanes, 1/1, v / v). MS m / z 302 (MNH ₄ ⁺ ). Found: C, 63.23; H, 4.23; N, 9.86; C ₁₅ H ₁₂ N ₂ O ₄ is C, 63.38; H, 4.23; N, 9.86% is required.
(f) 6-amino-3,4-dimethoxy-2-phenylbenzonitrile
A subtitle compound was prepared from the product of step (e) by the method of Example 1 (b). The crude product was purified on silica gel eluting with EtOAc / hexane (1/1, v / v) to afford the subtitle compound (60%) as a pale yellow solid. R _f 0.40 (EtOAc / hexanes, 1/1, v / v). MS m / z 272 (MNH ₄ ⁺ ). Found: C, 70.30; H, 5.50; N, 10.80; C ₁₅ H ₁₄ N ₂ O ₂ 0.1H ₂ O is C, 70.37; H, 5.55; N, 10.95% is required.
(g) 3,4-dimethoxy-6- {1- [4- (morpholin-4-carbonyl) -1,4-diazepane-1-yl] ethylideneamino} -2-phenylbenzonitrile
A subtitle compound was prepared from the product of step (f) and intermediate 4 by the method of Example 1 (c). The crude product was purified on silica gel eluting with CH ₂ Cl ₂ / MeOH (95/5, v / v) to give the subtitle compound (87%) as a colorless foam. MS m / z 492 (MH ⁺ ). Found: C, 64.75; H, 6.74; N, 13.67; C ₂₇ H ₃₃ N ₅ O ₄ 0.15CH ₂ Cl ₂ is C, 60.64; H, 6.61; N, 13.89% is required.
(h) 4-amino-6,7-dimethoxy-2- [4- (4-morpholinecarbonyl) -1,4-diazepan-1-yl] -5-phenylquinoline
The title compound was prepared from the product of step (g) using the method of Example 1 (d). The crude product was purified on silica gel eluting with CH ₂ Cl ₂ /MeOH/0.88NH ₃ (90/10/1, v / v) to afford the subtitle compound (46%) as a colorless foam. R _f 0.30 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 90/10/1, v / v). MS m / z 492 (MH ⁺ ). ¹ H NMR (CDCl ₃ ) δ: 2.05 (2H, m), 3.16 (4H, m), 3.35 (2H, m), 3.48 (3H, s), 3.63 (6H, m), 3.74 (2H, m) , 3.87 (2H, bs), 3.97 (2H, m), 4.00 (3H, s), 5.68 (1H, s), 7.13 (1H, bs), 7.39 (2H, m), 7.45 (3H, m). Found C, 63.02; H, 6.62; M, 13.35; C ₂₇ H ₃₃ N ₅ O ₄ 0.35CH ₂ Cl ₂ is C, 63.02; H, 6.47; N, 13.44% is required.
Example 4
4-amino-6,7-dimethoxy-5- (4-fluorophenyl) -2- [4- (4-morpholinecarbonyl) -1,4-diazepan-1-yl] quinoline
(a) 3,4-dimethoxy-2- (4-fluorophenyl) -6-nitrobenzonitrile
A subtitle compound was prepared from the compound of Example 3 (d) and 4-fluorophenylboronic acid by the method of Example 1 (a). Subtitle compound (83%) was obtained as a pale yellow solid. R _f 0.17 (toluene). MS m / z 303 (MH ⁺ ). Found: C, 59.19; H, 3.63; N, 8.84; C ₁₅ H ₁₂ N ₂ O ₄ 0.15H ₂ O is C, 59.04; H, 3.71; N, 9.18% is required.
(b) 6-amino-3,4-dimethoxy-2- (4-fluorophenyl) benzonitrile
A subtitle compound was prepared from the product of step (a) by the method of Example 1 (b). Subtitle compound (85%) was obtained as a white solid. R _f 0.73 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 90/10/1, v / v). MS m / z 273 (MH ⁺ ). Found: C, 66.09; H, 4.79; N, 10.28; C ₁₅ H ₁₃ N ₂ O ₂ F is C, 66.16; H, 4.81; N, 10.28% is required.
(c) 3,4-dimethoxy-2- (4-fluorophenyl) -6- {1- [4-morpholin-4-carbonyl) -1,4-diazepan-1-yl] ethylidene Amino} benzonitrile
A subtitle compound was prepared from the product of step (b) and intermediate 4 by the method of Example 1 (c). Subtitle compound (83%) was obtained as a colorless solid. Melting point 174-176 ° C. R _f 0.12 (EtOAc). MS m / z 510 (MH ⁺ ). Found: C, 63.61; H, 6.35; N, 13.68; C ₂₇ H ₃₂ N ₅ O ₄ F is C, 63.67; H, 6.33; N, 13.74% is required.
(d) 4-amino-6,7-dimethoxy-5- (4-fluorophenyl) -2- [4- (4-morpholinecarbonyl) -1,4-diazepan-1-yl] quinoline
The title compound was prepared from the product of step (c) by the method of Example 1 (d). The crude product was purified on silica gel, eluting with CH ₂ Cl ₂ /MeOH/0.88NH ₃ (95/5 / 0.5, v / v), then triturated with EtOAc and filtered to afford the subtitle compound (41%) as a colorless solid. Obtained. Melting point 189-192 ° C. R _f 0.15 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 95/5 / 0.5, v / v). MS m / z 510 (MH ⁺ ). ¹ H NMR (CDCl ₃ ) δ: 2.05 (2H, m), 3.13 (4H, m), 3.32 (2H, m), 3.48 (3H, s), 3.63 (6H, m), 3.74 (2H, m) , 3.77-4.23 (4H, bm), 4.00 (3H, s), 5.71 (1H, s), 7.15 (2H, m), 7.23 (1H, bs), 7.32 (2H, m). Found: C, 63.07; H, 6.41; N, 13.17; C ₂₇ H ₃₂ N ₅ O ₄ F 0.25 H ₂ O 0.15 EtOAc is C, 62.82; H, 6.39; N, 13.28% is required.
Example 5
(R / S) -4-amino-2- [4- (1,4-benzodioxane-2-carbonyl) -1,4-piperazin-1-yl] -6,7-dimethoxy-5 -Phenylquinoline
(a) 1-acetyl-4- (tert-butyloxycarbonyl) piperazine
The subtitle compound was prepared by the method of intermediates 1 and 2 using piperazine in place of homopiperazine and acetyl chloride in place of 4-morpholinecarbonyl chloride.
(b) 6- {1- [4- (tert-butyloxycarbonyl-1,4-piperazin-1-yl} ethylideneamino} -3,4-dimethoxy-2-phenylbenzonitrile
A subtitle compound was prepared from the compound of Example 3 (f) and the product of step (a) by the method of Example 1 (c). The crude product was purified on silica gel eluting with CH ₂ Cl ₂ / MeOH (97/3, v / v). Subtitle compound (96%) was obtained as a foam. R _f 0.35 (CH ₂ Cl ₂ / MeOH 95/5, v / v). MS m / z 465 (MH ⁺ ).
(c) 4-amino-2- [4- (tert-butyloxycarbonyl) -1,4-piperazin-1-yl] -6,7-dimethoxy-5-phenylquinoline
To the solution (270 mg, 0.58 mmol) of the product of step (b) in DMSO (3 mL) is added a thin piece of KOH (33 mg, 0.58 mmol), the reaction mixture is heated to 90 ° C. for 4 hours after the reaction has cooled, Add to H ₂ O and extract three times with EtOAc. The combined organic layers were dried over MgSO ₄ and evaporated under reduced pressure to give the subtitle compound (65 mg, 24%) as a foam. R _f 0.15 (CH ₂ Cl ₂ / MeOH 95/5, v / v). MS m / z 465 (MH ⁺ ).
(d) 4-amino-6,7-dimethoxy-5-phenyl-2- (1,4-pyrazin-1-yl) quinoline
HCl was bubbled through 0 solution (580 mg, 1.25 mmol) of the product of step (c) in CH ₂ Cl ₂ at 0 ° C. After 15 minutes, the reaction mixture is evaporated under reduced pressure and the residue is first taken up with CH ₂ Cl ₂ /MeOH/0.88NH ₃ (92/7/1, v / v) followed by CH ₂ Cl ₂ /MeOH/0.88NH ₃ Purification on silica gel eluting with (90/10/1, v / v) gave the subtitle compound (380 mg, 84%) as a light brown foam. R _f 0.16 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 92/7/1, v / v). MS m / z 365 (MH ⁺ ).
(e) (R / S) -4-amino-2- [4- (1,4-benzodioxane-2-carbonyl) -1,4-piperazin-1-yl] -6,7-dime Oxy-5-phenylquinoline
(R / S) -1,4-benzodioxane-2-carboxylic acid (50 mg, 0.28 mmol) was dissolved in CH ₂ Cl _{2 with} 1-hydroxybenzotriazole monohydrate (40 mg, 0.30 mmol) and 1- (3 -Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (70 mg, 0.38 mmol) was added to the solution. To this was successively added 4-methylmorpholine (0.6 mL, 0.55 mmol) and the product of step (d) (100 mg, 0.28 mmol), and then the reaction mixture was washed with H ₂ O, saturated aqueous sodium bicarbonate and saturated brine. Then stirred at room temperature under N ₂ for 20 h. The organic layer was separated, dried over MgSO ₄ and evaporated under reduced pressure. The crude product was purified on silica, eluting successively with EtOAc / hexane (1/1, v / v) and EtOAc to afford the title compound (120 mg, 79%) as a foam. R _f 0.30 (EtOAc / hexanes 1/1, v / v). MS m / z 527 (MH ⁺ ). ¹ H NMR (CDCl ₃ ) δ: 3.41 to 4.05 (2H, b), 3.52 (3H, s), 3.73 (4H, m), 3.90 (4H, m), 4.00 (3H, s), 4.35 (1H, dd), 4.50 (1H, dd), 4.87 (1H, dd), 5.80 (1H, s), 6.89 (4H, m), 7.16 (1H, m), 7.42 (5H, m). Found: C, 66.08; H, 5.94; N, 9.64; C ₃₀ H ₃₀ N ₄ O ₅ 0.5 EtOAc 0.5H ₂ O is C, 66.25; H, 6.04; N, 9.06% is required.
Example 6
4-amino-2- [4- (furan-2-carbonyl) -1,4-piperazin-1-yl] -6,7-dimethoxy-5-phenylquinoline
The title compound was prepared by the method of Example 5 (e) from the compound of Example 5 (d) and 2-furancarboxylic acid. The title compound (74%) was obtained as a foam. R _f 0.30 (EtOAc / hexanes 1/1, v / v). MS m / z 459 (MH ⁺ ). ¹ H NMR (CDCl ₃ ) δ: 3.41 to 4.05 (2H, b), 3.52 (3H, s), 3.73 (4H, m), 3.90 (4H, m), 4.00 (3H, s), 4.35 (1H, dd), 4.50 (1H, dd), 4.87 (1H, dd), 5.80 (1H, s), 6.89 (4H, m), 7.16 (1H, m), 7.42 (5H, m). Found: C, 65.03; H, 5.92; N, 11.03; C ₃₀ H ₃₀ N ₄ O ₅ 0.4 EtOAc H ₂ O is C, 64.73; H, 6.10; N, 10.94% is required.
Example 7
(R / S) -4-amino-6,7-dimethoxy-5-phenyl-2- [4- (tetrahydrofuran-2-carbonyl) -1,4-piperazin-1-yl] quinoline
The title compound was prepared by the method of Example 5 (e) from the compound of Example 5 (d) and (R / S) -tetrahydrofuran-2-carboxylic acid. The crude product was purified on silica eluting with CH ₂ Cl ₂ /MeOH/0.88NH ₃ (95 / 4.5 / 0.5, v / v) to give the title compound (53%) as a white foam. R _f 0.45 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 92/7/1, v / v). MS m / z 463 (MH ⁺ ). ¹ H NMR (CDCl ₃ ) δ: 1.82 to 2.05 (3H, m), 2.35 (1H, m), 3.20 to 4.00 (12H, m), 3.48 (3H, s), 4.00 (3H, s), 4.63 ( 1 H, m), 5.78 (1 H, s), 7.10 (1 H, s), 7.35-7.48 (5 H, m). Found: C, 65.57; H, 6.51; N, 11.60; C ₂₆ H ₃₀ N ₄ O ₄ 0.2CH ₂ Cl ₂ is C, 65.62; H, 6.39; N, 11.68% is required.
Example 8
4-amino-6,7-dimethoxy-2- [4- (furan-2-carbonyl) -1,4-diazepan-1-yl] -5-phenylquinoline
(a) 1-acetyl-4- (tert-butyloxycarbonyl) -1,4-diazepane
The subtitle compound was prepared by the method of intermediates 1 and 2 using acetyl chloride instead of 4-morpholinecarbonyl chloride. Subtitle compound (82%) was obtained as a yellow oil. R _f 0.28 (CH ₂ Cl ₂ / MeOH 95/5, v / v). MS m / z 243 (MH ⁺ ).
(b) 6- {1- [4- (tert-butyloxycarbonyl-1,4-diazepan-1-yl} ethylideneamino} -3,4-dimethoxy-2-phenylbenzonitrile
A subtitle compound was prepared by the method of Example 1 (c) from the compound of Example 3 (f) and the product of step (a). Subtitle compound (41%) was obtained as a pale yellow foam. R _f 0.21 (CH ₂ Cl ₂ / MeOH 97.5 / 2.5, v / v). MS m / z 479 (MH ⁺ ).
(c) 4-amino-2- [4- (tert-butyloxycarbonyl) -1,4-diazepan-1-yl] -6,7-dimethoxy-5-phenylquinoline
A subtitle compound was prepared by the method of Example 1 (d) from the product of step (b). Subtitle compound (63%) was obtained as a pale orange foam. R _f 0.51 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 92/7/1, v / v). MS m / z 479 (MH ⁺ ).
(d) 4-amino-6,7-dimethoxy-2- (1,4-diazepan-1-yl) -5-phenylquinoline
A subtitle compound was prepared by the method of Example 5 (d) from the product of step (c). A large amount of subtitle compound was obtained as a pale orange foam. R _f 0.07 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 92/7/1, v / v). MS m / z 379 (MH ⁺ ).
(e) 4-amino-6,7-dimethoxy-2- [4- (furan-2-carbonyl) -1,4-diazepan-1-yl] -5-phenylquinoline
The title compound was prepared by the method of Example 5 (e) from the product of step (d) and 2-furancarboxylic acid. The product was purified by slurrying in EtOAc to afford the title compound (72%) as a white foam. R _f 0.58 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 92/7/1, v / v). MS m / z 473 (MH ⁺ ). ¹ H NMR (CDCl ₃ ) δ: 2.10 (2H, m), 3.50 (3H, s), 3.74 (4H, m), 3.81 (2H, m), 4.00 (8H, m), 5.71 (1H, s) , 6.45 (1H, s), 7.01 (1H, bs), 7.65 (1H, bs), 7.44 (5H, m). Found: C, 67.57; H, 5.90; N, 11.63; C ₂₇ H ₂₈ N ₄ O ₄ 0.5H ₂ O is C, 67.34; H, 6.07; N, 11.63% is required.
Example 9
4-amino-6,7-dimethoxy-5-phenyl-2- [4- (tetrahydropyran-4-carbonyl) -1,4-diazepan-1-yl] quinoline
The title compound was prepared by the method of Example 5 (e) from the compound of Example 5 (d) and tetrahydropyran-2-carboxylic acid. The crude product was purified on silica eluting with CH ₂ Cl ₂ / MeOH (90/10, v / v) to give the title compound (44%) as a white solid. R _f 0.41 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 90/10/1, v / v). MS m / z 491 (MH ⁺ ). ¹ H NMR (CDCl ₃ ) δ: 1.74 (1H, m), 1.84 to 2.15 (3H, m), 2.68 (1H, m), 3.21 (1H, m), 3.50 (8H, m), 3.80 (7H, m), 4.01 (5H, m), 5.68 (1H, s), 7.65 (1H, bs), 7.21-7.55 (6H, m). Found: C, 66.97; H, 7.09; N, 10.77; C ₂₈ H ₃₄ N ₄ O ₄ 0.75 H ₂ O is C, 66.71; H, 7.10; N, 11.11% is required.
Example 10
4-amino-5- (4-chlorophenyl) -6,7-dimethoxy-2- [4- (4-morpholinecarbonyl) -1,4-diazepan-1-yl] quinoline
(a) 6-amino-3,4-dimethoxy-2-iodobenzonitrile
A subsidiary compound was prepared by the method of Example 2 (b) from Example 3 (d). Subtitle compound (81%) was obtained as a colorless oil. R _f 0.55 (EtOAc / hexanes 1/1, v / v). MS m / z 322 (MNH ₄ ⁺ ).
(b) 3,4-dimethoxy-2-iodo-6- {1- [4- (4-morpholinecarbonyl) -1,4-diazepan-1-yl] ethylideneamino} benzonitrile
The subtitle compound was prepared by the method of Example 1 (c) from the product of step (a) and intermediate 4. The crude product was purified on silica eluting with CH ₂ Cl ₂ / MeOH (97/3, v / v) to give the subtitle compound (87%) as a colorless solid. R _f 0.15 (CH ₂ Cl ₂ ). MS m / z 542 (MH ⁺ ). Found: C, 46.00; H, 5.17; N, 12.44; C ₂₁ H ₂₈ N ₅ O ₄ I 0.1CH ₂ Cl ₂ is C, 46.08; H, 5.17; N, 12.74% is required.
(c) 4-amino-6,7-dimethoxy-5-iodo-2- [4- (4-morpholinecarbonyl) -1,4-diazepan-1-yl] quinoline
Excipient compounds were prepared by the method of Example 1 (d) from the product of step (b), except reaction in THF / DMPU (5/1, v / v). The crude product was purified on silica eluting with CH ₂ Cl ₂ / MeOH (98/2, v / v). Subtitle compound (65%) was obtained as a light brown solid. R _f 0.50 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 90/10/1, v / v). MS m / z 542 (MH ⁺ ). Found: C, 45.71; H, 5.26; N, 12.44; C ₂₁ H ₂₈ N ₅ O ₄ I 0.25CH ₂ Cl ₂ is C, 45.37; H, 5.07; N, 12.46% is required.
(d) 4-amino-5- (4-chlorophenyl) -6,7-dimethoxy-2- [4- (4-morpholinecarbonyl) -1,4-diazepan-1-yl] quinoline
The title compound was prepared by the method of Example 1 (a) from the product of step (c) and 4-chlorophenylboronic acid. The crude product was purified on silica eluting with CH ₂ Cl ₂ /MeOH/0.88NH ₃ (90/10/1, v / v). The title compound (40%) was obtained as a pale yellow foam. R _f 0.45 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 90/10/1, v / v). MS m / z 526, 528 (MH ⁺ ). ¹ H NMR (CDCl ₃ ) δ: 2.06 (2H, m), 3.15 (4H, m), 3.35 (2H, m), 3.50 (3H, s), 3.53 to 3.68 (6H, m), 3.74 (2H, m), 3.97 (5H, m), 4.32 (2H, bs), 5.71 (1H, s), 7.29 (2H, d), 7.45 (2H, d), 7.69 (1H, bs). Found: C, 57.34; H, 5.71; N, 10.97; C ₂₇ H ₃₂ N ₅ O ₄ Cl 0.67CH ₂ Cl ₂ is C, 57.02; H, 5.76; N, 12.02% is required.
Example 11
4-amino-5- (3,5-dichlorophenyl) -6,7-dimethoxy-2- [4- (4-morpholinecarbonyl) -1,4-diazepan-1-yl] quinoline
The title compound was prepared by the method of Example 1 (a) from the compound of Example 10 (c) and 3,5-dichlorophenylboronic acid. The crude product was purified on silica gel eluting with CH ₂ Cl ₂ /MeOH/0.88NH ₃ (90/10/1, v / v). The title compound (24%) was obtained as a light white foam. R _f 0.50 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 90/10/1, v / v). MS m / z 560, 562, 564 (MH ⁺ ). ¹ H NMR (CDCl ₃ ) δ: 2.06 (2H, m), 3.15 (4H, m), 3.35 (2H, m), 3.55 (3H, s), 3.65 (6H, m), 3.74 (2H, m) , 3.99 (7H, m), 5.76 (1H, s), 7.10 to 7.55 (3H, m), 7.45 (1H, s). Found: C, 54.04; H, 5.31; N, 10.70; C ₂₇ H ₃₂ N ₅ O ₄ Cl ₂ 0.6CH ₂ Cl ₂ 0.6MeOH is C, 53.64; H, 5.49; N, 11.10% is required.
Example 12
4-amino-6,7-dimethoxy-5- (4-methoxyphenyl) -2- [4- (4-morpholinecarbonyl) -1,4-diazepan-1-yl] quinoline
The title compound was prepared by the method of Example 1 (a) from the compound of Example 10 (c) and 4-methoxyphenylboronic acid. The crude product was purified on silica gel eluting with CH ₂ Cl ₂ / MeOH (95/5, v / v). The title compound (30%) was obtained as a pale yellow foam. R _f 0.20 (CH ₂ Cl ₂ / MeOH 9/1, v / v). MS m / z 522 (MH ⁺ ). ¹ H NMR (CDCl ₃ ) δ: 2.06 (2H, m), 3.16 (4H, m), 3.35 (2H, m), 3.50 (3H, s), 3.53 to 3.80 (8H, m), 3.80 to 4.13 ( 4H, m), 3.90 (6H, s), 5.71 (1H, bs), 7.00 (2H, d), 7.06 (1H, bs), 7.31 (2H, d). Found: C, 61.75; H, 6.63; N, 12.34; C ₂₈ H ₃₅ N ₅ O ₅ 0.2CH ₂ Cl ₂ 0.7H ₂ O is C, 61.45; H, 6.73; N, 12.71% is required.
Example 13
4-amino-5- [3,5-bis (trifluoromethyl) phenyl] -6,7-dimethoxy-2- [4- (4-morpholinecarbonyl) -1,4-diazepane-1 -Yl] quinoline
The title compound was prepared by the method of Example 1 (a) from the compound of Example 10 (c) and 3,5-bis (trifluoromethyl) phenylboronic acid. The crude product was purified on silica gel eluting with CH ₂ Cl ₂ /MeOH/0.88NH ₃ (90/10/1, v / v). The title compound (24%) was obtained as a pale yellow foam. R _f 0.50 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 90/10/1, v / v). MS m / z 628 (MH ⁺ ). ¹ H NMR (CDCl ₃ ) δ: 2.06 (2H, m), 3.16 (4H, m), 3.35 (2H, m), 3.48 (3H, s), 3.61 (6H, m), 3.77 (2H, m) , 4.00 (7H, m), 5.80 (1H, s), 7.10 (1H, bs), 7.84 (2H, s), 7.95 (1H, s). Found: C, 53.51; H, 5.06; N, 10.03; C ₂₉ H ₃₁ N ₅ O ₄ F ₆ 0.4CH ₂ Cl ₂ 0.3MeOH is C, 53.10; H, 4.92; N, 10.43% is required.
Example 14
4-amino-6,7-dimethoxy-2- [4- (4-morpholincarbonyl) -1,4-diazepan-1-yl] -5-[(4-trifluoromethyl) phenyl] Quinoline
The title compound was prepared by the method of Example 1 (a) from the compound of Example 10 (c) and 4- (trifluoromethyl) phenylboronic acid. The crude product was purified on silica gel eluting with CH ₂ Cl ₂ /MeOH/0.88NH ₃ (90/10/1, v / v). The title compound (10%) was obtained as a pale yellow foam. R _f 0.45 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 90/10/1, v / v). MS m / z 560 (MH ⁺ ). ¹ H NMR (CDCl ₃ ) δ: 2.06 (2H, m), 3.03 to 4.13 (2H, b), 3.13 (4H, m), 3.34 (2H, m), 3.48 (3H, s), 3.65 (6H, m), 3.76 (2H, m), 4.03 (5H, m), 5.74 (1H, s), 7.16 (1H, bs), 7.50 (2H, d), 7.71 (2H, d). Found: C, 56.46; H, 5.78; N, 11.43; C ₂₈ H ₃₂ N ₅ O ₄ F ₃ 0.5CH ₂ Cl ₂ is C, 56.85; H, 5.52; N, 11.63% is required.
Example 15
4-amino-5- (3-chlorophenyl) -6,7-dimethoxy-2- [4- (4-morpholinecarbonyl) -1,4-diazepan-1-yl] quinoline
The title compound was prepared by the method of Example 1 (a) from the compound of Example 10 (c) and 3-chlorophenylboronic acid. The crude product was purified on silica gel eluting with CH ₂ Cl ₂ /MeOH/0.88NH ₃ (90/10/1, v / v) and then titrated with ether. The title compound (43%) was obtained as colorless foam. R _f 0.34 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 90/10/1, v / v); MS m / z 526, 528 (MH ⁺ ). ¹ H NMR (CDCl ₃ ) δ: 2.06 (2H, m), 3.15 (4H, m), 3.35 (2H, m), 3.52 (3H, s), 3.40 to 3.80 (8H, m), 3.99 (7H, m), 5.77 (1 H, s), 7.10 to 7.50 (4 H, m), 7.23 (1 H, s). Found: C, 59.82; H, 6.58; N, 11.96; C ₂₇ H ₃₂ N ₅ O ₄ Cl 0.25CH ₂ Cl ₂ 0.5 ether is C, 60.11; H, 6.47; N, 11.99% is required.
Example 16
4-amino-6,7-dimethoxy-2- [4- (4-morpholinecarbonyl) -1,4-diazepan-1-yl] -5-phenylquinazoline
(a) 2,4-dichloro-6,7-dimethoxy-5-nitroquinazoline
Nitronium tetafluoroborate (25.9 g, 0.19 mol) over 15 minutes in a suspension of 2,4-dichloro-6,7-dimethoxyquinazoline (30.0 g, 0.12 mol) in acetonitrile (550 mL) at 0 ° C. ) Was added dropwise. The reaction was stirred for 0.75 hours and then evaporated under reduced pressure. The resulting solid was suspended in a mixture of saturated aqueous sodium bicarbonate and EtOAc, the solid was filtered, dissolved in CH ₂ Cl ₂ , dried over MgSO ₄ and evaporated to give the subtitle compound (27 g) as a pale yellow solid. . The organic layer of the filtrate was separated, washed once with H ₂ O and once with saturated brine, dried over MgSO ₄ and filtered through a pad of silica to give additional material. Subsequently evaporated under reduced pressure, triturated with EtOAc and filtered to give the subtitle compound (3.9 g, 88% total yield) as a pale yellow solid. R _f 0.24 (ether / hexane 1/1, v / v).
(b) 2,4-dihydroxy-6,7-dimethoxy-5-nitroquinazoline
The product of step (a) (27.3 g, 90 mmol) is suspended in a mixture of glacial acetic acid (150 mL) and H ₂ O (5 mL), further addition of a fraction of H ₂ O (5 mL) and heating continuously The reaction mixture was heated to 150 ° C. for 0.5 h. After heating for a total of 1.5 hours, a third fraction of H ₂ O (5 mL) was added and heating continued for an additional 0.5 hours. The reaction mixture was then cooled, the solid filtered off, washed with ether and dried in vacuo at 80 ° C. to give the subtitle compound (22.2 g, 93%) as a pale yellow solid. R _f 0.38 (EtOAc / MeOH 95/5, v / v); MS m / z 285 (MNH ₄ ⁺ ).
(c) 5-amino-2,4-dihydroxy-6,7-dimethoxyquinazoline
A mixture of the product of step (b) (35.0 g, 0.13 mol) and 10% palladium (4.0 g) on carbon was suspended in glacial acetic acid (200 mL) and hydrogenated at 50 psi (3.4 atm) and 50 ° C. for 2.5 days. . The reaction was then cooled, suspended in MeOH / CH ₂ Cl ₂ (1/1, v / v, 1L) and filtered. The residue was transferred to a soxhlet apparatus and continuously extracted with MeOH for 3 days. The gray solid was evaporated and then dissolved in 2N NaOH, filtered through a pad of silica and washed with H ₂ O. The filtrate was then acidified with concentrated HCl. The resulting precipitate was isolated by filtration and washed successively with H ₂ O and acetone and then dried under vacuum at 60 ° C. to give the subtitle compound (22.7 g, 73%) as a white solid. R _f 0.42 (EtOAc / MeOH 95/5, v / v). MS m / z 238 (MH ⁺ ).
(d) 2,4-dihydroxy-6,7-dimethoxy-5-iodoquinazoline
H ₂ O (10 mL) was added to the suspension (5.5 g, 23.2 mmol) of the product of step (c) in HCl (10 mL) concentrated at −10 ° C., followed by an aqueous solution of sodium nitrate (2.4 g, 34.8 mmol in 10 mL). ) Was added and the temperature was kept below 0 ° C. The resulting yellow diazonium salt is carefully added to a solution of potassium iodide (40.0 g, 0.23 mol), and copper (I) iodide (4.4 g, 23 mmol) in H ₂ O (100 mL) is heated to 90 ° C., After the addition was terminated, heating was continued until gas evolution ceased. The mixture was then cooled, filtered and the solid residue was washed successively with H ₂ O and aqueous sodium thiosulfate. The crude product is first purified on silica gel, eluting with EtOAc / MeOH (95/5, v / v) followed by EtOAc / MeOH / AcOH (95/5/1, v / v) to give a solid suspended in MeOH. This was filtered to give the subtitle compound (2.2 g, 27%) as a yellow / orange solid mixed with the compound (0.4 g) of step (b). R _f 0.16 (CH ₂ Cl ₂ / MeOH 95/5, v / v). MS m / z 366 (MNH ₄ ⁺ ).
(e) 2,4-dihydroxy-6,7-dimethoxy-5-phenylquinazoline
A subtitle compound was prepared by the method of Example 1 (a) from the product of step (d) (mixture of compounds of 5.7 / 1, w / w) and phenylboronic acid. The crude product was purified on silica gel, eluting with CH ₂ Cl ₂ / MeOH (95/5, v / v) to give the subtitle compound (95) as an orange powder contaminated with the compound of step (b) (5%, w / w). %) Was obtained. R _f 0.16 (CH ₂ Cl ₂ / MeOH 95/5, v / v). MS m / z 299 (MH ⁺ ).
(f) 2,4-dichloro-6,7-dimethoxy-5-phenylquinazoline
The mixture (95/5, w / w, 1.75 g, 5.6 mmol of the subtitle compound of step (e)) produced in step (e) is suspended in POCl ₃ (10 mL, 16.5 g, 109 mmol) and the mixture is Treated with N, N-dimethylaniline (1.86 mL, 1.79 g, 14.7 mmol) and heated with reflux for 1.5 h. After cooling, excess POCl ₃ was evaporated under reduced pressure and the residue was azeotroduced twice with toluene and then partitioned between EtOAc and H ₂ O. The organic layer was separated, washed three times with H ₂ O and once with saturated brine, dried over MgSO ₄ , filtered through a pad of silica, washed with EtOAc to give the subtitle compound as a yellow gum while evaporating. . R _f 0.83 (EtOAc).
(g) 4-amino-2-chloro-6,7-dimethoxy-5-phenylquinazoline
The product of step (f) was suspended in a saturated solution of ammonia in MeOH, and CH ₂ Cl ₂ was added until all the solids were dissolved, then the reaction was stirred under N ₂ for 3 hours. The reaction mixture is then stirred for an additional 2.5 days at room temperature, the solvent is removed under reduced pressure and the resulting solid is suspended in MeOH, filtered, washed with ether and then dried under vacuum at 60 ° C. . This resulted in the subtitle compound (1.12 g, 65% from the product of step (e)) as a white solid. R _f 0.39 (EtOAc). MS m / z 316, 318 (MH ⁺ ).
(h) 4-amino-6,7-dimethoxy-2- [4- (4-morpholinecarbonyl) -1,4-diazepane-1-yl] -5-phenylquinazoline
To solution (200 mg, 0.63 mmol) of the product of step (g) in n-BuOH (10 mL) was added Intermediate 3 (250 mg, 1.0 mmol) and triethylamine (0.22 mL, 160 mg, 1.58 mmol) and the reaction was 18 Heated to 100 ° C. under N ₂ for hr. After cooling, the reaction mixture was partitioned between EtOAc and 2N NaOH, the organic layer was separated, washed with saturated brine, dried over MgSO ₄ and evaporated under reduced pressure. The crude product was purified on silica gel eluting with EtOAc, then suspended in a minimum volume of EtOAc, filtered under vacuum at 60 ° C. and dried to afford the title compound (180 mg, 58%) as a white solid. R _f 0.40 (EtOAc / MeOH 95/5, v / v). MS m / z 493 (MH ⁺ ). ¹ H NMR (CDCl ₃ ) δ: 2.00 (2H, m), 3.16 (4H, m), 3.35 (2H, m), 3.48 (3H, s), 3.52 (2H, m), 3.65 (4H, m) , 3.84 (2H, m), 3.94 (2H, m), 3.97 (3H, s), 4.52 (2H, bs), 6.92 (1H, s), 7.35 (2H, m), 7.40 to 7.52 (3H, m ). Found C, 62.82; H, 6.52; M, 16.70; C ₂₆ H ₃₂ N ₆ O ₄ 0.25H ₂ O is C, 62.85; H, 6.59; N, 16.91% is required.
Other production routes to 4-amino-2-chloro-6,7-dimethoxy-5-phenylquinazolin [compound of step (g)]
(Aa) 4-amino-6,7-dimethoxy-2-hydroxy-5-phenylquinazoline
Trifluoroacetic acid (8.1 mL, 0.10 mol) was added to a stirred solution of the compound of Example 3 (f) (12.9 g, 0.051 mol) and sodium cyanide (6.6 g, 0.10 mol) in CH ₂ Cl ₂ (200 mL). The reaction mixture was added dropwise and the reaction was allowed to stir at room temperature under N ₂ for 18 hours, after which an orange precipitate formed. The solid was filtered off, washed with hexanes and isolated by suction drying, then combined with a mixture of 2N aqueous NaOH (250 mL) and MeOH (250 mL). The mixture was heated in a steam bath until the solids dissolved, and after cooling, the solution was acidified with concentrated HCl and warmed in the steam bath until complete dissolution. The solution was cooled and neutralized with K ₂ CO ₃ , the precipitated solid was filtered off and separated by washing with H ₂ O, MeOH, CH ₂ Cl ₂ and the final ether to give the subtitle compound (12.4 g, 82%) as a colorless solid. Obtained. MS m / z 298 (MH ⁺ ).
(Ab) 4-amino-2-chloro-6,7-dimethoxy-2-hydroxy-5-phenylquinazoline
DMF (6.4 mL, 0.083 mole) was added dropwise to POCl ₃ (19.3 mL, 0.21 mole). Once the mixture was cooled once, the product of step (Aa) (12.34 g, 0.042 mol) was added, the temperature was maintained at 90 ° C. for 3 hours and then stirred at room temperature for 18 hours, after which the reaction was quenched carefully with ice. I was. The reaction was then basified with excess 2N NaOH and the temperature raised to 60 ° C. and maintained for 1 hour. The reaction mixture was then cooled, separated by filtration and dried under vacuum at 60 ° C. to give the subtitle compound (10.2 g, 78%) as an off-white solid.
Example 17
4-amino-6,7-dimethoxy-2- {4- [1- (3S, 4S-dihydroxypyrrolidine) carbonyl] -1,4-diazepan-1-yl} -5-phenyl Quinazoline hydrochloride
(a) N-benzyl-3S, 4S-bis (tert-butyldimethylsiloxy) pyrrolidine
A subtitle compound was prepared by the method of Arakawa et al. (Chem. Pharm. Bull., 39, 2219 (1991)).
(b) 1- {1- (3S, 4S-bis (tert-butyldimethylsilyloxy) pyrrolidine) carbonyl} -1,4-diazepane
To a stirred solution of the product of step (a) (12.0 g, 28 mmol) in toluene (150 mL) was added a solution of phosgene in toluene (1.93 M, 18 mL, 34 mmol). The resulting suspension was heated to reflux for 6 hours, then the solvent was removed under reduced pressure and the residue was redissolved in THF (200 mL). The solution was cooled to 0 ° C. and then added to a solution of homopiperazine (15.0 g, 150 mmol) in THF (100 mL). The resulting solution was heated to 60 ° C. for 1 h and stirred at rt for 18 h. The solvent was removed under reduced pressure and the residue was partitioned between CH ₂ Cl ₂ (200 mL) and H ₂ O (100 mL). The organic layer was washed with saturated brine (50 mL) and dried over MgSO ₄ . The solvent is evaporated under reduced pressure and the crude product is first taken up with CH ₂ Cl ₂ /MeOH/0.88NH ₃ (96 / 3.5 / 0.5, v / v) followed by CH ₂ Cl ₂ /MeOH/0.88NH ₃ (92/7 / Purification on silica gel eluting with 1, v / v) yielded the subtitle compound (7.64 g, 60%) as an oil which slowly crystallized upon standing. R _f 0.2 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 92/7/1, v / v). MS m / z 459 (MH ⁺ ).
(c) 4-amino-6,7-dimethoxy-2- {4- [1- (3S, 4S-dihydroxypyrrolidine) carbonyl] -1,4-diazepane-1-yl}- 5-phenylquinazoline hydrochloride
To the solution of Example 16 (g) compound (200 mg, 0.63 mmol) and triethylamine (0.22 mL, 1.7 mmol) in n-BuOH (10 mL) was added the product of step (b) (350 mg, 0.76 mmol) The reaction mixture was heated to 100 ° C. under N ₂ for 18 h. The reaction was then cooled, evaporated under reduced pressure, and HCl was bubbled through a solution of the residue in CH ₂ Cl ₂ for 20 minutes. The reaction mixture was then evaporated under reduced pressure, partitioned between EtOAc and H ₂ O and the aqueous layer was repeatedly extracted with EtOAc. The aqueous layer was then basified with 2N NaOH, extracted with CH ₂ Cl ₂ , the organic layer dried over MgSO ₄ and evaporated to give a gum, which was treated with etheric HCl. The resulting precipitate was filtered and washed with ether to give the title compound (210 mg, 61%) as a white foam. R _f 0.1 (CH ₂ Cl ₂ / MeOH 95/5, v / v). MS m / z 509 (MH ⁺ ). ¹ H NMR (CDCl ₃ ) δ: 1.58 to 2.23 (2H, bm), 3.03 to 4.35 (2H, bm), 3.23 (4H, m), 3.48 (3H, s), 3.52 (3H, m), 3.71 ( 4H, m), 4.02 (3H, s), 4.11 (4H, m), 5.16 (1H, bs), 7.32 (2H, m), 7.52 (3H, m), 8.45 (1H, s), 12.59 (1H) , bs). Found C, 55.42; H, 6.32; N, 13.90; C ₂₆ H ₃₂ N ₆ O ₅ HCl H ₂ O 0.5 EtOAc is C, 55.40; H, 6.48; N, 13.84% is required.
Example 18
4-amino-6,7-dimethoxy-2- [4- (3-dihydroxyazetidine-1-carbonyl) -1,4-diazepan-1-yl] -5-phenylquinazoline hydrochloride
A suspension of the compound of Example 16 (g) (205 mg, 0.65 mmol) in n-BuOH was treated with homopiperazine (1.3 g, 13.0 mmol) and the reaction heated with reflux under N ₂ for 18 h. After cooling, the reaction mixture was partitioned between EtOAc and 2N NaOH, the organic layer was separated and washed five times with H ₂ O, then evaporated under reduced pressure and azeotropically with toluene three times to give a foam (280 mg). It is dissolved in CH ₂ Cl ₂ (50 mL), triethylamine (0.11 mL, 0.78 mmol) is added and the solution is stirred with 4 μg molecular sieve for 2 hours, then CH at −5 ° C. over 1 hour. _To the solution of triphosgen (68.0 mg, 0.23 mmol) in ₂ Cl ₂ (10 mL) was added dropwise. Then it was a homogeneous suspension of 2-azetidinol in THF (prepared according to the method of Chatterjee et al., J. Chem. Soc. Chem. Commun., 93 (1968)) (142 mg). , 1.3 mmol) and triethylamine (0.32 mL, 2.3 mmol) and stirred beforehand using 4 kPa molecular sieve for 2 hours. After the reaction mixture was stirred under nitrogen continuously for 3 days at room temperature, the reaction mixture was partitioned between CH ₂ Cl ₂ and 1N NaOH, the organic layer was washed with saturated brine, dried over MgSO ₄ and evaporated. The crude product was initially eluted with EtOAc / MeOH (95/5, v / v) and then purified on silica gel, eluting with CH ₂ Cl ₂ /MeOH/0.88NH ₃ (90/10/1), followed by ethanol Treatment with soluble HCl afforded the title compound (153 mg, 46%) as a white foam. MS m / z 479 (MH ⁺ ). ¹ H NMR (CDCl ₃ ) δ: 1.61, 1.84 (2H, 2m), 3.10 (1H, m), 3.18 to 3.40 (3H, m), 3.40 to 3.73 (4H, m), 3.55 (3H, s), 3.90 (3H, bm), 4.10 (3H, s), 4.35 (2H, bm), 5.03 (0.5H, bm), 5.21 (1H, bs), 5.26 (0.5H, bm), 5.66 (0.5H, bm) ), 6.58 (0.5H, bm), 7.40 (2H, m), 7.55 (3H, m), 8.50 (1H, bs), 12.97 (1H, bs). Found C, 53.94; H, 6.40; N, 14.06; C ₂₅ H ₃₀ N ₆ O ₄ HCl 0.4 ether 2.5H ₂ O is C, 54.14; H, 6.78; N, 14.25% is required.
Example 19
4-amino-2- [4- (1,4-benzodioxane-2-carbonyl) -1,4-piperazin-1-yl] -6,7-dimethoxy-5-phenylquinazoline
(a) 4-amino-6,7-dimethoxy-5-phenyl-2- (1,4-piperazin-1-yl) quinazoline
Piperazine (2.29 g, 27 mmol) was added to a stirred suspension of Example 16 (g) compound (420 mg, 1.3 mmol) in n-BuOH (10 mL) and the reaction was heated to 80 ° C. for 3 h. After cooling, the reaction mixture was partitioned between EtOAc and 2N NaOH, and the organic layer was washed twice with H ₂ O and once with saturated brine, then dried over MgSO ₄ and evaporated under reduced pressure. The residue and toluene was azeotroped once, CH ₂ Cl ₂ and was azeotroped twice to give the sub-title compound (455mg, 94%) as a foam. R _f 0.4 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 90/10/1, v / v). MS m / z 366 (MH ⁺ ).
(b) (R / S) -4-amino-2- {4- (1,4-benzodioxane-2-carbonyl) -1,4-piperazin-1-yl} -6,7-dime Methoxy-5-phenylquinazoline
The title compound was prepared by the method of Example 5 (e) from the compound of step (a) and (R / S) -1,4-benzodioxane-2-carboxylic acid. The title compound (61%) was obtained as a foam. R _f 0.69 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 90/10/1, v / v). MS m / z 528 (MH ⁺ ). ¹ H NMR (CDCl ₃ ) δ: 3.42 to 4.16 (8H, b), 3.48 (3H, s), 4.00 (3H, s), 4.35 (1H, dd), 4.48 (1H, dd), 4.87 (1H, dd), 5.80 (1H, s), 6.89 (4H, m), 6.97 (1H, s), 7.16 (1H, m), 7.39 (2H, m), 7.50 (3H, m). Found C, 64.31; H, 5.58; N, 12.61; C ₂₉ H ₂₉ N ₅ O ₅ 0.2EtOAc 0.5H ₂ O is C, 64.54; H, 5.70; N, 12.63% is required.
Example 20
4-amino-6,7-dimethoxy-5- (4-fluorophenyl) -2- [4- (4-morpholinecarbonyl) -1,4-diazepan-1-yl] quinazoline
(a) 2,4-dichloro-6,7-dimethoxy-5-iodoquinazoline
A subtitle compound was prepared by the method of Example 16 (f) from Example 16 (d). The subtitle compound was obtained as a solid (contaminated with 2,4,5-trichloroquinazolin). R _f 0.16 (hexane / EtOAc 4/1, v / v).
(b) 4-amino-2-chloro-6,7-dimethoxy-5-iodoquinazoline
This material was prepared by the method of Example 16 (g) from the mixed product of step (a). A subtitle compound (61% from the compound of Example 16 (d)) was obtained as a yellow solid (containing 5-chloro analog). R _f 0.11 (hexane / EtOAc 4/1, v / v). MS m / z 366 (MH ⁺ ).
(c) 4-amino-6,7-dimethoxy-5-iodo-2- [4- (4-morpholinecarbonyl) -1,4-diazepan-1-yl] quinazoline
This material was prepared by the method of example 16 (h) from the product of step (b) (mixture of 3/2, w / w) and intermediate 3. The crude product was initially eluted with hexanes and then purified on silica eluting with EtOAc / hexanes (1/1, v / v). Subtitle compound (28% based on compound of step (b)) was obtained as an orange foam (containing 5-chloro analog). R _f 0.41 (EtOAc). MS m / z 543 (MH ⁺ ).
(d) 4-amino-6,7-dimethoxy-5- (4-fluorophenyl) -2- [4- (4-morpholinecarbonyl) -1,4-diazepan-1-yl] quina Sleepy
This material was prepared by the method of example 1 (a) from the product of step (c) (mixture of 1.2 / 1, w / w) and 4-fluorophenylboronic acid. The crude product was initially eluted with hexanes / EtOAc (4/1, v / v) and then purified on silica eluting with EtOAc. The title compound (63% based on the compound of step (c)) was obtained as white foam. R _f 0.18 (EtOAc). MS m / z 511 (MH ⁺ ). ¹ H NMR (CDCl ₃ ) δ: 2.00 (2H, m), 3.14 (4H, m), 3.35 (2H, m), 3.48 (3H, s), 3.55 (2H, m), 3.66 (4H, m) , 3.84 (2H, m), 3.94 (2H, m), 3.97 (3H, s), 4.52 (2H, bs), 6.90 (1H, bs), 7.16 (2H, m), 7.32 (2H, m). Found: C, 60.91; H, 6.32; N, 15.73; C ₂₆ H ₃₁ N ₆ O ₄ F 0.2 EtOAc is C, 60.90; H, 6.17; N, 15.91% is required.
Example 21
4-amino-6,7-dimethoxy-2- {1- [4- (4-morpholinecarbonyl) piperidine} -5-phenylquinazoline
The title compound was prepared by the method of Example 16 (h) from the compound of Example 16 (g) and 4- (4-morpholinecarbonyl) piperidine (see US Pat. No. 4,022,791). The crude product was purified by column chromatography on silica gel eluting with CH ₂ Cl ₂ /EtOH/0.88NH ₃ (96 / 3.5 / 0.5, v / v). Recrystallization from EtOAc gave the title compound (25%) as a colorless solid. R _f 0.10 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 96 / 3.5 / 0.5, v / v). MS m / z 478 (MH ⁺ ). ¹ H NMR (CDCl ₃ ) δ: 1.75 to 1.95 (4H, m), 2.70 (1H, m), 2.90 (2H, m), 3.50 (3H, s), 3.55 to 3.75 (8H, m), 4.00 ( 3H, s), 4.60 (2H, m), 6.95 (1H, bs), 7.40 (2H, m), 7.50 (3H, m). Found C, 65.34; H, 6.56; N, 14.55; C ₂₆ H ₃₁ N ₅ O ₄ is C, 65.39; H, 6.54; N, 14.66% is required.
Example 22
4-amino-2- {4- [1- (3S, 4S-dihydroxypyrrolidine) carbonyl)]-1,4-diazepan-1-yl} -6,7-dimethoxy-5- Phenylquinoline
(a) 6- {1-[(4-benzyl) -1,4-diazepan-1-yl] ethylideneamino} -3,4-dimethoxy-2-phenylbenzonitrile
The subtitle compound was prepared from the compound of Example 3 (f) and 1-acetyl-4-benzyl-1,4-diazepane (Sutton, "J. Med. Chem., 13, 1026 (1970)"). Prepared by the method of Example 1 (c) to give the subtitle compound (83%) as orange glass. R _f 0.36 (CH ₂ Cl ₂ / MeOH 95/5, v / v). MS m / z 469 (MH ⁺ ).
(b) 4-amino-2- (4-benzyl-1,4-diazepan-1-yl) -6,7-dimethoxy-5-phenylquinoline
The solution of the product of step (a) (440 mg, 0.94 mmol) in dimethoxyethane (10 mL) was treated with potassium tert-butoxide (316 mg, 2.82 mmol) and the reaction mixture was heated at reflux for 5 hours. After cooling, the mixture was partitioned between EtOAc and H ₂ O. The organic layer was dried over MgSO ₄ and evaporated under reduced pressure to give an oil. Trituration with MeOH and filtration gave the subtitle compound (300 mg, 68%) as a pale pink solid. R _f 0.39 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 92/7/1, v / v). ¹ H NMR (CDCl ₃ ) δ: 1.95 (2H, m), 2.65 (2H, m), 2.8 (2H, m), 3.5 (3H, s), 3.65 (3H, s), 3.7 to 3.9 (6H, m), 4.00 (3H, s), 5.7 (1H, s), 7.1 (1H, bs), 7.2 to 7.35 (5H, m), 7.4 (5H, m).
(c) 4-amino-2- (1,4-diazepan-1-yl) -6,7-dimethoxy-5-phenylquinoline
A mixture of the product of step (b) (700 mg, 0.5 mmol), palladium hydroxide (20% w / w, 140 mg) and acetic acid (0.17 mL, 3.0 mmol) in EtOH (30 mL) for 18 hours at 345 kPa (50 psi) and room temperature Hydrogenated at. The reaction was filtered through Arbocel (trade name) and the filtrate was evaporated under reduced pressure to give the subtitle compound (487 mg, 86%) as a pale yellow solid. R _f 0.10 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 90/10/1, v / v). ¹ H NMR (CDCl ₃ ) δ: 1.95 (2H, m), 2.85 (2H, m), 3.05 (2H, m), 3.50 (3H, s), 3.75 to 3.85 (6H, m), 4.0 (3H, s), 5.7 (1 H, s), 7.15 (1 H, s), 7.45 (5 H, m).
(d) 4-amino-2- (4-chlorocarbonyl-1,4-diazepan-1-yl) -6,7-dimethoxy-5-phenylquinoline
The product of step (c) (442 mg, 1.17 mmol) and triethyl in CH ₂ Cl ₂ (20 mL) over 1 h in a solution of triphosgene (128 mg, 0.43 mmol) in CH ₂ Cl ₂ (10 mL) at −10 ° C. A solution of amine (0.195 mL, 142 mg, 1.4 mmol) was added dropwise. The mixture was stirred for a further 1 h at -10 [deg.] C. and then evaporated under reduced pressure to yield the subtitle compound (514 mg, 100%) as a brown foam used without further treatment.
(e) 4-amino-2- {4- [1- (3S, 4S-dihydroxypyrrolidine) carbonyl)]-1,4-diazepane-1-yl} -6,7-dimethoxy -5-phenylquinoline
The product of step (d) in THF (20 mL) (257 mg, 0.58 mmol), 3S, 4S-bis (tert-butyldimethylsilyloxy) pyrrolidine [Nagel et al., Angew. Chem. Int. Ed Engl., 23, 435 (1984) "] (213 mg, 0.64 mmol) and triethylamine (0.098 mL, 71 mg, 0.7 mmol) were refluxed for 18 hours. After cooling, the mixture was partitioned between EtOAc and saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was washed again with EtOAc and finally washed with CH ₂ Cl ₂ . The combined organics were dried over MgSO ₄ and evaporated under reduced pressure. The crude product was purified on silica gel eluting with a gradient eluate of 3-7% MeOH in CH ₂ Cl ₂ . The purified material was treated with a methanolic solution of HCl (prepared by careful addition of acetyl chloride (0.07 mL) to MeOH (3 mL)) and stirred at room temperature for 2.5 hours. The mixture was basified with aqueous saturated NaHCO ₃ and evaporated under reduced pressure. The residue was extracted with CH ₂ Cl ₂ , the extract was evaporated under reduced pressure and the crude product was purified on silica gel, eluting with CH ₂ Cl ₂ /MeOH/0.88NH ₃ (92/7/1, v / v). The title compound (30 mg, 10%) was obtained as a colorless solid. R _f 0.25 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 84/14/2, v / v). MS m / z 508 (MH ⁺ ). ¹ H NMR (d ₃ -DMSO) δ: 1.87 (2H, m), 3.12 (2H, m), 3.34 (3H, s), 3.4 (2H, m), 3.52 (3H, m), 3.68 to 3.9 ( 8H, m), 4.6 (2H, bs), 4.87 (2H, m), 5.85 (1H, s), 6.93 (1H, s), 7.3 (2H, m), 7.45 (3H, m).
Example 23
4-amino-6,7-dimethoxy-2- [4- (4-fluoropiperidinecarbonyl) -1,4-diazepan-1-yl] -5-phenylquinoline
Product of step 22 (d) in THF (20 mL) (257 mg, 0.58 mmol), 4-fluoropiperidine hydrochloride [J. Org. Chem. 44, 771 (1979)] (90 mg, 0.64 mmol ) And triethylamine (0.18 mL, 1.29 mmol) were refluxed for 18 h. The reaction was cooled and evaporated under reduced pressure, then partitioned between EtOAc and saturated aqueous sodium bicarbonate. The organic layer was dried over MgSO ₄ and evaporated under reduced pressure. Purification on silica gel eluting with a gradient elution of 3-7% MeOH in CH ₂ Cl ₂ gave the title compound (102 mg, 35%) as a foam. R _f 0.31 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 92/7/1, v / v). MS m / z 508 (MH ⁺ ). ¹ H NMR (CDCl ₃ ) δ: 1.75 to 1.95 (4H, m), 2.05 (2H, m), 3.1 (2H, m), 3.35 (4H, m), 3.45 to 4.05 (12H, m), 4.70 to 4.85 (1 H, m), 5.70 (1 H, s), 7.1 (1 H, bs), 7.45 (5 H, m). Found C, 64.54; H, 6.76; N, 12.59; C ₂₈ H ₃₄ N ₅ O ₃ F 0.5 EtOAc 0.5H ₂ O is C, 64.27; H, 7.01; N, 12.49% is required.
Example 24
4-amino-6,7-dimethoxy-2- [4- (4-morpholinesulfonyl) -1,4-diazepan-1-yl] -5-phenylquinazoline
(a) 1- (tert-butyloxycarbonyl) -4- {4-morpholinesulfonyl} -1,4-diazepane
Subtitle compounds were prepared by the method of intermediate 2 from intermediate 1 and 4-morpholinesulfonyl chloride (Repine et al., J. Med. Chem., 34, 1935 (1991)). The reaction mixture was partitioned between CH ₂ Cl ₂ and 1N NaOH. The organic layer was washed again with 1N HCl, then with H ₂ O, dried over MgSO ₄ and evaporated under reduced pressure. Initially eluted with CH ₂ Cl ₂ /MeOH/0.88NH ₃ (98 / 1.25 / 0.25, v / v) and then with CH ₂ Cl ₂ /MeOH/0.88NH ₃ (96 / 3.5 / 0.5, v / v). Purification on silica gel eluting gave the subtitle compound (53%) as a gum. R _f 0.44 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 96 / 3.5 / 0.5, v / v). MS m / z 350 (MH ⁺ ). ¹ H NMR (CDCl ₃ ) δ: 1.4 (9H, s), 1.9 (2H, m), 3.17 (4H, m), 3.22 (2H, m), 3.4 (2H, m), 3.5 (2H, m) , 3.73 (6H, m).
(b) 1- (4-morpholinesulfonyl) -1,4-diazepane hydrochloride
A subtitle compound was prepared by the method of intermediate 3 from the product of step (a). Subtitle compound (97%) was obtained as a white solid. R _f 0.09 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 92/7/1, v / v). MS m / z 250 (MH ⁺ ). NMR (d ₆ -DMSO) δ: 2.1 (2H, m), 3.1 (4H, m), 3.4 (4H, m), 3.62 (8H, m), 9.2 (2H, b).
(c) 4-amino-6,7-dimethoxy-2- [4- (morpholinesulfonyl) -1,4-diazepan-1-yl]}-5-phenylquinazoline
The title compound was prepared by the method of Example 16 (h) from the product of step (b) and the compound of Example 16 (g). The mixture was purified on silica gel eluting with 3% MeOH in CH ₂ Cl ₂ . Evaporation under reduced pressure and recrystallization from EtOAc / hexanes gave the title compound (33%) as a colorless solid. R _f 0.27 (CH ₂ Cl ₂ / MeOH 95/5 v / v). MS m / z 529 (MH ⁺ ). ¹ H NMR (CDCl ₃ ) δ: 2.03 (2H, m), 3.08 (4H, m), 3.37 (2H, m), 3.47 (3H, s), 3.53 (2H, m), 3.63 (4H, m) , 3.9 (2H, m), 3.95 (2H, m), 3.98 (3H, s), 4.56 (2H, s), 6.9 (1H, s), 7.37 (2H, m), 7.44 (3H, m). Found C, 56.23; H, 6.06; N, 15.56; C ₂₅ H ₃₂ N ₆ O ₅ S 0.5H ₂ O is C, 56.42; H, 6.14; N, 15.79% is required.
Example 25
4-amino-2- [7-aminosulfonyl-1,2,3,4-tetrahydroisoquinolin-2-yl) -6,7-dimethoxy-5-phenylquinazoline
Example 16 (g) compound (500 mg, 1.6 mmol) and triethylamine (0.66 mL, 4.8 mmol) in a mixture of n-BuOH (10 mL) and DMA (3 mL) were 1,2,3,4-tetrahydro Isoquinoline-7-sulfonamide hydrochloride (RG Pendleton et al., The Journal of Pharmacology and Experimental Therapeutics, 208, 24, 1979) (597 mg, 2.4 mmol) was added and the reaction mixture Heated to 100 ° C. under N ₂ for 18 h. The reaction was then cooled, partitioned between 2N aqueous NaOH and EtOAc, and the organic layer was washed with H ₂ O, dried over MgSO ₄ and evaporated under reduced pressure. The residue was titrated with ether / hexanes and the resulting solid was isolated by filtration to give the title compound (360 mg, 46%) as a pale yellow solid. R _f 0.62 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 90/10/1, v / v). MS m / z 492 (MH ⁺ ). ¹ H NMR (D ₆ -DMSO) δ: 2.87 (2H, dd), 3.37 (3H, s), 3.90 (3H, s), 4.00 (2H, dd), 4.94 (2H, s), 6.90 (1H, s), 7.20 to 7.40 (6H, m), 7.45 to 7.65 (6H, m). Found C, 60.47; H, 5.39; N, 13.72; C ₂₅ H ₂₅ N ₅ O ₄ S 0.3 H ₂ O is C, 60.42; H, 5.19; N, 14.09% is required.
Example 26
4-amino-6,7-dimethoxy-5-phenyl-2- (3-pyridinemethylamino) quinazoline
To a solution of the compound of Example 16 (g) (300 mg, 0.95 mmol) and triethylamine (0.60 mL, 5.7 mmol) in a mixture of n-BuOH (10 mL) and DMA (2 mL), 3- (aminomethyl) pyridine was added. The reaction mixture was added and heated to 100 ° C. under N ₂ for 24 h, then additional fractions of DMA (2 mL) were added and continued to heat the next day. The reaction was then cooled, partitioned between H ₂ O and CH ₂ Cl ₂ , the organic layer washed with H ₂ O, dried over MgSO ₄ and evaporated under reduced pressure. The residue was chromatographed on silica gel eluting with CH ₂ Cl ₂ /MeOH/0.88NH ₃ (90/10/1, v / v) to give the title compound (65 mg, 18%) as colorless foam. R _f 0.52 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 84/14/2, v / v). MS m / z 388 (MH ⁺ ). ¹ H NMR (CDCl ₃ ) δ: 3.45 (2H, dd), 3.97 (3H, s), 4.65 (2H, bs), 4.71 (2H, bs), 5.40 (1H, bs), 6.94 (1H, s) , 7.15 to 7.30 (2H, m), 7.39 (2H, m), 7.50 (3H, m), 7.71 (1H, d), 8.50 (1H, d), 8.61 (1H, s). Found C, 65.48; H, 5.51; N, 16.68; C ₂₂ H ₂₁ N ₅ O ₂ 0.1MeOH 0.25CH ₂ Cl ₂ is C, 65.18; H, 5.36; N, 17.00% is required.
Example 27
4-amino-6,7-dimethoxy-5- (4-fluorophenyl) -2- [4- (morpholinecarbonylamino) -1-propaneamino] quinoline
To a solution of the compound of Example 4 (150 mg, 0.29 mmol) in THF (5 mL) at 0 ° C. under N ₂ is added a solution of 1.5 M lithium diisopropylamide in cyclohexane (0.2 mL, 0.3 mmol) and the reaction Was adjusted to room temperature and stirred for 1 hour. Then, an additional fraction of lithium diisopropylamide (0.4 mL, 0.6 mmol) was added and after 2 hours a final fraction of lithium diisopropylamide (0.2 mL, 0.3 mmol) was added. The reaction is then stirred for another 3 h at rt, then quenched with H ₂ O, the product is extracted with 2N aqueous HCl, the aqueous layer is separated, neutralized with sodium bicarbonate and 3 times with CH ₂ Cl ₂ Extracted and dried over MgSO ₄ and evaporated under reduced pressure. The resulting residue was purified by chromatography on silica eluting with CH ₂ Cl ₂ /MeOH/0.88NH ₃ (90/10/1, v / v) to afford the title compound (82 mg, 58%) as off-white solid. It was. R _f 0.17 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 90/10/1, v / v). MS m / z 484 (MH ⁺ ). ¹ H NMR (CDCl ₃ ) δ: 1.95 (2H, m), 3.27 (2H, m), 3.37 (2H, m), 3.48 (3H, s), 3.55 (2H, m), 3.65 (4H, m) , 3.90 (5H, bm), 3.99 (3H, s), 5.08 (1H, m), 5.70 (1H, s), 7.03 to 7.23 (3H, m), 7.31 to 7.44 (2H, m). Found C, 60.72; H, 6.37; N, 13.38; C ₂₅ H ₃₀ N ₅ O ₄ F 0.35 ether 0.7H ₂ O is C, 60.73; H, 6.74; N, 13.41% is required.
Example 28
4-amino-6,7-dimethoxy-5- (3-fluorophenyl) -2- [4- (4-morpholinecarbonyl) -1,4-diazepan-1yl] quinoline
Example 10 (b) compound (200 mg, 0.37 mmol) and 3-fluorophenylboronic acid (62 mg, 0.44) in a mixture of toluene (9 mL), 1 M aqueous Na ₂ CO ₃ (1.5 mL) and EtOH (5 mL) Tetrakis (triphenylphosphine) palladium (13 mg, 0.44 mmol) was added to the solution of mmol, and the reaction was heated to reflux for 1 hour. The reaction was then cooled, partitioned between EtOAc and H ₂ O, and the organic layer was dried over MgSO ₄ and evaporated to give a brown residue. It was dissolved in 1,2-dimethoxyethane and the solution was clarified with N ₂ , then potassium tert-butoxide (124 mg, 1.1 mmol) was added and the reaction heated to reflux for 1 hour. After cooling, the reaction mixture was partitioned between EtOH and H ₂ O, and the organic layer was dried over MgSO ₄ and evaporated in vacuo. The product was purified by chromatography on silica gel eluting with CH ₂ Cl ₂ /MeOH/0.88NH ₃ (96 / 3.5 / 0.5, v / v) to afford the title compound (136 mg, 72%) as brown foam. R _f 0.39 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 92/7/1, v / v). MS m / z 510 (MH ⁺ ). ¹ H NMR (CDCl ₃ ) δ: 2.03 (2H, m), 3.16 (4H, m), 3.34 (2H, m), 3.50 (3H, s), 3.59 (2H, m), 3.65 (4H, m) , 3.71 (2H, m), 3.80 (2H, bs), 3.94 (2H, m), 3.99 (3H, s), 5.74 (1H, s), 7.06 (1H, bs), 7.10 to 7.20 (3H, m ), 7.41 (1 H, m). Found C, 62.70; H, 6.22; N, 13.18; C ₂₇ H ₃₂ N ₅ O ₄ F 0.5 H ₂ O is C, 62.53; H, 6.41; N, 13.50% is required.
Example 29
4-amino-6,7-dimethoxy-2- (1-methylpiperidin-4-yl) -5-phenylquinoline
The title compound is obtained from the compound of Example 8 (d) and 1-methylpiperidine-4-carboxylic acid (Rogers et al., "Molecular Pharmacology 36, 333 (1989)") of Example 5 (e). It was prepared by the method. The product was purified by chromatography on silica gel eluting with EtOAc / diethylamine (90/10, v / v) to afford the title compound (63%) as an orange solid. R _f 0.15 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 92/7/1, v / v). MS m / z 504 (MH ⁺ ). ¹ H NMR (CDCl ₃ ) δ: 1.35 (4H, m), 2.06 (2H, m), 2.23 (3H, s), 2.30 (2H, m), 2.42 (1H, m), 2.80 to 2.95 (2H, m), 3.50 (3H, s), 3.59 (2H, m), 3.78 (6H, m), 3.95-4.13 (2H, bs), 4.00 (3H, s), 5.68 (1H, s), 7.13 (1H) , bs), 7.38 (1 H, m), 7.45 (3 H, m). Found C, 67.03; H, 7.37; N, 12.87; C ₂₉ H ₃₇ N ₅ O ₃ 0.5 H ₂ O 0.5 EtOAc is C, 66.88; H, 7.60; N, 12.58% is required.
Example 30
4-amino-6,7-dimethoxy-2- [3- (morpholinecarbonylamino) ethaneamino] -5-phenylquinazoline
(a) 4-amino-2- (3-aminoethaneamino) -6,7-dimethoxy-5-phenyl-quinazolin
This compound was prepared by the method of Example 16 (h) from the compound of Example 16 (g) and 10 molar equivalents of 1,2-ethanediamine in the presence of catalytic potassium iodide. Subtitle compound (66%) was obtained as a colorless foam. R _f 0.42 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 84/14/2, v / v). MS m / z 340 (MH ⁺ ).
(b) 4-amino-6,7-dimethoxy-2- [3- (morpholinecarbonylamino) ethaneamino] -5-phenylquinazoline
The solution of the product of step (a) (343 mg, 1.0 mmol) in CH ₂ Cl ₂ (3 mL) at 0 ° C. under N ₂ was treated with N-methomorpholine (0.14 mL, 1.3 mmol), followed by CH ₂ Cl ₂ A solution of 4-morpholinecarbonyl chloride (0.11 mL, 1.1 mmol) in (1 mL) was added dropwise. The reaction was adjusted to room temperature and stirred for 18 hours. The reaction was then terminated with H ₂ O, extracted with CH ₂ Cl ₂ , the organic layer was separated, washed with saturated brine, dried over MgSO ₄ and evaporated. Purification on silica gel eluting with (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 90/10/1, v / v), and then titration with ether gave the title compound (185 mg, 34%) as colorless foam. R _f 0.45 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 90/10/1, v / v). MS m / z 453 (MH ⁺ ). ¹ H NMR (CDCl ₃ ) δ: 3.32 to 3.80 (13H, mm), 4.00 (5H, s), 5.34 (3H, b), 5.94 (1H, bs), 7.03 (1H, bs), 7.32 (2H, m), 7.55 (3H, m). Found C, 53.68; H, 6.16; N, 16.45; C ₂₃ H ₂₉ N ₆ O ₄ 0.1 ether CH ₂ Cl ₂ is C, 53.77; H, 5.73; N, 16.43% is required.
Example 31
4-amino-6,7-dimethoxy-2- [4- (morpholinecarbonylamino) -1-N-methylpropaneamino] -5-phenylquinazoline
(a) 4-amino-2- (4-amino-1-N-methylpropaneamino) -6,7-dimethoxy-5-phenylquinazoline
This compound was prepared by the method of Example 16 (h) from the compound of Example 16 (g) and 10 molar equivalents of N-methyl-1,3-propanediamine in the presence of catalytic potassium iodide. Subtitle compound (17%) was obtained as a colorless foam. R _f 0.45 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 84/14/2, v / v). MS m / z 368 (MH ⁺ ).
(b) 4-amino-6,7-dimethoxy-2- [4- (morpholinecarbonylamino) -1-N-methylpropaneamino] -5-phenylquinazoline
The title compound was prepared by the method of Example 30 (b) from the product of step (a) and 4-morpholinecarbonyl chloride. The crude product was purified on silica gel eluting with (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 90/10/1, v / v) and then titrated with ether to give the title compound (49%) as colorless foam. . R _f 0.56 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 90/10/1, v / v). MS m / z 481 (MH ⁺ ). ¹ H NMR (CDCl ₃ ) δ: 1.81 (2H, m), 3.13 (3H, s), 3.32 (6H, m), 3.50 (3H, s), 3.65 (4H, m), 3.84 (2H, m) , 4.00 (3H, s), 4.71 (2H, bs), 5.65 (1H, bs), 7.00 (1H, bs), 7.35 (2H, m), 7.48 (3H, m). Found C, 58.84; H, 6.68; N, 15.69; C ₂₅ H ₃₂ N ₆ O ₄ 0.2 ether 0.5CH ₂ Cl ₂ is C, 58.72; H, 6.56; N, 15.63% is required.
Example 32
(R, S) -4-amino-6,7-dimethoxy-5-phenyl-2- [4- (tetrahydrofuran-2-carbonylamino) -1-N-methylpropaneamino] quinazoline
The title compound was prepared by the method of Example 5 (e) from the compound of Example 31 (a) and (R, S) -tetrahydrofuran-2-carboxylic acid. The crude product was purified on silica gel eluting with (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 90/10/1, v / v) and then titrated with ether to give the title compound (57%) as colorless foam. . R _f 0.51 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 90/10/1, v / v). MS m / z 466 (MH ⁺ ). ¹ H NMR (CDCl ₃ ) δ: 1.58 (1H, m), 1.71 to 1.97 (3H, m), 2.23 (2H, m), 2.94 (1H, m), 3.16 (3H, s), 3.39 (1H, m), 3.50 (3H, s), 3.71 (1H, m), 3.84 (1H, m), 3.89 to 4.05 (2H, m), 4.00 (3H, s), 4.40 (1H, t), 5.15 (2H , b), 7.05 (1H, bs), 7.40 (2H, m), 7.50 (3H, m), 8.39 (1H, bs). Found C, 63.71; H, 6.85; N, 14.64; C ₂₅ H ₃₁ N ₅ O ₄ 0.1CH ₂ Cl ₂ is C, 63.59; H, 6.63; N, 14.77% is required.
Example 33
4-amino-6,7-dimethoxy-2- [4- (morpholinecarbonylamino) -1-propaneamino] -5-phenylquinazoline
(a) 4-amino-2- (4-amino-1-propaneamino) -6,7-dimethoxy-5-phenylquinazoline
A subsidiary compound was prepared by the method of Example 16 (h) from the compound of Example 16 (g) and 10 molar equivalents of 1,3-propanediamine in the presence of catalytic potassium iodide. Subtitle compound (72%) was obtained as a colorless foam. R _f 0.11 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 84/14/2, v / v). MS m / z 354 (MH ⁺ ).
(b) 4-amino-6,7-dimethoxy-2- [4- (morpholinecarbonylamino) -1-propaneamino] -5-phenylquinazoline
The title compound was prepared by the method of Example 30 (b) from the product of step (a) and 4-morpholinecarbonyl chloride. The crude product was purified on silica gel eluting with (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 90/10/1, v / v) and then titrated with ether to give the title compound (71%) as colorless foam. . R _f 0.40 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 90/10/1, v / v). MS m / z 467 (MH ⁺ ). ¹ H NMR (CDCl ₃ ) δ: 1.80 (2H, m), 3.39 (6H, m), 3.50 (3H, s), 3.58 (2H, m), 3.68 (4H, m), 4.00 (3H, s) , 4.90 (2H, bs), 5.50 (1H, bs), 5.80 (1H, bs), 6.90 (1H, s), 7.37 (2H, m), 7.52 (3H, m). Found C, 58.69; H, 6.49; N, 16.53; C ₂₄ H ₃₀ N ₆ O ₄ 0.4CH ₂ Cl ₂ is C, 58.54; H, 6.20; N, 16.79% is required.
Example 34
(R, S) -4-amino-6,7-dimethoxy-5-phenyl-2- [4- (tetrahydrofuran-2-carbonylamino) -1-propaneamino] quinazoline
The title compound was prepared by the method of Example 5 (e) from the product of Example 33 (a) and (R, S) -tetrahydrofuran-2-carboxylic acid. The crude product was purified on silica gel eluting with (CH ₂ Cl ₂ / MeOH 90/10, v / v) and then titrated with toluene to give the title compound (52%) as colorless foam. R _f 0.70 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 84/14/2, v / v). MS m / z 452 (MH ⁺ ). ¹ H NMR (CDCl ₃ ) δ: 1.67 (2H, m), 1.90 (2H, m), 2.23 (2H, m), 3.06 (1H, m), 3.35 (2H, m), 3.50 (3H, s) , 3.61 (2H, m), 3.87 (1H, m), 3.99 (3H, s), 4.01 (1H, bs), 4.40 (1H, t), 5.35 (2H, b), 7.03 (1H, bs), 7.39 (2H, m), 7.52 (3H, m), 8.20 (1H, bs). Found C, 63.18; H, 6.50; N, 14.66; C ₂₄ H ₂₉ N ₅ O ₄ 0.1. Toluene 0.5H ₂ O is C, 63.16; H, 6.61; N, 14.91% is required.
Example 35
4-amino-6,7-dimethoxy-5-phenyl-2- [4- (2-pyrimidineamino) -1-propaneamino] quinazoline
The product of Example 33 (a) (230 mg, 0.65 mmol) was converted to 2-chloropyrimidine (82 mg, 0.72 mmol) and triethylamine (0.11 mL, 0.78 mmol) in a mixture of n-BuOH (3 mL) and DMA (1 mL). ) Solution. The reaction was heated to 80 ° C. under N ₂ for 18 h, after which the reaction was cooled, washed with H ₂ O, extracted with CH ₂ Cl ₂ and then saturated brine. The organic layer was separated, dried over MgSO ₄ , purified on silica gel eluting with (CH ₂ Cl ₂ / MeOH 0.88NH ₃ 90/10/1, v / v) and then titrated with ethylene. The title compound was obtained as a colorless foam (110 mg, 34%). R _f 0.57 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 84/14/2, v / v). MS m / z 432 (MH ⁺ ). ¹ H NMR (CDCl ₃ ) δ: 1.84 (2H, m), 3.41 (2H, m), 3.48 (3H, s), 3.55 (2H, m), 3.99 (3H, s), 6.4 to 8.4 (2H, b), 6.42 (1H, t), 6.90 (1H, bm), 7.05 (1H, s), 7.35 (2H, m), 7.52 (3H, m), 8.16 (2H, bs). Found C, 57.75; H, 5.70; N, 20.04; C ₂₃ H ₂₅ N ₇ O ₂ 0.75CH ₂ Cl ₂ is C, 57.59; H, 5.39; N, 19.80% is required.
Example 36
4-amino-6,7-dimethoxy-5-phenyl-2- [3- (2-pyridyl) ethaneamino] quinazoline
The title compound was prepared by the method of Example 16 (h) from the compound of Example 16 (g) and 5 molar equivalents of 2- (2-aminoethyl) pyridine in the presence of catalytic potassium iodide. The product was purified on silica gel eluting with (CH ₂ Cl ₂ / MeOH 0.88 NH ₃ 90/10/1, v / v) and then titrated with ether to give the title compound (31%) as colorless foam. R _f 0.27 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 90/10/1, v / v). MS m / z 402 (MH ⁺ ). ¹ H NMR (CDCl ₃ ) δ: 3.09 (2H, t), 3.45 (3H, s), 3.84 (2H, q), 4.00 (3H, s), 5.00 (2H, bs), 6.00 to 6.60 (1H, b), 6.99 (1H, s), 7.05 (1H, dd), 7.40 (1H, d), 7.35 (2H, m), 7.50 (3H, m), 7.59 (1H, t), 8.55 (1H, d ). Found C, 63.48; H, 5.84; N, 15.77; C ₂₃ H ₂₃ N ₅ O ₂ 0.5CH ₂ Cl ₂ is C, 63.57; H, 5.45; N, 15.78% is required.
Example 37
4-amino-2- [4- (furan-2-carbonyl) -1,4-piperazin-1-yl] -6,7-dimethoxy-5-phenylquinazoline
The title compound was prepared by the method of Example 5 (e) from the compound of Example 19 (a) and furan-2-carboxylic acid. The product was purified on silica gel eluting with (CH ₂ Cl ₂ / MeOH 0.88 NH ₃ 90/10/1, v / v) and then titrated with ether to give the title compound (66%) as a foam. R _f 0.67 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 90/10/1, v / v). MS m / z 460 (MH ⁺ ). ¹ H NMR (CDCl ₃ ) δ: 3.50 (3H, s), 3.74 (2H, m), 3.80 to 4.05 (6H, m), 3.97 (3H, s), 4.66 (2H, bs), 6.48 (1H, bs), 7.00 (2H, m), 7.39 (2H, m), 7.50 (4H, m). Found C, 65.71; H, 6.42; N, 14.80; C ₂₅ H ₂₅ N ₅ O ₄ 0.5 ether is C, 65.30; H, 6.09; N, 14.11% is required.
Example 38
(R / S) -4-amino-6,7-dimethoxy-5-phenyl-2- [4- (tetrahydrofuran-2-carbonyl) -1,4-piperazin-1-yl] quinazoline
The title compound was prepared by the method of Example 5 (e) from the compound of Example 19 (a) and (R / S) -tetrahydrofuran-2-carboxylic acid. The product was purified by chromatography on silica gel eluting with (CH ₂ Cl ₂ / MeOH 0.88NH ₃ 90/10/1, v / v) and then titrated with ether to give the title compound (52%) as a foam. It was. R _f 0.58 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 90/10/1, v / v). MS m / z 464 (MH ⁺ ). ¹ H NMR (CDCl ₃ ) δ: 1.81 to 2.16 (4H, m), 3.09 to 4.08 (10H, m), 3.50 (3H, s), 4.00 (3H, s), 4.61 (3H, bm), 6.97 ( 1 H, s), 7.37 (2 H, m), 7.50 (3 H, m). Found C, 63.14; H, 6.52; N, 14.00; C ₂₅ H ₂₉ N ₅ O ₄ 0.2CH ₂ Cl ₂ 0.3 ether is C, 63.07; H, 6.53; N, 13.88% is required.
Example 39
(R / S) -4-amino-6,7-dimethoxy-5-phenyl-2- [4- (tetrahydropyran-2-carbonyl) -1,4-piperazin-1-yl] quinazoline
The title compound was run from the compound of Example 19 (a) and (R / S) -tetrahydropyran-2-carboxylic acid (Nelson, et al., J. Org. Chem. 21, 798 (1956)). It manufactured by the method of Example 5 (e). The product was purified by chromatography on silica gel eluting with (CH ₂ Cl ₂ / MeOH 0.88NH ₃ 90/10/1, v / v) and then titrated with ether to give the title compound (59%) as a solid. It was. R _f 0.48 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 90/10/1, v / v). MS m / z 478 (MH ⁺ ). ¹ H NMR (CDCl ₃ ) δ: 1.44 to 2.02 (6H, m), 3.40 to 4.16 (10H, m), 3.50 (3H, s), 3.98 (3H, s), 4.11 (1H, dd), 4.60 ( 3H, bm), 6.94 (1H, s), 7.38 (2H, m), 7.50 (3H, m). Found C, 64.43; H, 6.45; N, 13.85; C ₂₆ H ₃₁ N ₅ O ₄ 0.1CH ₂ Cl ₂ 0.3 ether is C, 64.51; H, 6.82; N, 13.71% is required.
Example 40
4-amino-6,7-dimethoxy-2- [4- (morpholinecarbonyl) -1,4-piperazin-1-yl] -5-phenylquinazoline
The morpholine carbonyl chloride (0.07 mL, 0.66 mmol) of the compound of Example 19 (a) (220 mg, 0.60 mmol) and 4-methylmorpholine (0.08 mL) in CH ₂ Cl ₂ (5 mL) at 0 ° C. under N _2. , 0.72 mmol) in a stirred solution. The reaction was stirred for 18 hours, then washed with H ₂ O, extracted with CH ₂ Cl ₂ , washed with saturated brine, the organic layer was dried over MgSO ₄ and evaporated. The product was purified on silica gel eluting with (CH ₂ Cl ₂ / MeOH 0.88NH ₃ 90/10/1, v / v) and then triturated with ether to give the title compound (230 mg, 70%) as a solid. R _f 0.45 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 90/10/1, v / v). MS m / z 479 (MH ⁺ ). ¹ H NMR (CDCl ₃ ) δ: 3.30 (12H, m), 3.50 (3H, s), 3.84 (4H, m), 3.98 (3H, s), 4.60 (2H, bm), 6.97 (1H, s) , 7.38 (2H, m), 7.48 (3H, m). Found C, 60.33; H, 6.24; N, 15.43; C ₂₅ H ₃₀ N ₆ O ₄ 0.3CH ₂ Cl ₂ 0.5 ether is C, 60.35; H, 6.61; N, 15.46% is required.
Example 41
4-amino-6,7-dimethoxy-5-phenyl-2- [4- (thiomorpholine-1,1-dioxide-4-carbonyl) -1,4-diazepan-1-yl] phenylquina Sleepy
(a) Thiomorpholine-1,1-dioxide hydrochloride
2-Chloroethyl chloroformate (0.72 mL, 6.7 mmol) was added dropwise to a solution of 4-methylthiomorpholine-1,1-dioxide (1.0 g, 6.7 mmol) in toluene (10 mL) at 0 ° C. under N ₂ . After 10 minutes, the reaction was warmed and refluxed continuously for 2 hours. After cooling, the reaction mixture was evaporated, partitioned between EtOAc and H ₂ O, the organic layer was separated, washed successively with diluted HCl and saturated brine, the organic layer was dried over Na ₂ SO ₄ and evaporated. The residue was taken up in MeOH (10 mL) and heated to reflux for 2 hours, after which the reaction mixture was evaporated and triturated with EtOAc to give the subtitle compound (415 mg, 36%) as a solid. R _f 0.34 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 90/10/1, v / v). MS m / z 136 (MH ⁺ ).
(b) 4-amino-6,7-dimethoxy-5-phenyl-2- [4- (thiomorpholine-1,1-dioxide-4-carbonyl) -1,4-diazepan-1-yl Quinazoline
The title compound was prepared by the method of Example 18, using the product of step (a) in place of azetidinol. The product was purified by chromatography on silica gel eluting with (CH ₂ Cl ₂ / MeOH 0.88NH ₃ 90/10/1, v / v) and then titrated with ether to give the title compound (25%) as a foam. It was. R _f 0.58 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 90/10/1, v / v). MS m / z 541 (MH ⁺ ). ¹ H NMR (CDCl ₃ ) δ: 1.97 (2H, m), 3.00 (4H, m), 3.40 (2H, m), 3.50 (3H, s), 3.55 to 3.73 (6H, m), 3.84 (2H, m), 3.90 to 4.06 (2H, m), 3.98 (3H, s), 4.59 (2H, bm), 6.90 (1H, s), 7.38 (2H, m), 7.50 (3H, m). Found C, 55.90; H, 5.82; N, 14.35; C ₂₆ H ₃₂ N ₆ O ₄ S 0.3 CH ₂ Cl ₂ 0.2 ether is C, 55.82; H, 5.98; N, 14.40% is required.
Example 42
(R / S) -4-amino-6,7-dimethoxy-5-phenyl-2- [4- (tetrahydropyran-2-carbonyl) -1,4-diazepan-1-yl] quinazoline
(a) (R / S) -1- (tert-butyloxycarbonyl) -4- (tetrahydropyran-2-carbonyl) -1,4-diazepane
A subtitle compound was prepared by the method of Example 5 (e) using Intermediate 1 and (R / S) -tetrahydropyran-2-carboxylic acid. Subtitle compound (73%) was obtained as a solid. R _f 0.67 (CH ₂ Cl ₂ ). MS m / z 312 (MH ⁺ ).
(b) (R / S) -1- (tetrahydropyran-2-carbonyl) -1,4-diazepane hydrochloride
A subtitle compound was prepared by the method of intermediate 3 from the product of step (a). A large amount of subtitle compound was obtained as a hygroscopic solid. MS m / z 213 (MH ⁺ ).
(c) (R / S) -4-amino-6,7-dimethoxy-5-phenyl-2- [4- (tetrahydropyran-2-carbonyl) -1,4-diazepan-1-yl Quinazoline
The title compound was prepared by the method of Example 16 (h) from the product of step (b) and the compound of Example 16 (g). The product was purified by chromatography on silica gel eluting with (CH ₂ Cl ₂ / MeOH 0.88NH ₃ 90/10/1, v / v), and then triturated with ether to give the title compound (43%) as a foam. It was. R _f 0.61 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 90/10/1, v / v). MS m / z 492 (MH ⁺ ). ¹ H NMR (CDCl ₃ ) δ: 1.06 to 2.16 (8H, m), 3.16 to 4.40 (11H, m), 3.47 (3H, s), 3.98 (3H, s), 4.59 (2H, bm), 6.95 ( 1H, bs), 7.38 (2H, m), 7.50 (3H, m). Found C, 65.60; H, 7.20; N, 12.32; C ₂₇ H ₃₃ N ₅ O ₄ 0.8 ether is C, 65.84; H, 7.50; N, 12.71% is required.
Example 43
(S) -4-amino-6,7-dimethoxy-2- [2- (morpholinecarbonyl) pyrrolidin-1-yl] -5-phenylquinazoline
The title compound was replaced with (S) -proline morpholine amide [Cbz- (S) -proline with tBoc- (S) -proline, so that Asami et al., Bull. Chem. Soc. Jpn., 63, 721 (1990) "and the compound of Example 16 (g) by the method of Example 16 (h). The product was purified by chromatography on silica gel eluting with (CH ₂ Cl ₂ / MeOH 0.88NH ₃ 90/10/1, v / v) and then titrated with ether to give the title compound (53%) as a foam. It was. R _f 0.39 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 90/10/1, v / v). MS m / z 464 (MH ⁺ ). ¹ H NMR (CDCl ₃ ) δ: 1.99 (2H, m), 2.02 (2H, m), 3.48 (3H, s), 3.60 (6H, m), 3.84 (4H, m), 3.97 (3H, s) , 4.58 (2H, bm), 5.02 (1H, bs), 6.95 (1H, bs), 7.35 (2H, m), 7.47 (3H, m). Found C, 63.68; H, 6.54; N, 13.92; C ₂₅ H ₂₉ N ₅ O ₄ 0.5 ether 0.1CH ₂ Cl ₂ is C, 63.72; H, 6.75; N, 13.70% is required.
Example 44
4-amino-6,7-dimethoxy-5-phenyl-2- (5,6,7,8-tetrahydro-1,6-naphthyrid-6-yl) quinazolin
The title compound is described in 5,6,7,8, -tetrahydro-1,6-naphthyridine (Shiozawa et al., "Chem. Pharm. Bull., 32, 2522 (1984)") and Examples Prepared by the method of Example 16 (h) from the compound of 16 (g). The product was purified by chromatography on silica gel eluting with (CH ₂ Cl ₂ / MeOH 0.88NH ₃ 93/7/1, v / v) and then titrated with ether to give the title compound (33%) as a foam. It was. R _f 0.50 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 90/10/1, v / v). MS m / z 492 (MH ⁺ ). ¹ H NMR (CDCl ₃ ) δ: 3.10 (2H, t), 3.48 (3H, s), 3.98 (3H, s), 4.18 (2H, t), 4.66 (2H, bs), 5.00 (2H, s) , 7.01 (1H, s), 7.13 (1H, dd), 7.39 (2H, m), 7.50 (4H, m), 8.42 (1H, d). Found C, 68.05; H, 5.80; N, 15.85; C ₂₅ H ₂₃ N ₅ O ₂ 0.1CH ₂ Cl ₂ 0.4 ether is C, 68.35; H, 6.07; N, 15.51% is required.
Example 45
4-amino-6,7-dimethoxy-5-phenyl-2- (5,6,7,8-tetrahydro-1,3,6-triazanaft-6-yl) quinazoline
(a) 1- (tert-butyloxycarbonyl) -3- (N, N-dimethylmethylidene) -4-piperidone
Dimethylformamide dimethyl acetal (5.82 mL, 0.044 mole) was added to 1-Boc-4-piperidine in Ashf et al., Chem. Soc., Perkin 1, 641 (1985) in DMF (80 mL). ] Stirred solution (8.73 g, 0.044 mol) and the reaction mixture was heated to 80 ° C. under N ₂ for 18 h. After cooling, the DMF was removed under reduced pressure, the residue was partitioned between EtOAc and H ₂ O, the organic layer was washed with H ₂ O and saturated brine, dried over MgSO ₄ and evaporated to give the subtitle compound (8.44 g, 76%) was obtained as a solid. R _f 0.33 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 90/10/1, v / v). MS m / z 225 (MH ⁺ ).
(b) 6- (tert-butyloxycarbonyl)-(5,6,7,8-tetrahydro-1,3,6-triazanaphthalene)
Sodium (762 mg, 0.033 mole) was added to EtOH (150 mL), then to formamidine acetate (3.45 g, 0.033 mole) and the reaction stirred at room temperature under N ₂ for 30 minutes. Then a solution of the product of step (a) (8.43 g, 0.033 M) in EtOH (50 mL) was added and the mixture was cooled and concentrated under reduced pressure, then the reaction was heated to reflux for 18 h. The residue was partitioned between EtOAc and H ₂ O, and the organic layer was washed with saturated brine and dried over MgSO ₄ . Purification by chromatography on silica gel eluting with CH ₂ Cl ₂ / MeOH (96/4, v / v) gave the subtitle compound (5.09 g, 65%) as an oil. R _f 0.57 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 90/10/1, v / v). MS m / z 236 (MH ⁺ ).
(c) 5,6,7,8-tetrahydro-1,3,6-triazanaphthalene
HCl was bubbled through a solution of the product of step (b) (4.80 g, 0.020 mol) in a mixture of MeOH and ether (50 mL, 1/1, v / v) at 0 ° C. until saturated. The mixture was then adjusted to room temperature over 2 hours, after which a precipitate formed. This was isolated by pouring the supernatant, washed twice with ether and dried in vacuo to yield the subtitle compound (2.85 g, 81%) as a colorless solid. R _f 0.13 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 90/10/1, v / v). MS m / z 136 (MH ⁺ ).
(d) 4-amino-6,7-dimethoxy-5-phenyl-2- [5,6,7,8-tetrahydro-1,3,6-triazanaft-6-yl] quinazoline
The title compound was prepared by the method of Example 16 (h) from the product of step (c) and the compound of Example 16 (g). The product was purified by chromatography on silica gel eluting with (EtOAc / hexane 7/1, v / v) and then titrated with ether to give the title compound (42%) as a pale yellow foam. R _f 0.48 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 90/10/1, v / v). MS m / z 415 (MH ⁺ ). ¹ H NMR (CDCl ₃ ) δ: 3.03 (2H, t), 3.50 (3H, s), 4.00 (3H, s), 4.21 (2H, t), 4.68 (2H, bs), 5.00 (2H, s) , 7.00 (1H, s), 7.37 (2H, m), 7.50 (3H, m), 8.55 (1H, s), 8.99 (1H, s). Found C, 65.77; H, 5.48; N, 19.31; C ₂₃ H ₂₂ N ₆ O ₂ 0.2 ether 0.25 H ₂ O is C, 65.90; H, 5.69; N, 19.37% is required.
Example 46
4-amino-6,7-dimethoxy-2-[(4-methanesulfonamido) isoindolin-2-yl] -5-phenylquinazoline
(a) 4-methanesulfonamidophthalimide
Methanesulfonamidophthalimide (2.6 mL, 0.034 mole) was added dropwise to a stirred suspension of 4-aminophthalimide (5.0 g, 0.031 mole) in pyridine (50 mL). The mixture was stirred at room temperature under N ₂ for 48 hours, then the solid formed was isolated by filtration, washed well with H ₂ O and CH ₂ Cl ₂ and dried in vacuo to give the subtitle compound as a colorless solid (5.67 g, 76 %) Was obtained. R _f 0.52 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 90/10/1, v / v). MS m / z 241 (MH ⁺ ).
(b) 4- (methanesulfonamido) isoindolin hydrochloride
Borane THF complex (1M solution in THF, 106 mL, 0.11 mol) was added dropwise to the stirred suspension of the product of step (a) in THF (100 mL) and the reaction heated to reflux for 18 hours. The reaction mixture was then cooled to 0 ° C., MeOH (50 mL) was added carefully, followed by 6N HCl (70 mL). The mixture was then extracted three times with CH ₂ Cl ₂ and the aqueous layer was evaporated to dryness. The residue was added to CH ₂ Cl ₂ / MeOH (95/5, v / v) and the inorganic solids were filtered off. The filtrate was concentrated to give a solid that was titrated with CH ₂ Cl ₂ and dried in vacuo to yield the subtitle compound (2.67 g, 46%) as a colorless solid. R _f 0.09 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 90/10/1, v / v). MS m / z 213 (MH ⁺ ).
(c) 4-amino-6,7-dimethoxy-2-[(4-methanesulfonamido) isoindolin-2-yl] -5-phenylquinazoline
The title compound was prepared by the method of Example 16 (h) from the product of step (b) and the compound of Example 16 (g). The product was purified by chromatography on silica gel eluting with (EtOAc / hexane 7/1, v / v) and then titrated with ether to give the title compound (41%) as a solid. R _f 0.52 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 90/10/1, v / v). MS m / z 492 (MH ⁺ ). ¹ H NMR (CDCl ₃ ) δ: 3.03 (3H, s), 3.50 (3H, s), 4.00 (3H, s), 4.71 (2H, bs), 4.90 (4H, bs), 7.03 (1H, s) , 7.13 (1H, d), 7.21 (1H, s), 7.30 (1H, d), 7.40 (2H, m), 7.52 (4H, m). Found C, 59.87; H, 5.51; N, 12.72; C ₂₅ H ₂₅ N ₅ O ₄ S 0.8 EtOAc is C, 60.26; H, 5.63; N, 12.46% is required.
Example 47
(S) -4-amino-6,7-dimethoxy-2- [3- (morpholinecarbonyl) pyrrolidin-1-yl] -5-phenylquinazoline
(a) (R / S) -1- (tert-butyloxycarbonyl) -3- (morpholinecarbonyl) pyrrolidine
Subsidiary compounds were used as (R / S) -1-Boc-pyrrolidine-3-carboxylic acid (MacLeod et al., J. Med. Chem., 33, 2052 (1990)) and morpholine Prepared by the method of Example 5 (e), the subtitle compound (62%) was obtained as an oil, R _f 0.69 (CH ₂ Cl ₂ / MeOH 95/5, v / v) MS m / z 285 (MH ⁺ ).
(b) (R / S) -3- (morpholinecarbonyl) pyrrolidine hydrochloride
A subtitle compound was prepared by the method of Example 45 (c). Subtitle compound (64%) was obtained as a colorless solid. R _f 0.07 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 90/10/1, v / v). MS m / z 185 (MH ⁺ ).
(c) (S) -4-amino-6,7-dimethoxy-2- [3- (morpholinecarbonyl) pyrrolidin-1-yl] -5-phenylquinazoline
The title compound was prepared by the method of Example 16 (h) from the product of step (b) and the compound of Example 16 (g). The product was purified by chromatography on silica gel eluting with (CH ₂ Cl ₂ / MeOH / NH ₃ 90/10/1, v / v) and then titrated with ether to give the title compound (41%) as a foam. It was. R _f 0.52 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 90/10/1, v / v). MS m / z 464 (MH ⁺ ). ¹ H NMR (CDCl ₃ ) δ: 2.13 (1H, m), 2.35 (1H, m), 3.26 (1H, m), 3.47 (3H, s), 3.52 to 3.76 (10H, m), 3.84 (1H, m), 3.98 (3H, s), 4.00 (1H, m), 4.70 (2H, bs), 7.05 (1H, s), 7.38 (2H, m), 7.45 (3H, m). Found C, 62.55; H, 6.28; N, 14.27; C ₂₅ H ₂₉ N ₅ O ₄ 0.25CH ₂ Cl ₂ is C, 62.55; H, 6.13; N, 14.45% is required.
Example 48
4-amino-6,7-dimethoxy-5- (2-methoxyphenyl) -2- (5,6,7,8-terahydro-1,6-naphthyrid-6-yl) quinazoline
(a) 4-amino-6,7-dimethoxy-5-iodo-2- (5,6,7,8-terahydro-1,6-naphthyrid-6-yl) quinazolin
A subtitle compound was prepared by the method of Example 16 (h) from 1,2,3,4-terrahydro-1,6-naphthyridine and the compound of Example 20 (b). The subtitle compound was obtained in large quantities as brown foam. R _f 0.35 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 90/10/1, v / v). MS m / z 464 (MH ⁺ ).
(b) 4-amino-6,7-dimethoxy-5- (2-methoxyphenyl) -2- (5,6,7,8-terahydro-1,6-naphthyrid-6-yl) Quinazoline
The title compound was prepared by the method of Example 1 (a) using 2-methoxyphenylboronic acid and the product of step (a). The product was purified by titration with EtOAc / hexanes to give the title compound (18%) as an off-white solid. R _f 0.33 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 90/10/1, v / v). MS m / z 444 (MH ⁺ ). ¹ H NMR (D ₆ -DMSO) δ: 3.06 (2H, m), 3.50 (3H, s), 3.74 (3H, s), 4.00 (3H, s), 4.21 (2H, m), 4.74 (2H, s), 4.99 (2H, s), 6.90 to 7.16 (4H, m), 7.22 (1H, d), 7.39 to 7.55 (2H, m), 8.40 (1H, d). Found C, 66.52; H, 5.84; N, 14.83; C ₂₅ H ₂₅ N ₅ 0 ₃ 0.5H ₂ 0 0.1 hexanes was C, 66.67; H, 5.73; N, 15.20% is required.
Example 49
4-amino-11-methoxy-2- [4- (4-morpholincarbonyl) -1,4-diazepane-1-yl] -9H- [2] benzopyrano- [3,4-c Quinazoline
(a) 3-benzyloxy-4-methoxybenzonitrile
3-benzyloxy-4-methoxybenzaldehyde (50 g, 0.21 mol) is added to a solution of sodium acetate (33.9 g, 0.41 mol) and hydroxylamine hydrochloride (28.73 g, 0.41 mol) in acetic acid (200 mL), The resulting suspension was heated to reflux for 18 hours. After cooling, the reaction mixture was partitioned between CH ₂ Cl ₂ and H ₂ O and the aqueous phase was further extracted with CH ₂ Cl ₂ . The combined organic layers were dried over MgSO ₄ and evaporated to give the subtitle compound (43.9 g, 89%) as a tan solid. R _f 0.70 (toluene / EtOAc 4/1, v / v).
(b) 5-benzyloxy-4-methoxy-2-nitro-benzonitrile
The solution of the product of step (a) (43.8 g, 0.18 mol) in glacial acetic acid (87 mL) was added dropwise to concentrated nitric acid (70% w / w, 244 mL) with periodic cooling to maintain the reaction temperature below 30 ° C. . Once the addition was complete, the reaction was stirred for an additional 30 minutes, then the reaction was poured into H ₂ O (1 L) and stirred for 30 minutes. The resulting precipitate was isolated by filtration, washed with H ₂ O and dried in vacuo at 50 ° C. to give the subtitle compound (35.1 g, 68%) as a white solid. R _f 0.70 (EtOAc / hexanes 1/1, v / v).
(c) 2-amino-5-benzyloxy-4-methoxybenzonitrile
A solution of the product of step (b) (35.0 g, 0.12 mole) in CH ₂ Cl ₂ (500 mL) was added to tetra-n-butylammonium chloride (20.3 g, 0.074 mole) and then in H ₂ O (400 mL). To a solution of sodium dithionite hydrate (118.0 g, 0.61 mol) was added and the mixture was vigorously stirred at room temperature for 2 hours. Then a further amount of sodium dithionite hydrate (47.2 g) was added and stirred continuously for 1 hour. The reaction mixture was then basified with 2N aqueous NaOH and the phases separated. The aqueous layer was extracted two more times with CH ₂ Cl ₂ , and the combined organic layers were dried over MgSO ₄ and concentrated in vacuo to give a volume of 60 mL. Treatment with excess ether HCl gave a precipitate of an orange solid which was washed with ether and then dissolved in a mixture of CH ₂ Cl ₂ and 2N aqueous NaOH. The phases were separated and the organic phase was concentrated in vacuo, then dissolved in EtOAc and passed through a 5 cm plug of silica gel eluting with EtOAc. Evaporation and drying in vacuo gave the subtitle compound (26.7 g, 85%) as a yellow solid. R _f 0.76 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 90/10/1, v / v). MS m / z 255 (MH ⁺ ).
(d) 4-amino-6-benzyloxy-2-hydroxy-7-methoxyquinazoline
The solution of the product of step (c) in CH ₂ Cl ₂ (26.7 g, 0.10 mol) was treated with sodium cyanide (17.1 g, 0.26 mol) and trifluoroacetic acid (20.9 mL, 0.26 mol) was produced at room temperature. Dropwise to the mixture. After 45 minutes, the mixture was diluted with CH ₂ Cl ₂ (1 L) and stirred for an additional 18 hours. The mixture was then concentrated in vacuo, partitioned between MeOH and 2N aqueous NaOH and stirred for 2 hours. The MeOH was then removed in vacuo, the yellow solid was separated by filtration and washed successively with H ₂ O, acetone and ether to give the subtitle compound (18.0 g, 54%) as a yellow solid. The filtrate was concentrated, acidified with concentrated HCl (95 mL), warmed in a steam bath for 5 minutes, cooled and neutralized with solid potassium carbonate to afford additional product. The solid obtained was filtered and washed successively with H ₂ O, EtOH and ether to give the subtitle compound (12.11 g, mixed 93% yield) as a yellow solid. R _f 0.23 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 84/14/2, v / v). MS m / z 298 (MH ⁺ ).
(e) 4-amino-6-benzyloxy-2-chloro-7-methoxyquinazoline
DMF (7.9 mL, 0.10 mol) was added portionwise to POCl ₃ with stirring. After 10 minutes, the product of step (d) was added dropwise and the resulting mixture was heated at 90 ° C. for 1.5 h, then cooled and poured into EtOAc (750 mL). The mixture was neutralized by partial addition with aqueous sodium carbonate and the phases were separated. The organic layer was evaporated to dryness and the residue combined with the organic phase, which was then basified by aqueous NaOH (pH 10) and the mixture was heated at 90 ° C. for 2 hours. After cooling, the mixture was partitioned between CH ₂ Cl ₂ (1 L) and H ₂ O (1 L) and the organic phase was washed with H ₂ O, dried over MgSO ₄ and evaporated to give a yellow solid. Polishing with isopropanol gave the subtitle compound (4.64 g, 29%) as a colorless solid. R _f 0.64 (EtOAc / MeOH 95/5, v / v). MS m / z 316, 318 (MH ⁺ ).
(f) 2-amino-6-benzyloxy-7-methoxy-2- [4- (4-morpholincarbonyl) -1,4-diazepan-1-yl]
A subtitle compound was prepared by the method of Example 16 (h) from the product of step (e) and the compound of Example 16 (g). The product was purified on silica gel eluting with EtOAc / MeOH (9/1, v / v) to afford the subtitle compound (46%) as a foam. R _f 0.67 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 84/14/2, v / v). MS m / z 493 (MH ⁺ ).
(g) 2-amino-6-hydroxy-7-methoxy-2- [4- (4-morpholincarbonyl) -1,4-diazepan-1-yl]
The product of step (f) (360 mg, 0.73 mmol) was dissolved in EtOH (60 mL), 10% palladium on charcoal (100 mg, 0.09 mmol) was added and the reaction mixture was subjected to a pressure of 414 kPa (60 psi) for 18 hours. Hydrogenated at room temperature. The reaction mixture was filtered, concentrated in vacuo and the residue was purified on silica gel, eluting with CH ₂ Cl ₂ /MeOH/0.88NH ₃ (92/7/1, v / v) as a subtitle compound (135 mg, 47%) was obtained. R _f 0.33 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 84/14/2, v / v). MS m / z 403 (MH ⁺ ).
(h) 2-amino-6- (ortho-bromobenzyloxy) -7-methoxy-2- [4- (4-morpholinecarbonyl) -1,4-diazepan-1-yl]
Sodium hydride (60% dispersion in mineral oil, 100 mg, 2.5 mmol) was added to DMF (20 mL), followed by the product of step (g) (1.0 mg, 2.5 mmol) and the reaction was allowed to stand at room temperature for 20 minutes. Stirred. Ortho-bromobenzyl bromide (625 mg, 2.5 mmol) was then added to the reaction, stirred for 1 hour, then quenched with H ₂ O, extracted twice with EtOAc, and the combined organic layers were extracted with H ₂ O. Wash, dry over MgSO and evaporate to give product (1.2 g, 84%) as a foam. R _f 0.48 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 84/14/2, v / v). MS m / z 571, 573 (MH ⁺ ).
(i) 4-amino-11-methoxy-2- [4- (4-morpholinecarbonyl) -1,4-diazepan-1-yl] -9H- [2] benzopyrano- [3, 4-c] quinazoline
To a solution of the product of step (i) (1.2 g, 2.0 mmol) in DMF (10 mL) was added sodium carbonate (254 mg, 2.4 mmol) and palladium acetate (45 mg, 0.2 mmol) and the reaction mixture was stirred for 48 h under N ₂ . Heated to 130 ° C. The reaction mixture was then cooled and partitioned between EtOAc and H ₂ O, and the organic layer was dried over MgSO ₄ and evaporated. The product was purified on silica gel, eluting with CH ₂ Cl ₂ /MeOH/0.88NH ₃ (95/5 / 0.5, v / v), and then polished with hexane to afford the title compound (114 mg, 12%) as a pale yellow solid. It was. R _f 0.76 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 84/14/2, v / v). MS m / z 491 (MH ⁺ ). ¹ H NMR (CDCl ₃ ) δ: 2.06 (2H, m), 3.18 (4H, m), 3.42 (2H, m), 3.60 (2H, m), 3.68 (4H, m), 3.94 (2H, m) , 4.00 (5H, m), 4.90 (2H, bs), 5.09 (2H, s), 6.87 (1H, s), 7.21 to 7.52 (4H, m). Found C, 62.18; H, 6.34; N, 14.66; C ₂₆ H ₃₀ N ₆ O ₄ 0.6hexane 0.5CH ₂ Cl ₂ is C, 61.84; H, 6.74; N, 14.38% is required.
Example 50
4-amino-11-methoxy-2- [4- (4-morpholincarbonyl) -1,4-diazepane-1-yl] -9H- [2] benzopyrano- [3,4-c Quinoline
(a) 3- (ortho-bromobenzyloxy-4-methoxybenzonitrile
To a solution of 2-bromobenzyl alcohol (16.50 g, 88.2 mmol) in DMF (100 mL) was added sodium hydride (60% dispersion in mineral oil, 2.94 g, 73.5 mmol), followed by 3-fluoro-4-meth Toxybenzonitrile (8.88 g, 58.8 mmol) was added and the resulting mixture was heated to 90 ° C. for 2 h under N ₂ . After cooling, the mixture was partitioned between ether and H ₂ O and the organic layer was washed successively with 0.5 N HCl and saturated brine and then dried over MgSO ₄ . Titration with ether / pentane (1/3, v / v) gave the subtitle compound (13.35 g, 71%) as an off-white solid. R _f 0.27 (hexane / EtOAc 5/1, v / v). MS m / z 318, 320 (MH ⁺ ).
(b) 1-cyano-6H-dibenzo [b, d] pyran
A subtitle compound was prepared by the method of Example 49 (i) from the product of step (a). The product was chromatographed on silica gel, eluting with hexane / EtOAc (4/1, v / v), and then purified by titration with hexane / EtOAc (4/1, v / v) to give the subtitle compound as a colorless solid ( 41%) was obtained. R _f 0.16 (hexane / EtOAc 4/1, v / v). MS m / z 238 (MH ⁺ ).
(c) 1-cyano-2-nitro-6H-dibenzo [b, d] pyran
A subtitle compound was prepared by the method of Example 16 (a) from the product of step (b). The product was purified by chromatography on silica gel eluting with CH ₂ Cl ₂ to give the subtitle compound (42%) as a pale yellow solid. R _f 0.26 (hexane / CH ₂ Cl ₂ 1/2, v / v). MS m / z 283 (MH ⁺ ).
(d) 2-amino-1-cyano-6H-dibenzo [b, d] pyran
A subtitle compound was prepared by the method of Example 49 (c) from the product of step (c). The product was purified on silica gel eluting with CH ₂ Cl ₂ / MeOH (98/2, v / v) to give the subtitle compound (85%) as a yellow solid. R _f 0.81 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 93/7/1, v / v). MS m / z 253 (MH ⁺ ).
(e) 1-cyano-2- {1- [4- (morpholin-4-carbonyl) -1,4-diazepan-1-yl] ethylideneamino} -6H-dibenzo [b, d ] Piran
The subtitle compound was prepared by the method of Example 1 (c) from the product of step (d) and intermediate 4. The product was purified on silica gel eluting with CH ₂ Cl ₂ / MeOH (97/3, v / v) to give the subtitle compound (97%) as a yellow foam. R _f 0.56 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 93/7/1, v / v). MS m / z 490 (MH ⁺ ).
(f) 4-amino-11-methoxy-2- [4- (4-morpholinecarbonyl) -1,4-diazepan-1-yl] -9H- [2] benzopyrano- [3, 4-c] quinoline
The title compound was prepared by the method of Example 1 (d) from the product of step (e). The product was chromatographed on silica gel, eluting with CH ₂ Cl ₂ / MeOH (9/1, v / v), and then purified by dissolving in CH ₂ Cl ₂ , precipitated with toluene to give the subtitle compound as a yellow solid ( 40%) was obtained. R _f 0.35 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 93/7/1, v / v). MS m / z 490 (MH ⁺ ). ¹ H NMR (CDCl ₃ ) δ: 2.10 (2H, m), 3.16 (4H, m), 3.40 (2H, m), 3.65 (6H, m), 3.77 (2H, m), 3.98 (2H, m) , 4.01 (3H, s), 4.35 (2H, s), 4.90 (1H, d), 5.30 (1H, d), 5.94 (1H, s), 7.05 (1H, s), 7.21 to 7.52 (4H, m ). Found: C, 65.86; H, 6.33; N, 13.30; C ₂₇ H ₃₁ N ₅ O ₄ 0.2. Toluene 0.5H ₂ O is C, 65.98; H, 6.55; N, 13.55% is required.
Example 51
4-amino-7-methoxy-2- [4- (4-morpholincarbonyl) -1,4-diazepan-1-yl] -5-phenyl-6- (2,2,2-trifluoro Loethoxy) quinoline
(a) 4-methoxy-3- (2,2,2-trifluoroethoxy) benzoic acid methyl ester
Trifluoroethyl triflate in CH ₂ Cl ₂ [Burdon et al.] In a mixture of isovanic acid methyl ester (33.0 g, 0.18 mole) and potassium carbonate (41.4 g, 0.30 mole) in DMF (100 mL). "Tetrahedron 21, 1 (1965)"] (65.0 g, 0.28 mole) was added. The mixture was stirred at rt for 18 h, then the mixture was partitioned between ether and H ₂ O, the organic layer washed with H ₂ O and saturated brine, dried over MgSO ₄ and evaporated. The resulting solid was titrated with hexane to give the subtitle compound (42.55 g, 90%) as an off-white solid. R _f 0.47 (CH ₂ Cl ₂ ). MS m / z 265 (MH ⁺ ).
(b) 4-methoxy-3- (2,2,2-trifluoroethoxy) benzoic acid
The product of step (a) (42.3 g, 0.16 mole) was dissolved in MeOH (500 mL), 2N aqueous NaOH (160 mL, 0.32 mole) was added and the mixture was stirred at room temperature for 3 hours and then for 1 hour. Stir at 50 ° C. After cooling, the solution was concentrated in vacuo, treated with 2N HCl and extracted three times with EtOAc. The combined organic extracts were dried over MgSO ₄ , filtered and evaporated to give the subtitle compound (40.4 g, quant.) As a colorless solid. R _f 0.13 (hexane / EtOAc 1/1, v / v). MS m / z 251 (MH ⁺ ).
(c) 2- [4'-methoxy-3 '-(2,2,2-trifluoroethoxyphenyl)]-4,4-dimethyl-Δ ² -oxazoline
A subtitle compound was prepared by the method of Example 3 (a) from the product of step (b). The product was purified on silica gel eluting with CH ₂ Cl ₂ / MeOH (95/5) to afford the subtitle compound (80%) as a colorless solid. R _f 0.54 (EtOAc). MS m / z 304 (MH ⁺ ).
(d) 2- [2'-iodo-4'-methoxy-3 '-(2,2,2-trifluoroethoxyphenyl)]-4,4-dimethyl-Δ ² -oxazoline
A subtitle compound was prepared by the method of Example 3 (b) from the product of step (c). The product was eluted with EtOAc / hexane (3/2, v / v) and then purified on silica gel with titration with ether / hexane (1/3, v / v) to give the subtitle compound (26%) as a colorless solid. It was. R _f 0.27 (EtOAc / hexanes 1/1, v / v). MS m / z 430 (MH ⁺ ).
(e) 2-iodo-4-methoxy-3- (2,2,2-trifluoroethoxy) benzonitrile
A subtitle compound was prepared by the method of Example 3 (c) from the product of step (d). The product was purified by ether / hexane (1/3, v / v) to give the subtitle compound (97%) as a colorless solid. R _f 0.50 (EtOAc / hexanes 1/1, v / v). MS m / z 358 (MH ⁺ ).
(f) 2-iodo-4-methoxy-6-nitro-3- (2,2,2-trifluoroethoxy) benzonitrile
A subtitle compound was prepared by the method of Example 3 (d) from the product of step (e). The product was purified with ether to give the subtitle compound (61%) as a colorless solid. R _f 0.25 (EtOAc / hexane 1/2, v / v). MS m / z 403 (MH ⁺ ).
(g) 2-amino-6-iodo-4-methoxy-5- (2,2,2-trifluoroethoxy) benzonitrile
A subtitle compound was prepared by the method of Example 49 (c) from the product of step (f). The subtitle compound (70%) gave a colorless solid. R _f 0.74 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 93/7/1, v / v). MS m / z 373 (MH ⁺ ).
(h) 2-iodo-4-methoxy-6- {1- [4- (morpholin-4-carbonyl) -1,4-diazepan-1-yl] ethylideneamino} -3- ( 2,2,2-trifluoroethoxy) benzonitrile
A subtitle compound was prepared by the method of Example 1 (c) from the product of step (g). The product was chromatographed on silica gel with CH ₂ Cl ₂ / MeOH (9/1, v / v) and then crystallized from EtOAc to give the subtitle compound (64%) as a colorless solid. R _f 0.12 (EtOAc). MS m / z 610 (MH ⁺ ).
(i) 4-amino-5-iodo-7-methoxy-2- [4- (4-morpholincarbonyl) -1,4-diazepan-1-yl] -6- (2,2, 2-trifluoroethoxy) quinoline
A subtitle compound was prepared by the method of Example 1 (d) from the product of step (h). The product was purified by chromatography on silica gel with CH ₂ Cl ₂ / MeOH (9/1, v / v) to afford the subtitle compound (20%) as a colorless solid. R _f 0.15 (CH ₂ Cl ₂ / MeOH 9/1, v / v). ¹ H NMR (CDCl ₃ ) δ: 2.06 (2H, m), 3.16 (4H, m), 3.32 (2H, m), 3.58 (2H, m), 3.65 (4H, m), 3.70 (2H, m) , 3.90 (2H, m), 3.97 (3H, s), 4.37 (2H, t), 5.55 (2H, bs), 5.90 (1H, s), 7.05 (1H, bs).
(j) 4-amino-7-methoxy-2- [4- (4-morpholinecarbonyl) -1,4-diazepan-1-yl] -5-phenyl-6- (2,2,2 -Trifluoroethoxy) quinoline
A subtitle compound was prepared by the method of Example 1 (a) from the product of step (i) and phenylboronic acid. The product was purified by chromatography on silica gel with CH ₂ Cl ₂ / MeOH (9/1, v / v) to give the subtitle compound (55%) as a foam. R _f 0.12 (CH ₂ Cl ₂ / MeOH 9/1, v / v). MS m / z 560 (MH ⁺ ). ¹ H NMR (CDCl ₃ ) δ: 2.06 (2H, m), 3.16 (4H, m), 3.35 (2H, m), 3.55 to 3.80 (8H, m), 3.82 to 4.13 (9H, m), 5.70 ( 1H, s), 7.65 (1H, bs), 7.37 (2H, m), 7.45 (3H, m).
Example 52
2-amino-6,7-dimethoxy-5-phenyl-2- (5,6,7,8-tetrahydro-1,3,7-triazanaft-7-yl) quinazoline
(a) 1-trityl-3-piperidone
Trityl chloride (13.1 g, 47.0 mmol) was added to a stirred suspension of 3-piperidone hydrochloride (5.79 g, 42.7 mmol) and triethylamine (14.9 mL, 107 mmol) in CH ₂ Cl ₂ (100 mL), and The reaction was stirred at rt under N ₂ for 16 h. The resulting mixture was filtered and the filtrate was washed successively with H ₂ O and 5% aqueous citric acid, dried over MgSO ₄ and evaporated under reduced pressure. Grinding with pentane gave the subtitle compound (4.8 g, 33%) as a colorless solid. R _f 0.23 (CH ₂ Cl ₂ / pentane 2/3, v / v). ¹ H NMR (CDCl ₃ ) δ: 2.05 (2H, m), 2.35 (2H, m), 2.45 (2H, m), 2.85 (2H, s), 7.06 to 7.55 (15H, m).
(b) 4- (N, N-dimethylmethylidene) -1-trityl-3-piperidone
A subtitle compound was prepared by the method of Example 45 (a) from the product of step (a). Crystallization from ether gave the subtitle compound (52%) as a colorless solid. R _f 0.23 (CH ₂ Cl ₂ / pentane 2/3, v / v). ¹ H NMR (CDCl ₃ ) δ: 2.35 (2H, t), 2.87 (2H, t), 2.97 (2H, s), 3.13 (6H, s), 7.13 (3H, m), 7.24 (7H, m) , 7.50 (6H, m).
(c) 7-trityl- (5,6,7,8-tetrahydro-1,3,7-triazanaphthalene
A subtitle compound was prepared by the method of Example 45 (b) from the product of step (b). The product was purified by chromatography on silica gel eluting with CH ₂ Cl ₂ / ether (9/1) to afford the subtitle compound (51%). R _f 0.33 (CH ₂ Cl ₂ / ether 85/15, v / v). ¹ H NMR (CDCl ₃ ) δ: 2.60 (2H, t), 2.97 (2H, t), 3.58 (2H, s), 7.06 to 7.37 (8H, m), 7.52 (7H, m), 8.45 (1H, s), 8.90 (1 H, s).
(d) 5,6,7,8-tetrahydro-1,3,7-triazanaphthalene hydrochloride
A subtitle compound was prepared by the method of Example 45 (c) from the product of step (c). The product was crystallized from MeOH / ether to give the subtitle compound (65%) as an orange hygroscopic solid. ¹ H NMR (d ₆ -DMSO) δ: 3.06 (2H, m), 3.40 (2H, m), 4.26 (2H, s), 8.68 (1H, s), 9.00 (1H, s), 9.96 (2H, bs).
(e) 2-amino-6,7-dimethoxy-5-phenyl-2- (5,6,7,8-tetrahydro-1,3,7-triazanaft-7-yl) -quinazolin
The title compound was prepared by the method of Example 16 (h) from the product of step (d) and the compound of Example 16 (g). The product was purified by chromatography on silica gel with CH ₂ Cl ₂ / MeOH (95/5, v / v) to give the title compound (36%) as a foam. R _f 0.16 (CH ₂ Cl ₂ / MeOH 95/5, v / v). MS m / z 415 (MH ⁺ ). ¹ H NMR (CDCl ₃ ) δ: 2.90 (2H, m), 3.50 (3H, s), 4.00 (3H, s), 4.16 (2H, m), 4.65 (2H, bs), 5.05 (2H, s) , 7.00 (1H, s), 7.38 (2H, m), 7.50 (3H, m), 8.50 (1H, s), 9.02 (1H, s). Found C, 63.56; H, 5.20; N, 18.97; C ₂₃ H ₂₂ N ₆ O ₂ 0.3CH ₂ Cl ₂ is C, 63.49; H, 5.17; N, 19.06% is required.
Example 53
4-amino-6,7-dimethoxy-2- (4-methoxy-5,6,7,8-tetrahydro-1,3,7-triazanaft-7-yl) -5-phenylquinazoline
(a) 7-benzyl-4-chloro-5,6,7,8-tetrahydro-1,3,7-triazanaphthalene
7-benzyl-4-hydroxy-5,6,7,8-tetrahydro-1,3,7-triazanaphthalene (Ozeowska et al., Rocz. Chem. Ann. Soc. Chim. Pol. 50, 1771 (1976) "] (95.0 g, 15.9 mmol) was added to POCl ₃ and the mixture was heated to 100 ° C for 1 hour. The reaction was cooled, concentrated under reduced pressure, and the residue was quenched with ice. After neutralization with K ₂ CO ₃ , the product was extracted with CH ₂ Cl ₂ , the organic layer was washed with H ₂ O, dried over MgSO ₄ and evaporated to give the subtitle compound (3.33 g, 81%) as a brown oil. . R _f 0.45 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 92/7/1, v / v).
(b) 7-benzyl-4-methoxy-5,6,7,8-tetrahydro-1,3,7-triazanaphthalene
Sodium (380 mg, 16.5 mmol) was added in portions to MeOH (7 mL) and the solution was added dropwise to the product of step (a) (3.3 g, 12.7 mmol) in THF (30 mL). After stirring for 18 hours at room temperature, the reaction mixture was concentrated under reduced pressure, partitioned between H ₂ O and CH ₂ Cl ₂ , the aqueous layer was extracted with CH ₂ Cl ₂ and the combined organic layers were dried over MgSO ₄ . Evaporation under reduced pressure yielded the subtitle compound (3.1 g, 95%) as a brown oil. R _f 0.64 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 92/7/1, v / v).
(c) 4-methoxy-5,6,7,8-tetrahydro-1,3,7-triazanaphthalene
To the solution (3.1 g, 12.0 mmol) of the product of step (b) in EtOH (40 mL) is added palladium hydroxide (20%, w / w, 614 mg) and the mixture is hydrogenated at a pressure of 345 kPa [50 psi] for 18 hours. After addition, additional EtOH (40 mL) and palladium hydroxide (614 mg) were added and hydrogenation continued for an additional 18 hours. Filtration, evaporation under reduced pressure and chromatography on silica gel eluting with CH ₂ Cl ₂ / MeOH (90/10, v / v) gave the subtitle compound (1.09 g, 55%) as a pale orange oil. . R _f 0.06 (CH ₂ Cl ₂ / MeOH 95/5, v / v). MS m / z 166 (MH ⁺ ).
(d) 4-amino-6,7-dimethoxy-2- (4-methoxy-5,6,7,8-tetrahydro-1,3,7-triazanaft-7-yl) -5- Phenylquinazoline
The title compound was prepared by the method of Example 16 (h) from the product of step (c) and the compound of Example 16 (g) in the presence of 1 molar equivalent of ammonium chloride. The product was chromatographed on silica gel eluting with EtOAc to afford the title compound (10%) as a foam. R _f 0.42 (EtOAc / MeOH 95/5, v / v). MS m / z 445 (MH ⁺ ). ¹ H NMR (CDCl ₃ ) δ: 2.74 (2H, t), 3.48 (3H, s), 3.98 (3H, s), 4.00 (3H, s), 4.10 (2H, t), 4.61 (2H, bs) , 4.95 (2H, s), 6.97 (1H, s), 7.38 (2H, m), 7.50 (3H, m), 8.57 (1H, s). Found: C, 63.88; H, 5.59; N, 17.82; C ₂₄ H ₂₄ N ₆ O ₃ 0.2EtOAc 0.3H ₂ O is C, 63.71; H, 5.65; N, 17.98% is required.
Example 54
4-amino-6,7-dimethoxy-2- [6- (2-methyl-4,5,6,7-tetrahydrothiazolo- [5,4-c] pyridyl)]-5-phenylquina Sleepy
(a) 2-methyl-4,5,6,7-tetrahydrothiazolo- [5,4-c] pyridine-hydrochloride
3-bromo-4-piperidone hydrobromide (Scarponi et al., "Farmaco, Ed. Sci. 43, 575 (1998)") in EtOH (100 mL) (2.58 g, 0.01 mole) and thioacet A mixture of amide (940 mg, 0.013 mole) was heated under reflux for 3 hours. The reaction mixture was cooled, evaporated under reduced pressure and the resulting residue was triturated with acetone to give a solid. It is dissolved in H ₂ O, washed three times with EtOAc, the aqueous phase is basified with saturated aqueous Na ₂ CO ₃ , extracted five times with EtOAc, the combined organic extracts are washed with saturated brine and dried over MgSO ₄ . I was. The product was purified by chromatography on silica gel eluting with CH ₂ Cl ₂ /MeOH/0.88NH ₃ (90/10/1, v / v), then filtered and dried in vacuo using ethereal HCl. Conversion to the chloride salt gave the subtitle compound (380 mg, 20%) as a white solid. R _f 0.67 (CH ₂ Cl ₂ /MeOH/0.88NH ₃ 90/10/1, v / v). MS m / z 155 (MH ⁺ ).
(b) 4-amino-6,7-dimethoxy-2- [6- (2-methyl-4,5,6,7-tetrahydrothiazolo- [5,4-c] pyridyl)]-5 -Phenylquinazoline
The title compound was prepared by the method of Example 16 (h) from the product of step (a) and the compound of Example 16 (g). The product was purified by chromatography on silica gel eluting with EtOAc, then titrated with ether to give the title compound (11%) as a solid. R _f 0.24 (EtOAc). MS m / z 434 (MH ⁺ ). ¹ H NMR (CDCl ₃ ) δ: 2.66 (3H, s), 2.90 (2H, t), 3.50 (3H, s), 3.97 (3H, s), 4.16 (2H, t), 4.61 (2H, bs) , 4.97 (2H, s), 6.95 (1H, s), 7.38 (2H, m), 7.48 (3H, m).
Example 55
The compound of Example 17 was tested on the first screen described above (“the contractile response of the human prostate”) to find that the pA ₂ value was 8.5.

权利要求:
Claims (15)
[1" claim-type="Currently amended] Compound of Formula (I) or a pharmaceutically acceptable salt thereof:
Formula I

Where
R ¹ is C _1-4 alkoxy optionally substituted with one or more fluorine atoms;
R ² is H; Or C _1-6 alkoxy optionally substituted with one or more fluorine atoms;
R ³ is one or more groups independently selected from H, halogen, C _1-4 alkoxy and CF ₃ ;
In addition, the R ² and one R ³ groups may together be —OCH ₂ —, wherein the methylene group is attached to the ortho-position of the pendant phenyl ring;
R ⁴ is a 4-, 5- and 6-membered heterocyclic ring containing one or two heteroatoms selected from N, O and S, wherein the ring is optionally fused to a benzene ring, or N, O and 5- or 6-membered heterocyclic rings containing 1 or 2 heteroatoms selected from S, wherein the ring systems are all OH, C _1-4 alkyl, C _1-4 alkoxy, halogen, SO ₂ NR ⁸ R ⁹ And optionally substituted with one or more groups independently selected from NHSO ₂ (C _1-4 alkyl), wherein when S is a member of a ring system, it may be substituted with one or two oxygen atoms;
R ⁸ and R ⁹ are independently H or C _1-4 alkyl;
X is CH or N;
L is absent or is a vent of formula (Ia) or a chain of formula (Ib):
Formula Ia

[Wherein,
N is attached to the 2-position of the quinoline or quinazoline ring;
A is absent or is CO or SO ₂ ;
Z is CH or N;
m is 1 or 2, and in addition, m may be 0 when Z is CH;
n is 1, 2 or 3, but the sum of m and n is 2, 3, 4 or 5.] Formula Ib

[Wherein,
N is attached to the 2-position of the quinoline or quinazoline ring;
A 'and Z' are the same as A and Z, respectively;
R ⁶ and R ⁷ are independently H or C _1-4 alkyl;
p is 1, 2 or 3, and in addition, p may be 0 when Z 'is CH.] [2" claim-type="Currently amended] The method of claim 1,
R ¹ is methoxy.
[3" claim-type="Currently amended] The method according to claim 1 or 2,
R ² is methoxy.
[4" claim-type="Currently amended] The method according to claim 1 or 2,
Wherein the R ² and R ³ groups together are —OCH ₂ —.
[5" claim-type="Currently amended] The method according to any one of claims 1 to 4,
R ³ is H or 4-fluoro.
[6" claim-type="Currently amended] The method according to any one of claims 1 to 5,
R ⁴ is a group of formula (II), formula (III), formula (IV), formula (V) or formula (VI):
Formula II

Formula III

Formula IV

Formula V

Formula VI

Where
Y is O, CH ₂ , SO ₂ , NR ⁵ or CHF;
R ⁵ is H or C _1-4 alkyl.
[7" claim-type="Currently amended] The method of claim 6,
R ⁴ is a group of formula (II).
[8" claim-type="Currently amended] The method of claim 7, wherein
Y is O.
[9" claim-type="Currently amended] The method according to any one of claims 1 to 8,
A compound absent or a group of formula (VII).
Formula VII

[10" claim-type="Currently amended] A pharmaceutical formulation comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in claim 1 together with a pharmaceutically acceptable adjuvant, diluent or carrier.
[11" claim-type="Currently amended] The method of claim 1,
A compound of formula (I), or a pharmaceutically acceptable salt thereof, for use as a medicament.
[12" claim-type="Currently amended] Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of benign hyperprostatitis.
[13" claim-type="Currently amended] A method of treating benign hyperprostatitis, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in claim 1 to a patient in need of treatment of benign hyperprostatitis.
[14" claim-type="Currently amended] (a) when X is CH, cyclizes a compound of formula (X);
(b) when A or A 'is present and Z or Z' is N, reacting the appropriate compound of Formula (XIIIa) or Formula (XIIIb) with a compound of Formula (XIV);
(c) reacting a compound of formula (XVIII) with a compound of formula (XIX);
(d) when X is N, reacting a compound of formula (XXII) with a suitable compound of formula (XXIIIa) or formula (XXIIIb);
(e) when A or A 'is CO, reacting the appropriate compound of formula (XXVIIIa) or formula (XXVIIIb) with a compound of formula (XXIX);
(f) by the action of a strong base, a compound of formula (I), wherein L is a ventilator of formula (Ia), wherein L is a chain of formula (Ib), wherein R ⁶ and R ⁷ are each H To the corresponding compound of;
(g) when A or A 'is absent and Z or Z' is N, reacting a compound of Formula (XIIIa) or Formula (XIIIb) with a compound of Formula (XXX); or
(h) when R ² and one R ³ together are —OCH ₂ —, cyclize the compound of formula (XXXI),
Converting the resulting compound of formula (I) into a pharmaceutically acceptable salt or vice versa if desired or necessary,
A process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined in claim 1.
Formula X

[Wherein,
R ^1-4 and L are as defined in claim 1].
Formula XIIIa

Formula XIIIb

[Wherein,
R ^1-3 , R ⁶ , R ⁷ , X, m, n and p are as defined in claim 1].
Formula XIV

[Wherein,
R ⁴ is as defined in claim 1, A 'is CO or SO ₂ and Lg is a leaving group.] Formula XVIII

[Wherein,
R ¹ , R ² , R ⁴ , X, and L are as defined in claim 1.] Formula XIX

[Wherein,
R ³ is as defined in claim 1].
Formula XXII

[Wherein,
R ^1-3 is as defined in claim 1].
Formula XXIIIa

Formula XXIIIb

[Wherein,
R ⁴ , R ⁶ , R ⁷ , A, A ', Z, Z', m, n and p are as defined in claim 1].
Formula XXVIIIa

Formula XXVIIIb

[Wherein,
R ^1-3 , R ⁶ , R ⁷ , X, Z, Z ', m, n and p are as defined in claim 1 and Lg is a leaving group.] Chemical Formula XXIX
HR ^4a
[Wherein,
R ^4a is a group defined as R ⁴ in claim 1 containing a nucleophilic nitrogen atom attached to H in the ring.] Formula XXX
R ⁴ -Hal
[Wherein,
R ⁴ is as defined in claim 1 and Hal is a halogen atom attached to the ring.] Formula XXXI

[Wherein,
R ^1, R ^4, X and L are as defined in claim 1, R ^3a is R ² and R ^3a groups together -OCH ₂ - is the same as the R ³ except that it does not.
[15" claim-type="Currently amended] A compound of formula (X), formula (XIIIa), formula (XIIIb), formula (XVIII), formula (XXII), formula (XXVIIIa), formula (XXVIIIb) and formula (XXXI) as defined in claim 12.

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同族专利:

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公开号 | 公开日

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GB9526546D0|1996-02-28|

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AP9600900A0|1997-01-31|

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SK81698A3|2000-04-10|

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JP3070958B2|2000-07-31|

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OA10703A|2002-11-28|

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CO4480106A1|1997-07-09|

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AU708979B2|1999-08-19|

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DK877734T3|

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US20030220332A1|2003-11-27|

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EP0877734B1|2000-07-12|

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US6103738A|2000-08-15|

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WO1997023462A1|1997-07-03|

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HU9903560A3|2000-07-28|

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BR9612263A|1999-07-13|

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ES2151192T3|2000-12-16|

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GR3034225T3|2000-12-29|

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CA2236814C|2001-09-18|

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AR005166A1|1999-04-14|

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DE69609353T2|2000-12-07|

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BG102559A|1999-03-31|

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CA2236814A1|1997-07-03|

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DE69609353D1|2000-08-17|

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PL327610A1|1998-12-21|

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TNSN96161A1|2005-03-15|

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YU68896A|1999-07-28|

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TR199801195T2|1998-10-21|

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US6642242B2|2003-11-04|

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AP715A|1998-12-30|

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AT194598T|2000-07-15|

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PT877734E|2000-12-29|

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EP0877734A1|1998-11-18|

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HN1996000082A|1997-06-30|

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JPH11501668A|1999-02-09|

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US20020049322A1|2002-04-25|

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MA26414A1|2004-12-20|

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HU9903560A2|2000-05-28|

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NO982913D0|1998-06-22|

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NZ325248A|1999-09-29|

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US6750214B2|2004-06-15|

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ZA9610784B|1998-06-22|

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DK0877734T3|2000-11-20|

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IS4731A|1998-04-29|

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AU1371997A|1997-07-17|

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HRP960616A2|1998-06-30|

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NO982913L|1998-07-30|

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CZ197698A3|1999-03-17|

引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
1995-12-23|Priority to GBGB9526546.8A

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1995-12-23|Priority to GB9526546.8

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1996-12-05|Application filed by 디. 제이. 우드, 무어 제임스 더블유, 화이자 리써치 앤드 디벨로프먼트 캄파니 엔.브이./에스.에이.

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1996-12-05|Priority to PCT/EP1996/005609

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1999-10-15|Publication of KR19990076693A

优先权:

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申请号 | 申请日 | 专利标题

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GBGB9526546.8A|GB9526546D0|1995-12-23|1995-12-23|Compounds useful in therapy|

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GB9526546.8|1995-12-23|

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PCT/EP1996/005609|WO1997023462A1|1995-12-23|1996-12-05|Quinoline and quinazoline compounds useful in therapy|