Field of the Invention
The present invention relates to quinazoline derivatives, which can be used to treat a disease or disorder mediated through α1a and/or α1dadrenergic receptors. Compounds and pharmaceutical compositions disclosed herein can be used to treat benign prostatic hyperplasia (BPH) and related symptoms thereof. Further, such compounds can be used to treat lower urinary tract symptoms that may or may not be associated with BPH. The present invention also relates to processes to prepare the disclosed compounds, pharmaceutical compositions thereof, and methods of treating BPH or related symptoms thereof.
Background of the Invention Benign prostatic hyperplasia (BPH) is a condition that typically develops in elderly males. BPH causes benign overgrowth of the stromal and epithelial elements of the prostate with aging. Symptoms of BPH can vary and commonly involve changes or problems with urination, such as hesitation, interruption, weak stream, urgency, leaking, dribbling or increased frequency, particularly at night. BPH can consequently cause hypertrophy of bladder smooth muscle, a decompensated bladder or an increased incidence of urinary tract infection.
The symptoms of BPH are a result of two pathological components affecting the prostate gland: a static component and a dynamic component. The static component is related to enlargement of the prostate gland, which may result in compression of the urethra and obstruction to the flow of the urine from the bladder. The dynamic component is related to increased smooth muscle tone of the bladder neck and prostate itself and is regulated by a-1 adrenergic receptor.
Currently, the most effective treatment for BPH is a surgical procedure known as transurethral resection of the prostate (TURP), which involves removing obstructing tissue (C. Chappie, Br. Med. Journal, 304:1198-1199 (1992)). TURP is directed both to the static and dynamic components of the BPH. However, TURP is associated with mortality (1 %), adverse events, e.g., incontinence (2-4 %), infection (5-10 %), and impotence (5-10 %). Therefore, noninvasive alternative treatments are highly desirable.
Some drug therapies address the static component of BPH. Administration of finasteride is one such therapy, which is indicated for the treatment of symptomatic BPH. This drug is a competitive inhibitor of the enzyme 5-a reductase that is responsible for the conversion of testosterone to dihydrotestosterone in the prostate gland. Dihydrotestosterone appears to be the major mitogen for prostate growth and agents, which inhibit 5-a reductase, reduce the size of the
prostate and improve urine flow through the prostatic urethra. Although finasteride is a potent 5-a reductase inhibitor that causes a marked decrease in serum and tissue concentrations of dihydrotestosterone, it is moderately effective in the treatment of symptomatic BPH. The effects of finasteride take 6-12 months to become evident and for many men the clinical development is minimal.
The dynamic component of BPH has been addressed by the use of adrenergic receptor blocking agents, which act by decreasing the smooth muscle tone within the prostate gland. A variety of α1a AR antagonists, for example, terazosin, doxazosin, prazosin, alfuzosin and tamulosin, have been investigated for the treatment of symptomatic bladder outlet obstruction due to BPH. However, these drugs are associated with vascular side effects (e.g., postural hypertension, syncope, dizziness, headache etc.) due to lack of selectivity of action between prostatic and vascular α1 adrenoceptors. There are several lines of evidence suggesting that selectivity for α1a adrenoceptor over α1b adrenoceptor will result in relative lack of vascular side effects, thus lead to better olerability. Mice deficient in aib adrenoreceptors show diminished blood pressure response to phenylephrine injection when compared to homozygous controls (decreased blood pressure response in mice deficient of a^ adrenergic receptor. (Proc. Nat'I Acad. Sci. USA, 94:1589-11594 (1997)). In-vivo studies in healthy subjects comparison of ctia/aid selective antagonists (e.g., tamsulosin) or ocia selective antagonists (e.g., urapidil) with non selective antagonists (e.g., doxazosin, prazosin, or terazosin) under a variety of experimental conditions (e.g., involving the administration of exogenous agonist or release of endogenous agonist by cold stimulation) in several vascular beds including the skin circulation in finger tips, the dorsal hand vein, or with total peripheral resistance have been reported. (Eur. J. Clin. Pharmacol, 49:371-375 (1996); N. Schmiedeberg, Arch. Pharmacol, 354:557-561 (1996); Jpn. J. Pharmacol, 80:209-215 (1999); Br. J. Clin. Pharmacol, 47:67-7'4 (1999)). These studies reported that an antagonist with high affinity for α1a orα1a/α1d receptors can cause some degree of vasodilation, although it is much lower than with non-subtype-selective α1a adrenoceptor antagonists. Further, there is increased vascular α1b adrenoceptor expression in elderly patients and thus α1a/aid-selective agents with selectivity over α1b adrenoceptor subtype would be of particular importance in benign prostatic hyperplasia. Antagonism of both α1a adrenoceptor and α1d adrenoceptor is important to relieve lower urinary tract symptoms especially associated with BPH. Targeting α1a adrenoceptors with antagonists is important in relaxing prostate smooth muscle and relieving bladder outlet obstruction, whereas α1d adrenoceptor antagonism is important to target irritative symptoms.
The synthesis of l-(4-arylpiperazin-l-yl)-co-[N- (a, co-dicarboximido)]-alkanes useful as uro-selective α1-adrenoceptor blockers are disclosed in US Patent Nos. 6,083,950, 6,090,809, 6,410,735, 6,420,559 and 6,420,366, WO 00/05206, US Patent Appl. No. 2002/0156085 and WO 02/44151. These compounds exhibited ai-adrenergic blocking activity and selectivity. Each of these patents is incorporated by reference herein in their entirety.
WO 97/20821 discloses quinazoline derivatives used for the treatment of disorders and diseases associated with NPY receptor subtype Y5; WO 02/102315 discloses quinazoline and pyrido[2,3-d] pyrimidine as inhibitors of phosphodiesterase 7; EP 0887344 discloses quinolines and quinazolines; quinazoline derivatives as alpha-1 adrenergic antagonists and quinazolinyl amino derivatives having alpha-antagonist activity are disclosed in WO 02/02/18348 and WO 95/25726, respectively; US 6,313,293 discloses the process for the preparation of quinazoline derivatives; hydrazones and hydrazone analogs as cholesterol lowering agents are provided in WO 01/64646; WO 98/ 38984 discloses formulation for hydrophobic pharmaceutical agents; derivatives of quinazoline useful for the treatment of patients having precancerous lesions are disclosed in US 6,262,059; novel 4-amino or 4-hydrazino-2-(substituted piperazinyl)-6,7-dimethoxyquinazolines having antihypertensive and phosphodiesterase inhibiting properties are disclosed in US 4,060,615; WO 89/052797 discloses quinazoline derivatives useful in therapy as inhibitors of gastric acid secretion; US 6,313,294 discloses a process for preparing an amide.
Summary of the Invention
Generally provided herein are quinazoline derivatives, which can be used to treat a disease or disorder mediated through ocia and/or a^ adrenergic receptors. Processes for the synthesis of these compounds, pharmaceutical compositions thereof, are also provided. Encompassed pharmaceutical compositions may also contain one or more pharmaceutically acceptable carriers or diluents. Pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, conjugates or prodrugs of such compounds having the same type of activity are also provided, which can be useful to treat a disease or disorder mediated through α1a and/or α1adadrenergic receptors. Pharmaceutical compositions comprising the compounds disclosed herein, their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, conjugates or prodrugs in combination with one or more pharmaceutically acceptable carriers and optionally included excipients, are also included, which can be useful to treat a disease or disorder mediated through α1a and/or α1d adrenergic receptors.
Other aspect and properties of this matter will be set forth in description which follows, and will be apparent from the description or may be learnt by the practice thereof.
In one aspect, provided herein are compounds having the structure of Formula I,
(Formula Removed)

Formula I
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, prodrugs, stereoisomers, tautomeric forms, N-oxides and metabolites thereof, wherein:
Ri can be halogen, hydroxy, alkyl, alkoxy, cyano, nitro, amino, alkylamino or thio, each Ri can be same or different; n is an integer of from 1 to 4; R' and R" independently can be hydrogen, alkyl, cycloalkyl, aryl, alkenyl or C(=V)Rt [wherein R4 can be hydrogen, OH, OR5, NR2R3, V can be O, S or NH];
(Formula Removed)

wherein,
A1-A4 and Ag independently in each occurrence can be -CH-, -CH2-, -CR4R5-, N, NR5, O or
S(0)o-2, A5-A7 independently in each occurrence can be CR4 or N, T can be no atom,
-N-Bi, O or S, Y can be no atom, carbonyl, -(CH2)m-, aryl, heterocyclyl or cycloalkyl, R2 and R3
independently in each occurrence can be hydrogen, C(=V)R4, alkyl, (CH2)m, SO2R5, aryl,
heterocyclyl, cycloalkyl or R2 and R3 together with the nitrogen to which they are attached can
form a 4-7 membered heterocyclyl which can be optionally substituted with R, Mi and M2
independently in each occurrence can be R2, halogen, C(=V)NHR6, CH20CH2C(=V)R4)
OCH2C(=V)R4, CH2C(=V)R4, NHC(=V)NHR5, hydroxyl, amino, nitro, cyano, alkoxy, acyl or M1 and M2 together can form a bridging group (C0-3), {[wherein (R4 is the same as defined above), (R5 can be hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, NHC(=V)R6, NR6SO2R6, NHC(=V)CH2OR6, NHC(=V)O(CH2)0-1R6, C(=V)R6 or NHC(=V)(CH2)o.iCH(Ar)2), (V is the same as defined above), (m is an integer of from 0-4), (Bi can be hydrogen, alkyl or aryl), (each -CH2 in -(CH2)m- group may optionally be substituted with one or more halogen, hydroxy, amino, alkylamino, alkyl or aryl), (R6 can be hydrogen, alkyl, heterocyclyl or aryl)]}.
In another aspect, provided herein are methods for the treatment of a patient suffering from a disease or disorder mediated through alpha la and/or alpha Id adrenergic receptor, comprising administering to a patient, a therapeutically effective amount of one or more compounds (or compositions) disclosed herein.
In another aspect, provided herein are methods for the treatment of a patient suffering from benign prostatic hyperplasia (BPH) and related symptoms, lower urinary tract symptoms (LUTS) with or without BPH comprising administering to a patient, therapeutically effective amount of one or more compounds (or compositions) disclosed herein. LUTS may include, for example, irritative symptoms such as frequent urination, urgent urination, nocturia and unstable bladder contractions, obstructive symptoms such as hesitancy, poor stream, prolong urination, and feelings of incomplete emptying.
In another aspect, provided herein are processes for the preparation of the compounds described herein.
In yet another aspect, provided herein are methods for the treatment of a patient suffering from BPH or LUTS with or without BPH, comprising administering to a patient, therapeutically effective amount of one or more compounds (or compositions) disclosed herein in combination with one or more agents selected from bladder selective muscarinic receptor antagonist, testosterone 5 alpha-reductase inhibitor, endothelin antagonists, melanocortin receptor agonist, cGMP elevators, HMG-CoA reductase inhibitors (e.g. statins, 5-HT antagonists) or combination thereof.
The compounds of this invention are potent adrenergic receptor antagonists. Compounds disclosed herein exhibit affinity towards α1a and α1Dadrenergic receptor subtypes and selectivity for α1av/s α1b. Alpha la adrenergic receptors are involved in relieving the obstructive symptoms whereas α1b adrenoreceptor antagonism is associated with alleviation of irritative symptoms.
The relatively low affinity at the α1b adrenergic receptor limits the cardiovascular side effects, for example, orthostatic hypotension. The present invention therefore provides pharmaceutical compositions for treatment of a disease or disorder mediated through α1a and/ or α1dadrenoceptors. Compounds and compositions described herein can be administered orally, parenterally, subcutaneously, transdermally or topically.
The term "alkyl," unless otherwise specified, refers to a monoradical branched or unbranched saturated hydrocarbon chain having from 1 to 20 carbon atoms. This term can be exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-decyl, tetradecyl, and the like. Alkyl groups may be substituted further with one or more substituents selected from alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, carboxyalkyl, aryl, heterocyclyl, heteroaryl, arylthio, thiol, alkylthio, aryloxy, nitro, aminosulfonyl, aminocarbonylamino, -NHC(=0)Rf, -NRfRq, -C(=0)NRfRq, -NHC(=0)NRfRq>, -C(=0)heteroaryl, C(=0)heterocyclyl, -O-C(=0)NRfRq {wherein Rf and Rq are independently selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl}, nitro, or -SO2R6 (wherein R<$ is alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, aryl, heterocyclyl, heteroaryl, heteroarylalkyl or heterocyclylalkyl). Unless otherwise constrained by the definition, alkyl substituents may be further substituted by 1-3 substituents selected from alkyl, carboxy, -NRfRq, -C(=0)NRfRq, -OC(=0) NRfRq , -NHC(=0)NRfRq (wherein Rf and Rq are the same as defined earlier), hydroxy, alkoxy, halogen, CF3, cyano, and -SO2R=, (wherein R6are the same as defined earlier); or an alkyl group also may be interrupted by 1-5 atoms of groups independently selected from oxygen, sulfur or -NRa- {wherein Ra is selected from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, acyl, aralkyl,-C(=0)ORf (wherein Rf is the same as defined earlier), SO2R6 (where R6 is as defined earlier), or -C(=0)NRfRq (wherein Rf and Rq are as defined earlier)}. Unless otherwise constrained by the definition, all substituents may be substituted further by 1-3 substituents selected from alkyl, carboxy, -NRfRq, -C (=0)NRfRq, -O-C(=0)NRfRq (wherein Rf and Rq are the same as defined earlier) hydroxy, alkoxy, halogen, CF3, cyano, and -SO2R= (where R6 is same as defined earlier); or an alkyl group as defined above that has both substituents as defined above and is also interrupted by 1-5 atoms or groups as defined above.
The term "alkenyl or alkynyl" stands for unsaturated hydrocarbon having two to six carbon atoms. One or more hydrogen of said alkenyl or alkynyl can be replaced by halogen. Examples of alkenyl and alkynyl include, but are not limited to, ethylene, propylene, ethynyl, propynyl, and the like.
The term "cycloalkyl," unless otherwise specified, refers to cyclic alkyl groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings, which may optionally contain one or more olefinic bonds, unless otherwise constrained by the definition. Such cycloalkyl groups can include, for example, single ring structures, including cyclopropyl, cyclobutyl, cyclooctyl, cyclopentenyl, and the like, or multiple ring structures, including adamantanyl, and bicyclo [2.2.1] heptane, or cyclic alkyl groups to which is fused an aryl group, for example, indane, and the like. Spiro and fused ring structures can also be included. Cycloalkyl groups may be substituted further with one or more substituents selected from alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, carboxyalkyl, arylthio, thiol, alkylthio, aryl, aralkyl, aryloxy, aminosulfonyl, aminocarbonylamino, -NRfRq, -NHC (=0) NRfRq, -NHC (=0) Rf, -C (=0) NRfRq, -0-C (=0)NRfRq (wherein Rf and Rq are the same as defined earlier), nitro, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl, or SO2-R6 (wherein R6is same as defined earlier). Unless otherwise constrained by the definition, cycloalkyl substituents optionally may be substituted further by 1-3 substituents selected from alkyl, carboxy, hydroxy, alkoxy, halogen, CF3, -NRfRq, -C(=0)NRfRq, -NHC(=0)NRfRq , -OC(=0)NRfRq (wherein Rf and Rq are the same as defined earlier), cyano or -SO2R6 (where R^ is same as defined earlier). "Cycloalkylalkyl" refers to alkyl-cycloalkyl group linked through alkyl portion, wherein the alkyl and cycloalkyl are the same as defined earlier.
The term "halogen" refers to fluorine, chlorine, bromine or iodine.
The term "aryl or Ar" unless otherwise specified, refers to carbocyclic aromatic groups, for example, phenyl, biphenyl or napthyl ring and the like, optionally substituted with 1 to 3 substituents selected from halogen (e.g., F, CI, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, acyl, aryloxy, CF3, cyano, nitro, COORe (wherein Re is hydrogen, alkyl, alkenyl, cycloalkyl, aralkyl, heterocyclylalkyl, heteroarylalkyl), NHC(=0)Rf, -NRfRq, -C(=0)NRfRq, -NHC(=0)NRfRq , -0-C(=0)NRfRq (wherein Rf and Rq are the same as defined earlier), -SO2R6 (wherein R6 is same as defined earlier), carboxy, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl or amino carbonyl amino. The aryl group optionally may be fused with a cycloalkyl group, wherein the cycloalkyl group may optionally contain heteroatoms selected from O, N or S.
The term "heterocyclyl" refers to non-aromatic or aromatic ring system having one or more heteroatom (s) wherein the said hetero atom (s) is/ are selected from the group comprising of nitrogen, sulphur and oxygen and the ring system includes mono, bi or tricyclic and/or optionally substituted with 1 to 4 substituent(s) selected from halogen (e.g., F, CI, Br, I),
hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, acyl, carboxy, aryl, alkoxy, aralkyl, cyano, nitro, heterocyclyl, heteroaryl, -NRfRq, CH=NOH, -(CH2)wC(=0)Rg {wherein w is an integer from 0-4 and Rg is hydrogen, hydroxy, ORf, NRfRq, -NHORz or -NHOH}, -C(=0)NRfRq and -NHC(=0)NRfRq , -S02R6, -0-C(=0)NRfRq, -0-C(=0)Rf, -0-C(=0)ORf (wherein Re, Rf and Rq are as defined earlier, and Rz is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl) or guanidine. Unless otherwise constrained by the definition, the substituents are attached to a ring atom, i.e., carbon or heteroatom in the ring. Also, unless otherwise constrained by the definition, the heterocyclyl ring optionally may contain one or more olefinic bond(s). Examples of heteroaryl groups include oxazolyl, imidazolyl, pyrrolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, thiazolyl, oxadiazolyl, benzoimidazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, triazinyl, furanyl, benzofuranyl, indolyl, benzothiazolyl, benzoxazolyl, oxazolidinyl, tetrahydrofuranyl, dihydrofuranyl, dihydropyridinyl, dihydroisoxazolyl, dihydrobenzofuryl, azabicyclohexyl, dihydroindolyl, pyridinyl, isoindole 1,3-dione, piperidinyl or piperazinyl and the like.
The said heterocyclyl may be fused with an aryl or heterocyclyl ring. Examples include, but not limited to, 1, 2, 3, 4-tetrahydro-quinoline, 1, 2, 3, 4-tetrahydro-isoquinoline, and the like.
The groups "aryl and heterocyclyl" can optionally be substituted with 'substituent(s)' selected from alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl, heteroarylalkyl, heterocycloalkyl, halogen, hydroxy, alkoxy, cyano, nitro, aryloxy, haloalkoxy, CORb, CSRb, COORb, S(0)aRb, OCOORb, NHS02Rb, NHCORb, NHCSRb, (CH)0.2C(=O)NRcRd or NRcRj (wherein Rb, Re and Ra are independently selected from hydrogen, alkyl, aryl, heterocyclyl and a is an integer of from 0-2. Unless otherwise constrained, all substituents may optionally be further substituted by 'substituent(s)' defined earlier.
The term "alkoxy" herein refers to ORa wherein Ra can be alkyl, alkenyl or alkynyl.
The term "protecting group" herein refers to a removable group that is attached to a reactive group in order to block or reduce the reactivity of the said group when the reactions are carried out over the other functional groups. Examples are elaborately cited in "Protective Groups in Organic Synthesis" by T. Greene and Wuts, John Wiley and Sons, New York, 1981.
The term "polymorphs" includes all crystalline form as well as amorphous form for compounds described herein and as such are intended to be included in the present invention.
The term "pharmaceutically acceptable carriers" is intended to include non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
The term "pharmaceutically acceptable salts" refer to a salt prepared from pharmaceutically acceptable organic or inorganic acids, such salts includes hydrochlorides,
sulfates, phosphates, tartarates, fumarates, citrates and the like. The free base forms of compounds of the present invention may be prepared from the salt forms, if desired, by contacting the salt with dilute aqueous solution of a base. The acid addition salts may differ from the free base forms of the compounds of this invention in such physical characteristics as solubility and melting point.
The salt forms differ from the compound described herein in certain physical properties such as solubility, but the salts are otherwise equivalent for purposes of this invention.
The term "pharmaceutically acceptable" means approved by regulatory agency of the federal or a state government or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly in humans.
The term "pharmaceutically acceptable solvates" refers to solvates with water (i.e hydrates, hemihydrate or sesquihydrate) or pharmaceutically acceptable solvents, for example solvates with common organic solvents as ethanol and the like. Such solvates are also encompassed within the scope of the disclosure.
The present invention also includes, within its scope," prodrugs" of these agents. In general, such prodrugs will be functional derivatives of these compounds, which are readily convertible in vivo into the required compound. They may be carrier-linked or bioprecursors. The carrier-linked prodrugs may be bipartite, tripartite or mutual prodrugs. Prodrugs are intended to improve drug efficacy by improving solubility and consequently absorption and distribution as desired. Conventional procedure for the selection and preparation of suitable prodrug derivatives are described, for example, in "design of prodrugs", ed. H Bundgaard and, Elsevier, 1985. Enantiomers and Diastereomers, are as defined by the IUPAC 1974 Recommendations for Section E.
Detailed Description of the Invention
The compounds described herein may be prepared by techniques well known in the art and familiar to the average synthetic organic chemist. In addition, the compounds described herein may be prepared by the following reaction sequences as depicted in schemes I, II, III, IV, V, VI and VII.
(Scheme Removed)

Compounds of Formula 8 can be prepared according to Scheme I. Thus, compounds of Formula 2 can be reacted with a protecting agent, P, (e.g. f-butoxycarbonyl, benzyloxycarbonyl, 9-Fluorenylmethoxycarbonyl, and the like) to form compounds of Formula 3 (wherein Mi and M2 are as defined earlier). Compounds of Formula 3 can be debenzylated to form compounds of Formula 4. Compounds of Formula 4 can be treated with compounds of Formula 5 (wherein hal is halogen) to form compounds of Formula 6. Compounds of Formula 6 can be deprotected to form compounds of Formula 7. Compounds of Formula 7 can be treated with compounds of Formula Q-XL (wherein XL is halogen or hydroxy, Q is R4CO or R4SO2 and R4 is as defined earlier) to form compounds of Formula 8. Compounds of Formula 8 can be converted into their pharmaceutically acceptable salts using the methods known to one of ordinary skill in the art.
Compounds of Formula 2 can be reacted with a protecting agent in one or more solvents, for example, ether solvents (e. g. tetrahydrofuran or dioxane), chlorinated solvents (e.g. chloroform, dichloromethane or dichloroethane) or mixture thereof. These reactions can also be carried out in the presence of one or more organic bases, for example, triethylamine, pyridine, tributylamine, diisopropylethylamine or mixture thereof.
Compounds of Formula 3 can be debenzylated in one or more solvents, for example, polar protic solvents (e.g. methanol, ethanol or isopropyl alcohol), ether solvents (e.g. tetrahydrofuran or dioxane) or mixture thereof. The debenzylation can also be carried out in presence of
reducing agents (e. g. hydrogen on palladium-carbon, sodium/liquid ammonia, ammonium formate or /-butyllithium/ tetrahydrofuran).
Compounds of Formula 4 can be reacted with compounds of Formula 5 in one or more polar protic solvents, for example, methanol, ethanol, n-propyl alcohol, isopropyl alcohol or n-butanol. These reactions can also be carried out in presence of one or more bases, for example, inorganic bases (e.g. potassium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate or cesium carbonate), organic bases (e.g. triethylamine, trimethylamine or pyridine) or mixture thereof.
Compounds of Formula 6 can be deprotected in one or more solvents, for example, polar protic solvents (e.g. methanol, ethanol, n-propanol, isopropanol, n-butanol or f-butanol), ether solvents (e.g. tetrahydrofuran or dioxane), chlorinated solvents (e.g. dichloromethane, dichloroethane or chloroform) or mixture thereof. The deprotection can also be carried out in presence of one or more agents, for example, hydrochloric acid, trifluroacetic acid, trimethylsilyl iodide, tetrabutylammonium fluoride, zinc bromide, boron trifluoride or eerie ammonium nitrate.
Compounds of Formula 7 can be reacted with Q-XL in one or more solvents, for example, chlorinated solvents (e.g. chloroform, dichloromethane or dichloroethane), polar protic solvents (e.g. n-propyl alcohol or isopropyl alcohol), ether solvents (e.g. tetrahydrofuran, diethyl ether or dioxane) or mixture thereof.
(Scheme Removed)

Compounds of Formula 9 can be prepared according to Scheme II. Thus, 2-(4-aminopiperidin-l-yl)-6,7-dimethoxyquinazolin-4-amine of Formula 7 can be reacted with compounds of Formula R5-N-C=0 to form compounds of Formula 9 (wherein R5 is the same as defined earlier). Compounds of Formula 9 can be converted into their pharmaceutically acceptable salts using the methods known to one of ordinary skill in the art.
2-(4-aminopiperidin-l-yl)-6,7-dimethoxyquinazolin-4-amine of Formula 7 can be reacted with compounds of Formula Rs-N=C=0 in one or more solvents, for example,
chlorinated solvents (e.g. dichloromethane, dichloroethane or chloroform), polar protic solvents (e.g. n-propyl alcohol, isopropyl alcohol or n-butanol) or mixture thereof.
(Scheme Removed)

Compounds of Formula 17 can be prepared according to Scheme III. Thus, compounds of Formula 10 can be treated with hydroxy lamine to form compounds of Formula 11. Compounds of Formula 11 can be reacted with compounds of 13 to form compounds of Formula 14. Compounds of Formula 14 can be cyclized to form compounds of Formula 15. Compounds of Formula 15 can be deprotected to form compounds of Formula 16. Compounds of Formula 16 can be treated with compounds of Formula 5 to form compounds of Formula 17 (wherein Z is the same as defined earlier). Compounds of Formula 17 can be converted into their pharmaceutically acceptable salts using the methods known to one of ordinary skill in the art.
Compounds of Formula 10 can be reacted with hydroxy lamine in one or more solvents, for example, polar protic solvents (e.g. methanol, ethanol, n-propanol, isopropanol, n-butanol or /-butanol), aprotic polar solvents (e.g. acetonitrile, acetone, dimethylsulfoxide or dimethylformamide) or mixture thereof. The protection of compound of Formula 12 with a protecting agent (e.g. f-butoxycarbonyl anhydride, 9- fluorenylmethoxycarbonyl chloride, phthalaimide, and the like) can be carried in one or more ether solvents, for example, tetrahydrofuran or dioxane. The protection can also be carried out in presence of one or more bases, for example, organic bases (triethylamine, trimethylamine or pyridine), inorganic bases (ammonium chloride or ammonium bromide) or mixture thereof.
Compounds of Formula 11 can be reacted with compounds of Formula 13 in one or more chlorinated solvents, for example, dichloromethane, chloroform or dichloroethane. These reactions can also be carried out in presence of a coupling agent, for example, dicylohexylcarbodiimide or N,N'-Carbonyldiimidazole.
Compounds of Formula 14 can be cyclized at a temperature of from about 105 °C to about 115 °C.
Compounds of Formula 15 can be converted into compounds of Formula 16 in one or more solvents, for example, polar protic solvents (e.g. methanol, ethanol, n-propyl alcohol or isopropyl alcohol), polar aprotic solvents (e.g. acetonitrile, dimethylsulfoxide or dimethylformamide) or mixture thereof. The solvents can be acidified with an acid (e.g. hydrochloric acid, sulphuric acid or acetic acid).
Compounds of Formula 16 can be reacted with compounds of Formula 5 in one or more solvents, for example, polar protic solvents (e.g. methanol, ethanol, n-propanol or isopropanol), polar aprotic solvents (e.g. acetonitrile, dimethylsulfoxide or dimethylformamide) or mixture thereof. These reactions can also be carried out in presence of one or more bases, for example, inorganic bases (e.g. potassium carbonate, sodium carbonate, sodium hydrogen carbonate or potassium hydrogen carbonate), organic bases (triethylamine, pyridine or diisopropylethyamine) or mixture thereof.
(Scheme Removed)

Compounds of Formula 20 can be prepared according to Scheme IV. Thus, compounds of Formula 5 can be reacted with 4-aminophenol of Formula 18 to form compounds of Formula 19. 2-(4-aminophenoxy)-6,7-dimethoxyquinazolin-4-amine
of Formula 19 can be treated with compounds of Formula Q-XL to form compounds of Formula 20 (wherein Q is the same as defined earlier). Compounds of Formula 20 can be converted into
their pharmaceutically acceptable salts using the methods known to one of ordinary skill in the art.
Compounds of Formula 5 can be reacted with compounds of Formula 18 in one or more solvents, for example, chlorobenzene, 1,2-dichlorobenzene, dimethylsulfoxide, dimethylformamide or N-methylpyrrolidone. These reactions can also be carried out in presence of one or more inorganic bases, for example, potassium hydroxide, sodium hydroxide, sodium hydride, potassium carbonate or sodium carbonate.
Compounds of Formula 19 can be reacted with compounds of Formula Q-XL in presence
of one or more solvents, for example, ether solvents (e.g. dioxane or tetrahydrofuran), aprotic
polar solvents (e.g. dimethylformamide or dimethylacetamide) or mixture thereof. These
reactions can also be carried out in presence of one or more bases, for example, inorganic bases
(e.g. sodium carbonate or potassium carbonate), organic bases (e.g. triethylamine,
trimethylamine or pyridine). schemev
(Scheme Removed)

Compounds of Formula 29 can be prepared according to Scheme V. Thus, compounds of Formula 21 can be reacted with 1-phenylmethanamine of Formula 22 to form compounds of Formula 23. Compounds of Formula 23 can be treated with a protecting agent to form compounds of Formula 24 (wherein hal is halogen). Compounds of Formula 24 can be reacted with compounds of Formula 25 to form compounds of Formula 26. Compounds of Formula 26 can be deprotected to form compounds of Formula 27. Compounds of Formula 27 can be debenzylated to form compounds of Formula 28. Compounds of Formula 28 can be treated with compounds of Formula 5 to form compounds of Formula 29 (wherein A1, A2, A5-A7 are the same as defined earlier). Compounds of Formula 29 can be converted into their pharmaceutically acceptable salts using the methods known to one of ordinary skill in the art.
Compounds of Formula 21 can be reacted with compounds of Formula 22 in one or more hydrocarbon solvents, for example, hexane, cyclopentane, heptane or toluene.
Compounds of Formula 23 can be reacted with a protecting agent, P (e.g. t-butoxycarbonyl, benzyloxycarbonyl or 9- Fluorenylmethoxycarbonyl) in one or more solvents, for example, ether solvents (e.g.tetrahydrofuran, dioxane or diethylether), halogenated solvents (e.g. chloroform, dichloromethane or dichloroethane) or mixture thereof.
Compounds of Formula 24 can be reacted with compounds of Formula 25 in one or more solvents, for example, protic polar solvents (e.g. methanol, ethanol, n-propanol, isopropanol or n-butanol), aprotic polar solvents (e.g. acetonitrile, dimethylformamide or dimethylsulfoxide), halogenated solvents (e.g. chloroform, dichloromethane or dichloroethane), ether solvents (e.g. tetrahydrofuran or dioxane) or mixture thereof. These reactions can also be carried out in presence of one or more inorganic bases, for example, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, potassium hydrogen carbonate or sodium hydrogen carbonate.
Compounds of Formula 26 can be deprotected in one or more solvents, for example, protic polar solvents (e.g. acetic acid, methanol, ethanol, n-propyl alcohol, isopropanol or n-butanol), halogenated solvents (e.g. chloroform, dichloromethane or dichloroethane) or mixture thereof. The deprotection can also be carried out in presence of an acid, for example, acetic, trifluoroacetic or trichloroacetic acid.
Compounds of Formula 27 can be debenzylated in one or more solvents, for example, protic polar solvents (e.g. methanol, ethanol, n-propanol, isopropanol or n-butanol), aprotic polar solvents (e.g. acetonitrile, dimethylformamide or dimethylsulfoxide) or mixture thereof. The debenzylation can also be carried out in presence of one or more hydrogenolytic agents, for example, hydrogen/palladium-carbon, ammonium formate, sodium/liquid ammonia or t-butyllithium/ tetrahydrofuran.
Compounds of Formula 28 can be reacted with compounds of Formula 5 in one or more solvents, for example, protic polar solvent (e.g. methanol, ethanol, n-propanol, isopropanol or n-butanol), aprotic polar solvents (e.g. acetonitrile, dimethylformamide or dimethylsulfoxide) or mixture thereof. These reactions can also be carried out in presence of one or more inorganic bases, for example, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, potassium hydrogen carbonate or sodium hydrogen carbonate.
(Scheme Removed)

Compounds of Formula 33 can be prepared according to the Scheme VI. Thus, compounds of Formula 25 can be reacted with
a) acrylonitrile to form compounds of Formula 30,
b) 2-(3-bromopropyl)-lH-isoindole-l,3(2H)-dione to form compounds of Formula 31.
Compounds of Formula 30 can be reduced to form compounds of Formula 32. Compounds of
Formula 31 can be deprotected with hydrazine hydrate to form compounds of Formula 32.
Compounds of Formula 32 can be treated with compounds of Formula 5 to form compounds of
Formula 33 (wherein A1, A2, A5-A7 are the same as defined earlier). Compounds of Formula 33
can be converted into their pharmaceutically acceptable salts using the methods known to one of
ordinary skill in the art.
Compounds of Formula 25 can be reacted with acrylonitrile in one or more solvents, for example, protic polar solvents (e.g. methanol, ethanol, n-propanol, isopropanol or n-butanol), aprotic polar solvents (e.g. acetonitrile, dimethylformamide or dimethylsulfoxide) or mixture thereof. These reactions can also be carried out in presence of one or more bases, for example, organic bases (e.g. triethylamine, trimethylamine or pyridine), inorganic bases (e.g. potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, potassium hydrogen carbonate or sodium hydrogen carbonate) or mixture thereof.
Compounds of Formula 30 can be reduced in one or more solvents, for example, protic polar solvent (e.g. methanol, ethanol, n-propanol, isopropanol or n-butanol). These reductions
can also be carried out in presence of one or more reducing agents, for example, catalytic reducing agent (e.g raney nickel/hydrogen and ammonia, palladium-carbon/hydrogen, platinum-carbon/hydrogen), boron reducing agents (e.g. sodium borohydride or sodium cyanoborohydride) or mixture thereof.
Compounds of Formula 25 can be reacted with 2-(3-bromopropyl)-lH-isoindole-l,3(2H)-dione in one or more aprotic polar solvent, for example, dimethylformamide, acetonitrile or dimethylsulfoxide. These reactions can also be carried out in presence of one or more inorganic bases, for example, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, potassium hydrogen carbonate or sodium hydrogen carbonate.
Compounds of Formula 31 can be deprotected in one or more solvents, for example, protic polar solvent (e.g. methanol, ethanol, n-propanol, isopropanol or n-butanol) or ether solvents (e.g. tetrahydrofuran or dioxane). The deprotection can also be carried out in presence of one or more reagents, for example, hydrazine hydrate, phenyl hydrazine/ n-butylamine, sodium sulfide, sodium borohydride or methylamine.
Compounds of Formula 32 can be reacted with compounds of Formula 5 in one or more protic polar solvent, for example, methanol, ethanol, n-propanol, isopropanol or n-butanol. These reactions can also be carried out in presence of one or more inorganic bases sodium carbonate, potassium carbonate, potassium hydrogen carbonate or sodium hydrogen carbonate.
(Scheme Removed)

Compounds of Formula 38 can be prepared according to the Scheme VII. Thus, compounds of Formula 25 can be reacted with ethyl acrylate to form compounds of Formula 34. Compounds of Formula 34 can be reduced to form compounds of Formula 35. Compounds of Formula 35 can be treated with a protecting group, P (e.g. methane sulphonate, benzyl
sulphonate, tosyl chloride and the like) to form compounds of Formula 36. Compounds of Formula 36 can be deprotected by methylamine to form compounds of Formula 37. Compounds of Formula 37 can be treated with compounds of Formula 5 to form compounds of Formula 38. Compounds of Formula 38 can be converted into their pharmaceutically acceptable salts using the methods known to one of ordinary skill in the art.
Compounds of Formula 25 can be reacted with ethyl acrylate in one or more solvents, for example, protic polar solvents (e.g. methanol, ethanol, n-propanol, isopropanol or n-butanol), aprotic polar solvents (e.g. acetonitrile, dimethylformamide or dimethylsulfoxide) or mixture thereof.
Compounds of Formula 34 can be reduced in one or more ether solvents, for example, tetrahydrofuran or dioxane. The hydrolysis can also be carried out in presence of one or more inorganic bases, for example, lithium aluminum hydride, sodium hydroxide, potassium hydroxide or sodium hydride.
Compounds of Formula 35 can be with a protecting agent, P, in presence of one or more bases, for example, organic bases (e.g. triethylamine, trimethylamine, tertiary butylamine or pyridine), inorganic bases ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, potassium hydrogen carbonate or sodium hydrogen carbonate.
Compounds of Formula 36 can be deprotected in presence of methylamine.
Compounds of Formula 37 can be reacted with compounds of Formula 5 in one or more protic polar solvent, for example, methanol, ethanol, n-propanol, isopropanol or n-butanol) and in presence of one or more inorganic bases (e.g. sodium carbonate, potassium carbonate, potassium hydrogen carbonate or sodium hydrogen carbonate).
In the above schemes, where the specific bases, coupling agents, solvents, etc., are mentioned, it is to be understood that bases, coupling agents, solvents, etc., known to those skilled in the art may be used. Similarly, the reaction temperature and duration may be adjusted according to the desired needs.
Compounds of the present invention useful for such purpose are listed below:
jV-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo [3.1.0]hex-6-yl]acetamide (Compound No.l) and its hydrochloride salt (Compound No.2),
1 -(4-amino-6,7-dimethoxy quinazolin-2-yl)-4-(2-methoxyphenyl) piperidin-4-ol (Compound No.3)and its hydrochloride salt (Compound No.4),
6,7-dimethoxy-2-[4-(2-methoxyphenyl)piperidin-l-yl]quinazolin-4-amine (Compound No.5) and its hydrochloride salt (Compound No.6),
Ar-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo [3.1.0] hex-6-yl] tetrahydrofuran-2-carboxamide (Compound No. 7) and its hydrochloride salt (Compound No. 8),
N-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo[3.1.0] hex-6-yl]benzamide (Compound No.9) and its hydrochloride salt (Compound No. 10),
N-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo[3.1.0] hex-6-yl] benzenesulfonamide (Compound No.l 1) and its hydrochloride salt (Compound No. 12),
N-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo[3.1.0] hex-6-yl] methanesulfonamide (Compound No. 13) and its hydrochloride salt (Compound No. 14),
2-(6-amino-3-azabicyclo [3.1.0]hex-3-yl)-6,7-dimethoxyquinazolin-4-amine (Compound No. 15) and its hydrochloride salt (Compound No. 16),
N-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo[3.1.0] hex-6-yl]-4-fluorobenzamide (Compound No. 17) and its hydrochloride salt (Compound No. 18),
jV-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo[3.1.0] hex-6-yl]thiophene-2-carboxamide (Compound No. 19) and its hydrochloride salt (Compound No.20),
Af-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo[3.1.0] hex-6-yl]-2-(2-methoxy phenoxy)acetamide (Compound No.21) and its hydrochloride salt (Compound No.22),
N-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo[3.1.0] hex-6-yl]-3,5-dimethyl benzamide (Compound No.23) and its hydrochloride salt (Compound No.24),
N-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo[3.1.0] hex-6-yl]-3,4,5-trimethoxy benzamide (Compound No.25) and its hydrochloride salt (Compound No.26),
N-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo[3.1.0] hex-6-yl]-2-ethoxybenzamide (Compound No.27) and its hydrochloride salt (Compound No.28),
N-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo[3.1.0] hex-6-yl]-4-nitrobenzamide (Compound No.29) and its hydrochloride salt (Compound No.30),
Ar-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo [3.1.0] hex-6-yl]-4-(difluoromethyl)benzamide (Compound No.31) and its hydrochloride salt (Compound No.32),
N-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo[3.1.0] hex-6-yl]-4-chlorobenzamide (Compound No.33) and its hydrochloride salt (Compound No.34),
Benzyl [3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo[3.1.0] hex-6-yl]carbamate (Compound No.35) and its hydrochloride salt (Compound No.36),
6,7-dimethoxy-2-[4-(3-phenyl-l,2,4-oxadiazol-5-yl)piperidin-l-yl] quinazolin-4-amine (Compound No.37) and its hydrochloride salt (Compound No.38),
N-[l-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperidin-4-yl]-4-fluorobenzamide (Compound No.39) and its hydrochloride salt (Compound No.40),
N-[ 1 -(4-amino-6,7-dimethoxyquinazolin-2-yl)piperidin-4-yl] benzenesulfonamide (Compound No.41) and its hydrochloride salt (Compound No.42),
N-[l-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperidin-4-yl] acetamide (Compound No.43) and its hydrochloride salt (Compound No.44),
N-[l-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperidin-4-yl]benzamide (Compound No.45) and its hydrochloride salt (Compound No.46),
N-[l-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperidin-4-yl]-3,4,5-trimethoxybenzamide (Compound No.47) and its hydrochloride salt (Compound No.48),
Ar-[l-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperidin-4-yl]thiophene-2-carboxamide (Compound No.49) and its hydrochloride salt (Compound No.50),
N-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo [3.1.0]hex-6-yl] pentanamide (Compound No.51) and its hydrochloride salt (Compound No.52),
Af-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo [3.1.0]hex-6-yl] hexanamide (Compound No.53) and its hydrochloride salt (Compound No.54),
Af-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo [3.1.0]hex-6-yl]-3,4-dimethoxybenzamide (Compound No.55) and its hydrochloride salt (Compound No.56),
Af-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo [3.1.0]hex-6-yl]-4-methoxybenzamide (Compound No.57) and its hydrochloride salt (Compound No.58),
N-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo[3.1.0]hex-6-yl]-2,2-diphenyl acetamide (Compound No.59) and its hydrochloride salt (Compound No.60),
2-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-l-yl]-6,7-dimethoxyquinazolin-4-amine (Compound No.61) and its hydrochloride salt (Compound No.62),
6,7-dimethoxy-Af2-{3-[4-(2-methoxyphenyl)piperazin-l-yl]propyl}quinazoline-2,4-diamine (Compound No.63) and its hydrochloride salt (Compound No.64),
iV-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo[3.1.0]hex-6-yl]-3,3-diphenylpropanamide (Compound No.65) and its hydrochloride salt (Compound No.66),
l-[(4-amino-6,7-dimethoxyquinazolin-2-yl)(methyl)amino]-3-[4-(2-methoxyphenyl) piperazin-l-yl]propan-2-ol (Compound No.67) and its hydrochloride salt (Compound No.68),
Ar2-{3-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-l-yl]propyl}-6,7-dimethoxy-Af2-methylquinazoline-2,4-diamine (Compound No.69) and its hydrochloride salt (Compound
No.70),
Ar-{4-[(4-amino-6,7-dimethoxyquinazolin-2-yl)oxy]phenyl}benzamide (Compound No.71) and its hydrochloride salt (Compound No.72),
N-{4-[(4-amino-6,7-dimethoxyquinazolin-2-yl)oxy]phenyl}acetamide (Compound No.73) and its hydrochloride salt (Compound No.74),
N-{4-[(4-amino-6,7-dimethoxyquinazolin-2-yl)oxy]phenyl}morpholine-4-carboxamide (Compound No.75) and its hydrochloride salt (Compound No.76),
N-{4-[(4-amino-6,7-dimethoxyquinazolin-2-yl)oxy]phenyl}-4-fluorobenzamide (Compound No. 77) and its hydrochloride salt (Compound No. 78),
N-{4-[(4-amino-6,7-dimethoxyquinazolin-2-yl)oxy]phenyl}-3,4,5-trimethoxybenzamide (Compound No. 79) and its hydrochloride salt (Compound No. 80),
N-{4-[(4-amino-6,7-dimethoxy quinazolin-2-yl)oxy]phenyl} benzenesulfonamide (Compound No.81) and its hydrochloride salt (Compound No.82),
N-{4-[(4-amino-6,7-dimethoxyquinazolin-2-yl)oxy]phenyl}-3,4-dimethoxybenzamide (Compound No.83) and its hydrochloride salt (Compound No.84),
N-{4-[(4-amino-6,7-dimethoxyquinazolin-2-yl)oxy]phenyl}thiophene-2-carboxamide (Compound No.85) and its hydrochloride salt (Compound No.86),
N-[l-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperidin-4-yl]-./V-phenylbenzenesulfonamide (Compound No.87) and its hydrochloride salt (Compound No.88),
JV-[l-(4-amino-6,7-dimethoxy quinazolin-2-yl)piperidin-4-yl]pyrazine-2-carboxamide (Compound No.89) and its hydrochloride salt (Compound No.90),
iV-[l-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperidin-4-yl]-2,3-dihydro-l,4-benzodioxine-2-carboxamide (Compound No.91) and its hydrochloride salt (Compound No.92),
A/-[l-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperidin-4-yl]isoxazole-5-carboxamide (Compound No.93) and its hydrochloride salt (Compound No.94),
N-[ 1 -(4-amino-6,7-dimethoxyquinazolin-2-yl)piperidin-4-yl]-2-furamide (Compound No.95) and its hydrochloride salt (Compound No.96),
4-methoxypheny 1 [ 1 -(4-amino-6,7-dimethoxyquinazolin-2-y l)piperidin-4-y ljcarbamate (Compound No.97) and its hydrochloride salt (Compound No.98),
3-(trifluoromethyl)phenyl [l-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperidin-4-yl] carbamate (Compound No.99) and its hydrochloride salt (Compound No. 100),
2-{4-[3-(4-fluorophenyl)-l,2,4-oxadiazol-5-yl]piperidin-l-yl}-6,7-dimethoxyquinazolin-4-amine (Compound No. 101) and its hydrochloride salt (Compound No. 102),
Ar-[l-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperidin-4-yl]-2,2-diphenylacetamide (Compound No. 103) and its hydrochloride salt (Compound No. 104),
N-[l-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperidin-4-yl]-3,4-dimethoxybenzamide (Compound No. 105) and its hydrochloride salt (Compound No. 106),
N-[l-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperidin-4-yl]-4-methoxybenzamide (Compound No. 107) and its hydrochloride salt (Compound No. 108),
N-[l-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperidin-4-yl]morpholine-4-carboxamide
(Compound No. 109) and its hydrochloride sNt (Compound No.l 10),
N-[l-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperidin-4-yl]-3,3-diphenylpropanamide(Compound No.l 11) and its hydrochloride sNt (Compound No.l 12),
N-[l-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperidin-4-yl]-2-ethoxybenzamide (Compound No. 113) and its hydrochloride sNt (Compound No. 114),
N-[l-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperidin-4-yl]tetrahydrofuran-2-cNboxamide (Compound No.l 15) and its hydrochloride sNt (Compound No.l 16),
A'-[l-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperidin-4-yl]-2-(2-methoxyphenoxy) acetamide (Compound No.l 17) and its hydrochloride sNt (Compound No.l 18),
N-[l-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperidin-4-yl]-4-(difluoromethoxy) benzamide (Compound No.l 19) and its hydrochloride sNt (Compound No. 120),
N-[l-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperidin-4-yl]-AP-(4-methoxyphenyl)urea (Compound No. 121) and its hydrochloride sNt (Compound No. 122),
N- {4-[(4-amino-6,7-dimethoxyquinazolin-2-yl)oxy]phenyl} -./V-phenylurea (Compound No. 123) and its hydrochloride sNt (Compound No. 124),
6,7-dimethoxy-2-{[l-(phenylsulfonyl)piperidin-4-yl]oxy}quinazolin-4-amine (Compound No. 125) and its hydrochloride sNt (Compound No. 126),
2-[(l-benzoylpiperidin-4-yl)oxy]-6,7-dimethoxyquinazolin-4-amine (Compound No. 127) and its hydrochloride sNt (Compound No. 128),
6,7-dimethoxy-2-{[l-(morpholin-4-ylcNbonyl)piperidin-4-yl]oxy}quinazolin-4-amine(Compound No. 129) and its hydrochloride sNt (Compound No. 130),
4-[(4-amino-6,7-dimethoxyquinazolin-2-yl)oxy]-N-phenylpiperidine-l-cNboxamide (Compound No. 131) and its hydrochloride sNt (Compound No. 132),
N-{4-[(4-amino-6,7-dimethoxyquinazolin-2-yl)oxy]phenyl}-4-methoxybenzamide (Compound No.133) and its hydrochloride sNt (Compound No.134),
N-{4-[(4-amino-6,7-dimethoxyquinazolin-2-yl)oxy]phenyl}-2,2-diphenylacetamide (Compound No. 135) and its hydrochloride sNt (Compound No. 136),
4-methylphenyl {4-[(4-amino-6,7-dimethoxyquinazolin-2-yl)oxy]phenyl}cNbamate (Compound No.137) and its hydrochloride sNt (Compound No.138),
4-methoxyphenyl {4-[(4-amino-6,7-dimethoxyquinazolin-2-yl)oxy]phenyl}cNbamate (Compound No. 139) and its hydrochloride sNt (Compound No. 140),
N-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo[3.1.0]hex-6-yl]-2-methoxybenzamide (Compound No. 141) and its hydrochloride sNt (Compound No. 142),
N-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo[3.1.0]hex-6-yl]-3-methoxybenzamide (Compound No. 143) and its hydrochloride sNt (Compound No. 144),
N-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo[3.1.0]hex-6-yl]morpholine-4-cNboxamide (Compound No. 145) and its hydrochloride sNt (Compound No. 146),
N-[8-(4-amino-6,7-dimethoxyquinazolin-2-yl)-8-azabicyclo[3.2.1]oct-3-yl]benzenesulfonamide (Compound No.147) and its hydrochloride sNt (Compound No.148)
phNmaceuticNly acceptable sNts, phNmaceuticNly acceptable solvates, polymorphs, prodrugs, stereoisomers, tautomeric forms, N-oxides and metabolites thereof.
In another aspect, there is provided phNmaceuticN composition, which may comprise of an effectNe amount of compound or admixture of compounds with apposite excipients and other assisting agents, if required, for orN, sublinguN, pNenterN, topicN, rectN or transdermN administration. Compounds of this invention may be administered with or without one or more phNmaceuticNly acceptable cNriers.
Compounds described herein can be administered to a patient (e.g., human or animN) orNly, pNenterNly, topicNly, rectNly, internasNly, subcutaneously or transdermNly. PhNmaceuticN compositions of the present invention can comprise phNmaceuticNly effectNe amounts of one or more compounds of the present invention formulated together with one or more phNmaceuticNly acceptable cNriers.
The term "phNmaceuticNly acceptable cNriers" is intended to include non-toxic, inert solid, semi-solid or liquid filter, diluent, encapsulating materiN or formulation auxiliNy of any type.
Solid form prepNations for orN administration include capsules, tablets, pills, powder, granules, cachets or suppositories. For solid form prepNations, one or more actNe compounds can be mixed with one or more inert, phNmaceuticNly acceptable excipients or cNriers, for example, sodium citrate, dicNcium phosphate and/or one or more fillers or extenders, for example, stNch, lactose, sucrose, glucose, mannitol, silicic acid or mixtures thereof; one or more binders, for example, cNboxymethylcellulose, Nginates, gelatins, polyvinylpyrolidinone, sucrose, acacia or mixtures thereof; disintegrating agents, for example, agN-agN, cNcium cNbonate, potato stNch, Nginic acid, certA1n silicates, sodium cNbonate or mixtures thereof; absorption accelators, for example, quaternNy ammonium compounds; wetting agents, for example, cetyl Ncohol, glycerol, monosteNate or mixtures thereof; adsorbents, for example, kaolin; lubricants, for example, tNc, cNcium steNate, magnesium steNate, solid polyethyleneglycol, sodium lauryl sulfate or mixtures thereof.
For capsules, tablets or pills, dosage forms can Nso comprise one or more buffering agents.
Solid prepNations of tablets, capsules, pills or granules can Nso be prepNed with one or more coatings and/or shells, for example, enteric coating and other coatings well known in the phNmaceuticN formulating Nt.
Liquid form prepNations for orN administration include phNmaceuticNly acceptable emulsiops, solutions, suspensions, syrups or elixirs. For liquid form prepNations, one or more actNe compounds can be mixed with water and/or other solvent(s), one or more solubilizing agents or emulsifiers, for example, ethyl Ncohol, isopropyl Ncohol, ethyl cNbonate, ethyl acetate, benzyl Ncohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils {e.g., cottonseed, groundnut, corn, germ, olNe, castor or sesame oil), glycerol, fatty acid esters of sorbitan or mixtures thereof. In addition to inert diluents, orN compositions can Nso include one or more adjuvants, for example, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents or mixtures thereof.
Injectable prepNations {e.g., sterile injections, aqueous or oleaginous suspensions) may be formulated according to methods known to one of ordinNy skill in the Nt, for example, using one or more suitable dispersing agents, wetting agents, suspending agents or mixtures thereof. Acceptable cNriers or solvents that may be employed include, for example, water, Ringer's solution, U.S.P., isotonic sodium chloride or mixtures thereof.
Dosage forms for topicN or transdermN administration includes ointments, pastes, creams, lotions, gel, powders, solutions, spray, inhNants or patches. ActNe compound can be admixed under sterile conditions with one or more phNmaceuticNly acceptable cNriers, as well as any preservatNes or buffers as may be required. OphthNmic formulations, eNdrops, eye ointments, powders and solutions Ne Nso encompassed within the scope of this invention.
PhNmaceuticN prepNations may be in unit dosage form. In pNticulN, prepNations may be subdNided into unit dosage forms contA1ning appropriate and therapeuticNly effectNe quantities of one or more actNe ingredients. Unit dosage forms can be packaged prepNations contA1ning discrete capsules, powders, in viNs or ampoules, ointments, capsules, cachets, tablets, gels, creams, or any combination thereof and in appropriate numbers of unit dosages.
Formulations of the present invention may be formulated by methods known to one of ordinNy skill in the Nt to provide immediate release, as well as sustA1ned- or delayed-release of actNe ingredients Nter administration to a patient.
Compounds described herein, bladder selectNe muscNinic receptor antagonists and/or 5a reductase inhibitors can be formulated in combination to achieve desired therapeutic effects,
i.e., combination therapies. As such, the dosage amounts of such actNe ingredients can be adjusted accordingly, without undue experimentation and well within the abilities of one of ordinNy skill in the Nt. As one of ordinNy skill in the Nt can appreciate, dosage amounts of compounds described herein, bladder selectNe muscNinic receptor antagonists and/or 5a reductase inhibitors may be independently optimized and combined to achieve a synergistic therapeutic result. In accordance with methods encompassed herein, indNiduN components of any combination can be administered sepNately in any sequence at the same or different times during the course of therapy, or concurrently in dNided or single combination forms.
While the present invention has been described in terms of its specific embodiments, certA1n modifications and equNNents will be appNent to those skilled in the Nt and Ne included within the scope of the present invention. The examples Ne provided to illustrate pNticulN aspects of the disclosure and do not limit the scope of the present invention as defined by the clA1ms.
ExperimentN DetA1ls
Scheme I
PrepNation of fert-butyl (l-benzvlpiperidin-4-yl) cNbamate [Formula 31
A solution of l-benzylpiperidin-4-amine (131.3 mmol, commerciNly avA1lable) in dichloromethane was cooled to 0-5°C. To it was added triethylamine (131.3 mmol). This was followed by drop wise addition of f-butoxycNbonyl anhydride (131.3 mmol). Tetrahydrofuran (50 ml) was then added to this solution and the entire reaction mixture was Nlowed to stir at room temperature for about 5 hours. It was then concentrated under reduced pressure, the residue was then taken in water and extraction was done with dichloromethane. The solvent was then evaporated to Nford tert-buty\ (l-benzylpiperidin-4-yl) cNbamate. Yield: 100%.
PrepNation of tert-butvl piperidin-4-vlcNbamate [Formula 41
To a solution of tert-buty\ (l-benzylpiperidin-4-yl)cNbamate (68.9 mmol) in methanol was added pNladium/cNbon (20% w/w). The reaction mixture was hydrogenated in pan-appNatus under 50 psi pressure of hydrogen for about 5 hours. The reaction mixture was then filtered through a bed of celite. The bed was washed well with methanol and then filtrate was concentrated to Nford ter/-butyl piperidin-4-ylcNbamate. Yield: 100%.
PrepNation of fert-butyl [l-(4-amino-6J-dimethoxvquinazolin-2-yDpiperidin-4-yl1cNbamate [Formula 6]
A solution of tert-butyl piperidin-4-ylcNbamate (68.8 mmol), 6,7-dimethoxy-2-chloro-4-amino quinazoline (62.5 mmol) and potassium cNbonate (125 mmol) in n-butanol was refluxed
for about 48 hours. The reaction mixture was cooled and filtered. The residue was washed well with n-butanol and 10% methanol-dichloromethane. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtA1n tert-butyl [l-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperidin-4-yl]cNbamate. Yield: 38%. PrepNation of 2-(4-aminopiperidin-l-vl")-6.7-dimethoxvquinazolin-4-amine [Formula 71
A solution of tert-butyl [l-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperidin-4-yl] cNbamate (24.9 mmol) in ethanol and ethanolic hydrochloric acid (2.5 N, 33 ml) was stirred overnight at room temperature. The solvent was then evaporated and the residue was dried well to obtA1n 2-(4-aminopiperidin-1 -yl)-6,7-dimethoxyquinazolin-4-amine. Yield: 100%.
PrepNation of compound of Formula 8
a) A solution of 2-(4-aminopiperidin-l-yl)-6,7-dimethoxyquinazolin-4-amine (1 equN.) in dichloromethane was cooled in ice under inert conditions followed by addition of triethylamine (.5 equN.). To this was added a solution of compound of Formula Q-XL in dichloromethane dropwise and the reaction mixture was then stirred overnight at room temperature. Dichloromethane was then added to reaction mixture and it was washed with saturated sodium bicNbonate solution. The organic extract was concentrated under reduced pressure and then purified by silica gel column chromatography to compound of Formula 8.
b) A solution of a compound of Formula Q-XL (1.5 equN.) in thionyi chloride was refluxed for about 2 hours. Thionyi chloride was then removed. The residue was taken in solvent system of dichloromethane/dichloroethane and was added to the mixture of compound of Formula 7 and triethylamine (3 equN.) under Ngon. The reaction mixture was then stirred overnight at room temperature. The reaction mixture was diluted with dichloromethane and the organic extract was washed with saturated sodium bicNbonate solution. The organic extract was concentrated under reduced pressure and then purified by silica gel column chromatography to compounds of Formula 8.
Scheme II PrepNation of compound of Formula 9
Same as described above for compound of Formula 8 (step b)
Scheme III PrepNation of N-hvdroxv benzamide [Formula 11]
A solution of benzonitrile (38.8 mmol) and hydroxylamine (50% wt in water, 42.72 mmol) in methanol (250 mL) was heated at about 50°C for few minutes. The reaction mixture was then refluxed for about 3 hours. It was then cooled and solvent was removed under reduced pressure. The residue was taken in ethyl acetate and washed well with water. The organic layer was removed to Nford N-hydroxy benzamide. Yield: 93%.
PrepNation of piperidine-l,4-dicNboxylic acid mono-tert-butyl ester TFormula 131 A solution of piperidine-4-cNboxylic acid of Formula 12 (30.96 mmol) in tetrahydrofuran was cooled to about 0°C. To it was added triethylamine followed by dropwise addition of t -butoxycNbonyl anhydride (30.96 mmol). The reaction mixture was then stirred at room temperature overnight. The solvent was then removed and the residue taken in water. The solid was then extracted in dichloromethane. The organic layer was evaporated and the resulting solid was purified by column chromatography to obtA1n piperidine-l,4-dicNboxylic acid mono-tert-butyl ester. Yield: 30%.
PrepNation of compound of Formula 14
To a solution of a compound of Formula 11 (1.0 equN.) and piperidine-l,4-dicNboxylic acid mono-tert-butyl ester of Formula 13 (1.0 equN.) in dichloromethane were added dicyclohexylcNbodiimde (4.796 mmol) and 4-dimethylaminopyridine in inert conditions. The reaction mixture was then stirred overnight at room temperature. The solid obtA1ned was filtered and washed with dichloromethane. The filtrate was concentrated and purified by column chromatography to obtA1n compound of Formula 14.
PrepNation of compound of Formula 15
A compound of Formula 14 was heated at about 100-110°C for about 5 hours. The solid obtA1ned was then purified by column chromatography to obtA1n compound of Formula 15.
PrepNation of compound of Formula 16
To a solution of a compound of Formula 15 in ethanol was added ethanolic hydrochloric acid (1.2 N). The reaction mixture was stirred overnight at room temperature. The solvent was then removed to obtA1n a residue which was taken in aqueous sodium hydroxide (10%) and the solid was then extracted with dichloromethane. The organic layer was concentrated to obtA1n compound of Formula 16.
PrepNation of compound of Formula 17
A solution of a compound of Formula 16(1.1 equN.), 4-amino-6,7-dimethoxy-2 chloro quinazoline (1.0 equN.) and potassium cNbonate (2.2 equN.) in butanol was refluxed for about 48 hours. The reaction mixture was then cooled. The reaction mixture was filtered and the residue was washed well with butanol and methanol-dichloromethane (10%). The filtrate was concentrated and purified by column chromatography to yield compound of Formula 17.
Scheme N PrepNation of 2-(4-aminophenoxvV6.7-dimethoxv-quinazolin-4-ylamine [Formula 191 To a solution of 4-amino-2-chloro-6,7-dimethoxyquinazoline (41.7 mmol) and 4-aminophenol (41.7 mmol) in 1,2-dichlorobenzene was added potassium cNbonate (83.4 mmol). The reaction mixture was refluxed for about 8 hours. Hexane (100 mL) was added to the reaction mixture at about 50°C and stirred at room temperature for about 2 hours. The mixture was then filtered and the residue was washed with hexane. The residue was then purified by column chromatography to get 2-(4-aminophenoxy)-6,7-dimethoxy-quinazolin-4-ylamine. Yield: 32.2%.
PrepNation of compound of Formula 20
To a solution of 2-(4-aminophenoxy)-6,7-dimethoxy-quinazolin-4-ylamine.(l equN.) and triethylamine (1 equN.) in dioxane at 0°C was added a compound of Formula Q-XL (1 equN.). The reaction mixture was stirred at room temperature for about 2 hours. The reaction mixture was poured in water (100 mL) and stirred for about 15 min., and then filtered. The residue was washed with dichloromethane to get crude product, which was purified by column chromatography to gNe compound of Formula 20.
Scheme V PrepNation of compound of Formula 23
A solution of a compound of Formula 21 (1.0 equN.) and benzylamine of Formula 22 (1.0 equN.) in hexane (40 mL) was stirred at room temperature for about 3 days. Hexane (300 mL) was then added and stirred at room temperature for about 30 minutes. The solid was then filtered and washed with hexane and dried well to Nford compound of Formula 23.
PrepNation of compound of Formula 24
A solution of a protecting group, P, (1.0 equN.) and triethylamine (2.0 equN.) in tetrahydrofuran was cooled in ice. A compound of Formula 23 (1.0 equN.) was then added portion wise in cold. Nter completion of addition, stirring was continued overnight at room temperature. Solvent was then removed, residue was taken in water and extraction was done in
ethyl acetate. The organic extract was then dried and concentrated to Nford compound of Formula 24.
PrepNation of compound of Formula 26
A solution of potassium hydroxide in methanol was cooled in ice (6.0 equN.) to it was added a compound of Formula 25 (1.0 equN.). This was followed by the addition of a solution of compound of Formula 24 in methanol (1.0 equN.). The reaction mixture was Nlowed to come to room temperature and stirred overnight. Solvent was then removed and extraction was done with dichloromethane. The organic extract was concentrated and purified by column chromatography using methanol-dichloromethane as eluent to form compound of Formula 26.
PrepNation of compound of Formula 27
To a solution of a compound of Formula 26 (1.0 equN.) in dichloromethane was added trifluoroacetic acid (7.17 mL) and the reaction mixture was stirred overnight at room temperature. The reaction mixture was then poured into aqueous sodium hydroxide (25%) in cold. The extraction was done with dichloromethane. The organic extract was dried, concentrated to Nford compound of Formula 27.
PrepNation of compound of Formula 28
To a solution of a compound of Formula 27 (1 equN.) in methanol was added pNladium/cNbon (1 g) and ammonium formate and the reaction mixture was refluxed overnight. The reaction mixture was then cooled and filtered through a bed of celite, the bed being washed well with methanol. The filtrate was then concentrated to Nford compound of Formula 28.
PrepNation of compound of Formula 29
A solution of a compound of Formula 28 (1.0 equN.), compound of Formula 5 (1.0 equN.) and potassium cNbonate (2.0 equN.) in n-butanol was refluxed for about 48 hours. The reaction mixture was cooled and then filtered. The filtrate was washed well with n-butyl Ncohol and was then concentrated. The residue was then purified by column chromatography to obtA1n compound of Formula 29.
Scheme VI PrepNation of compound of Formula 30
To a solution of a compound of Formula 25 (1.0 equN.) in methanol was added triethylamine (1.1 equN.) and acrylonitrile (2.0 equN.) at room temperature and stirred overnight. Solvent was then removed and residue was taken in water followed by extraction with
dichloromethane. The organic extract was concentrated and then purified by column chromatography to obtA1n compound of Formula 30.
PrepNation of compound of Formula 31
The compound of Formula 25 (1.0 equN.), hNopropyl phthNimide (1.2 equN.) and potassium cNbonate (3.0 equN.) Ne taken in dimethylformamide and heated overnight at about 60-70°C. The reaction mixture is then cooled, poured into excess of water and extracted with ethyl acetate. The organic extract is dried, concentrated and purified by column chromatography using silica gel to yield compound of Formula 31.
PrepNation of compound of Formula 32
To a solution of a compound of Formula 30 (1.0 equN.) in methanol was added raney nickel (135 mg) followed by addition of methanol-ammonia. The reaction mixture was hydrogenated in pNr appNatus for about 6 hours. The reaction mixture was filtered through a bed of celite, the bed washed well with methanol. The filtrate was then concentrated to Nford compound of Formula 32.
PrepNation of compound of Formula 33
A solution of a compound of Formula 32 (1.2 equN.), compound of Formula 5 (1.0 equN.) and potassium cNbonate (1.5 equN.) in n-butanol was refluxed for about 48 hours. The reaction mixture was cooled and the residue was triturated with water. Aqueous washing were discNded. The residue was taken in dichloromethane: methanol (1:1) and purified by column chromatography to obtA1n compound of Formula 33.
Scheme VII PrepNation of compound of Formula 34
In a dry round bottom flask fitted with a stirring (3.35 mL) bN and guNd tube was placed a compound of Formula 25 (5.0 g), triethylamine (3.35mL) and methanol (20 mL). To this solution under stirring at -10°C was added dropwise ethyl acrylate (5.69 mL). The reaction mixture was slowly Nlowed to come to room temperature and then stirred overnight at room temperature. The reaction mixture was then concentrated under vacuum. The solid residue obtA1ned was then purified on silica gel column to Nford compound of Formula 34.
PrepNation of compound of Formula 35
In a dry round bottom flask equipped with a stirring bN was placed tetrahydrofuran (90 mL) and was chilled in an ice bath, to it was added lithium Numinum hydride (1.0 equN.)
cNefully to form slurry. To this slurry was added a compound of Formula 34 (3.8 equN.) in cold condition. The reaction mixture was then stirred at room temperature overnight. Lithium Numinum hydride was added further and the reaction mixture was then stirred overnight. The reaction mixture was quenched by the addition of cold water and sodium hydroxide solution (15%), and then water was further added. The solid was filtered, hot extracted with tetrahydrofuran and organic extracts concentrated in vacuum to Nford compound of Formula 35. PrepNation of compound of Formula 36
In a dry round bottom flask with a stirring bN and guNd tube was placed a compound of Formula 35 (5.4 g), dichloromethane (40 mL), triethylamine (9.025 mL) and 4-dimethylaminopyridine. To this mixture in cold condition under stirring was added mesyl chloride in dichloromethane. The reaction mixture was then stirred at room temperature overnight. The reaction mixture was quenched with saturated sodium bicNbonate solution. The organic layer was washed with water and brine solution, concentrated under vacuum. The crude obtA1ned was purified on silica gel column chromatography to obtA1n compound of Formula 36.
PrepNation of compound of Formula 37
In a dry auto clave, a compound of Formula 36 (5.3 g) and methanol was placed. To this aqueous methylamine solution (40%, 12.8 mL) was added. The reaction mixture was then heated at 90°C overnight in Ngon atmosphere then cooled to room temperature. The contents were transferred to round bottom flask, and then concentrated under vacuum. The crude obtA1ned was purified by silica gel column chromatography to yield compound of Formula 37.
PrepNation of compound of Formula 38
In a dry autoclave was placed a compound of Formula 5 (1.0 equN.), compound of Formula 37 (1.8 equN.) and 3-methyl-l-butanol under inert atmosphere. The reaction was closed and heated under stirring at about 130 °C (oil bath temperature) for about 22 hours. The reaction mixture was then cooled to room temperature. The contents were transferred to round bottom flask and concentrated under vacuum. The crude was purified by column chromatography to obtA1n compound of Formula 38.
PrepNation of hydrochloride sNts of compounds of Formulae 8, 9, 17, 20, 29, 33 and 38
An equimolN quantity of isopropanol and hydrochloric acid was added to the base of compound of Formula 8, 9, 17, 20, 29, 33 or 38 at 10-15 °C. The solid, which precipitates, was then filtered to obtA1n the hydrochloride sNt of the respectNe compound.
The following compounds were prepNed anNogously, following the above generN procedures:
Compound No. 1: N-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo [3.1.0]hex-6-yl]acetamide, hygroscopic; and it's hydrochloride sNt (Compound No. 2), Mass (m/z):344(M++l),
Compound No.3: l-(4-amino-6,7-dimethoxy quinazolin-2-yl)-4-(2-methoxyphenyl) piperidin-4-ol, hygroscopic; and its hydrochloride sNt (Compound No. 4), Mass (m/z): 411
(M++l),
Compound No.5: 6,7-dimethoxy-2-[4-(2-methoxyphenyl)piperidin-l-yl]quinazolin-4-amine, hygroscopic; and its hydrochloride sNt (Compound No. 6), Mass (m/z): 395 (M++l),
Compound No.7: N-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo [3.1.0] hex-6-yl] tetrahydrofuran-2-cNboxamide, hygroscopic; and its hydrochloride sNt (Compound No. 8), Mass (m/z): 400 (M++l),
Compound No.9: N-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo[3.1.0] hex-6-yl]benzamide, hygroscopic; and its hydrochloride sNt (Compound No. 10), Mass (m/z): 406(M++1),
CompoundNo.il: 7^-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo[3.1.0] hex-6-yl] benzenesulfonamide, hygroscopic; and its hydrochloride sNt (Compound No. 12) Mass (m/z): 442 (M++l),
Compound No. 13: N-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo[3.1.0] hex-6-yl] methanesulfonamide, hygroscopic; and its hydrochloride sNt (Compound No. 14) Mass (m/z): 380 (M++l),
Compound No. 15: 2-(6-amino-3-azabicyclo [3.1.0]hex-3-yl)-6,7-dimethoxyquinazolin-4-amine, hygroscopic; and its hydrochloride sNt (Compound No. 16) Mass (m/z): 302 (M++l),
Compound No. 17: N-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo[3.1.0] hex-6-yl]-4-fluorobenzamide, hygroscopic; and its hydrochloride sNt (Compound No. 18) Mass (m/z): 424 (M++l),
Compound No. 19: N-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo[3.1.0] hex-6-yl]thiophene-2-cNboxamide, hygroscopic; and its hydrochloride sNt (Compound No.20) Mass (m/z): 412 (M++l),
Compound No.21: N-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo[3.1.0] hex-6-yl]-2-(2-methoxy phenoxy)acetamide, hygroscopic; and its hydrochloride sNt (Compound No.22) Mass (m/z): 466 (M++l),
Compound No.23: N-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo[3.1.0] hex-6-yl]-3,5-dimethyl benzamide, hygroscopic; and its hydrochloride sNt (Compound No.24) Mass (m/z): 434 (M++l),
Compound No.25: N-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo[3.1.0] hex-6-yl]-3,4,5-trimethoxy benzamide, hygroscopic; and its hydrochloride sNt (Compound No.26) Mass (m/z): 496 (M++l),
Compound No.27: N-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo[3.1.0] hex-6-yl]-2-ethoxybenzamide, hygroscopic; and its hydrochloride sNt (Compound No.28) Mass (m/z):450(M++l),
Compound No.29: N-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo[3.1.0] hex-6-yl]-4-nitrobenzamide, hygroscopic; and its hydrochloride sNt (Compound No.30) Mass (m/z):451(M++l),
Compound No.31: N-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo [3.1.0] hex-6-yl]-4-(difluoromethyl) benzamide, hygroscopic; and its hydrochloride sNt (Compound No.32) Mass (m/z): 472 (M++l),
Compound No.33: N-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo[3.1.0] hex-6-yl]-4-chlorobenzamide, hygroscopic; and its hydrochloride sNt (Compound No.34) Mass (m/z): 440 (M++l),
Compound No.35: Benzyl [3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo[3.1.0] hex-6-yl]cNbamate, hygroscopic; and its hydrochloride sNt (Compound No.36) Mass (m/z): 436 (M++l),
Compound No.37: 6,7-dimethoxy-2-[4-(3-phenyl-l,2,4-oxadiazol-5-yl) piperidin-1-yl] quinazolin-4-amine, hygroscopic; and its hydrochloride sNt (Compound No.38) Mass (m/z): 433 (M++l),
Compound No.39: N-[l-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperidin-4-yl]-4-fluorobenzamide, hygroscopic; and its hydrochloride sNt (Compound No.40) Mass (m/z): 426
(M++l),
Compound No.41: N-[l-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperidin-4-yl] benzenesulfonamide, hygroscopic; and its hydrochloride sNt (Compound No.42) Mass (m/z): 444 (M++l),
Compound No.43: N-[l-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperidin-4-yl] acetamide, hygroscopic; and its hydrochloride sNt (Compound No.44) Mass (m/z): 346 (M++l),
Compound No.45: N-[ 1 -(4-amino-6,7-dimethoxyquinazolin-2-yl)piperidin-4-yl]benzamide, hygroscopic; and its hydrochloride sNt (Compound No.46) Mass (m/z): 408
(M++l),
Compound No.47: N[l-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperidin-4-yl]-3,4,5-trimethoxybenzamide, hygroscopic; and its hydrochloride sNt (Compound No.48) Mass (m/z): 498 (M++l),
Compound No.49: N-[l-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperidin-4-yl]thiophene-2-cNboxamide, hygroscopic; and its hydrochloride sNt (Compound No.50) Mass (m/z):414(M++l),
Compound No.51: N-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo [3.1.0]hex-6-yl]pentanamide, hygroscopic; and its hydrochloride sNt (Compound No.52) Mass (m/z): 386 (M++l),
Compound No.53: N-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo [3.1.0]hex-6-yl]hexanamide, hygroscopic; and its hydrochloride sNt (Compound No.54) Mass (m/z): 400 (M++l),
Compound No.55: N-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo [3.1.0]hex-6-yl]-3,4-dimethoxybenzamide, hygroscopic; and its hydrochloride sNt (Compound No.56) Mass (m/z): 466 (M++l),
Compound No.57: N-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo [3.1.0]hex-6-yl]-4-methoxybenzamide, hygroscopic; and its hydrochloride sNt (Compound No.58) Mass (m/z): 436 (M++l),
Compound No.59: N-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo[3.1.0]hex-6-yl]-2,2-diphenyl acetamide, hygroscopic; and its hydrochloride sNt (Compound No.60) Mass (m/z): 496 (M++l),
Compound No.61: 2-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-l-yl]-6,7-dimethoxyquinazolin-4-amine, hygroscopic; and its hydrochloride sNt (Compound No.62) Mass (m/z): 442 (M++l),
Compound No.63: 6,7-dimethoxy-A'2-{3-[4-(2-methoxyphenyl)piperazin-l-yl]propyl} quinazoline-2,4-diamine, hygroscopic; and its hydrochloride sNt (Compound No.64) Mass (m/z): 452 (M++l),
Compound No.65: N-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo[3.1.0]hex-6-yl]-3,3-diphenylpropanamide, hygroscopic; and its hydrochloride sNt (Compound No.66) Mass (m/z): 510 (M++l),
Compound No.67: l-[(4-amino-6,7-dimethoxyquinazolin-2-yl)(methyl)amino]-3-[4-(2-methoxyphenyl) piperazin-l-yl]propan-2-ol, hygroscopic; and its hydrochloride sNt (Compound No.68) Mass (m/z): 483 (M++l),
Compound No.69: N2-{3-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-l-yl]propyl}-6,7-dimethoxy-N2-methylquinazoline-2,4-diamine, hygroscopic; and its hydrochloride sNt (Compound No.70) Mass (m/z): 513 (M++l),
Compound No.71: N-{4-[(4-amino-6,7-dimethoxyquinazolin-2-yl)oxy]phenyl}benzamide, hygroscopic; and its hydrochloride sNt (Compound No.72) Mass (m/z):417(M++l),
Compound No.73: N-{4-[(4-amino-6,7-dimethoxyquinazolin-2-yl)oxy]phenyl}acetamide, hygroscopic; and its hydrochloride sNt (Compound No.74) Mass (m/z): 355 (M++l),
Compound No.75: N-{4-[(4-amino-6,7-dimethoxyquinazolin-2-yl)oxy]phenyl}morpholine-4-cNboxamide, hygroscopic; and its hydrochloride sNt (Compound No.76) Mass (m/z): 426 (M++l),
Compound No.77: N-{4-[(4-amino-6,7-dimethoxyquinazolin-2-yl)oxy]phenyl}-4-fluorobenzamide, hygroscopic; and its hydrochloride sNt (Compound No.78) Mass (m/z): 435 (M++l),
Compound No.79: N-{4-[(4-amino-6,7-dimethoxyquinazolin-2-yl)oxy]phenyl}-3,4,5-trimethoxybenzamide, hygroscopic; and its hydrochloride sNt (Compound No.80) Mass (m/z): 507 (M++l),
Compound No.81: N-{4-[(4-amino-6,7-dimethoxy quinazolin-2-yl)oxy]phenyl} benzenesulfonamide, hygroscopic; and its hydrochloride sNt (Compound No. 82) Mass (m/z): 453 (M++l),
Compound No.83: N-{4-[(4-amino-6,7-dimethoxyquinazolin-2-yl)oxy]phenyl}-3,4-dimethoxybenzamide, hygroscopic; and its hydrochloride sNt (Compound No.84) Mass (m/z): 477 (M++l),
Compound No.85:N-{4-[(4-amino-6,7-dimethoxyquinazolin-2-yl)oxy]phenyl}thiophene-2-cNboxamide, hygroscopic; and its hydrochloride sNt (Compound No.86) Mass (m/z): 423 (M++l),
Compound No.87: N-[l-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperidin-4-yl]-N-phenylbenzenesulfonamide, hygroscopic; and its hydrochloride sNt (Compound No.88) Mass (m/z): 520 (M++l),
Compound No.89: N-[l-(4-amino-6,7-dimethoxy quinazolin-2-yl)piperidin-4-yl]pyrazine-2-cNboxamide, hygroscopic; and its hydrochloride sNt (Compound No.90) Mass (m/z): 410 (M++l),
Compound No.91: N-[l-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperidin-4-yl]-2,3-dihydro-l,4-benzodioxine-2-cNboxamide, hygroscopic; and its hydrochloride sNt (Compound No.92) Mass (m/z): 466 (M++l),
Compound No.93: N-[l-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperidin-4-yl]isoxazole-5-cNboxamide, hygroscopic; and its hydrochloride sNt (Compound No.94) Mass (m/z): 399 (M++l),
Compound No.95:N-[l-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperidin-4-yl]-2-furamide, hygroscopic; and its hydrochloride sNt (Compound No.96) Mass (m/z): 398 (M++l),
Compound No.97: 4-methoxyphenyl [l-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperidin-4-yl]cNbamate, hygroscopic; and its hydrochloride sNt (Compound No.98) Mass (m/z): 454 (M++l),
Compound No.99: 3-(trifluoromethyl)phenyl [l-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperidin-4-yl]cNbamate, hygroscopic; and its hydrochloride sNt (Compound No. 100) Mass (m/z): 492 (M++l),
Compound No.101: 2-{4-[3-(4-fluorophenyl)-l,2,4-oxadiazol-5-yl]piperidin-l-yl}-6,7-dimethoxyquinazolin-4-amine, hygroscopic; and its hydrochloride sNt (Compound No. 102) Mass (m/z): 451 (M++l),
Compound No. 103: N-[l-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperidin-4-yl]-2,2-diphenylacetamide, hygroscopic; and its hydrochloride sNt (Compound No. 104) Mass (m/z): 498 (M++l),
Compound No. 105: N-[l-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperidin-4-yl]-3,4-dimethoxybenzamide, hygroscopic; and its hydrochloride sNt (Compound No. 106) Mass (m/z): 468 (M++l),
Compound No. 107: N-[l-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperidin-4-yl]-4-methoxybenzamide, hygroscopic; and its hydrochloride sNt (Compound No. 108) Mass (m/z): 438 (M++l),
Compound No. 109: N-[l-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperidin-4-yl]morpholine-4-cNboxamide, hygroscopic; and its hydrochloride sNt (Compound No.l 10) Mass (m/z): 417 (M++l),
Compound No.l 11: N[l-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperidin-4-yl]-3,3-diphenylpropanamide, hygroscopic; and its hydrochloride sNt (Compound No.l 12) Mass (m/z): 512 (M++l),
Compound No.l 13: N-[l-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperidin-4-yl]-2-ethoxybenzamide, hygroscopic; and its hydrochloride sNt (Compound No.l 14) Mass (m/z): 452 (M++l),
Compound No.l 15: N-[l-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperidin-4-yl] tetrahydrofuran-2-cNboxamide, hygroscopic; and its hydrochloride sNt (Compound No.l 16) Mass (m/z): 402 (M++l),
Compound No.l 17: N-[l-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperidin-4-yl]-2-(2-methoxyphenoxy)acetamide, hygroscopic; and its hydrochloride sNt (Compound No.l 18) Mass (m/z):468(M++l),
Compound No.l 19: N-[l-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperidin-4-yl]-4-(difluoromethoxy) benzamide, hygroscopic; and its hydrochloride sNt (Compound No. 120) Mass (m/z): 474 (M++l),
Compound No. 121: N-[l-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperidin-4-yl]-N'-(4-methoxyphenyl)urea, hygroscopic; and its hydrochloride sNt (Compound No. 122) Mass (m/z): 453 (M++l),
Compound No. 123: N4-[(4-amino-6,7-dimethoxyquinazolin-2-yl)oxy]phenyl}-.N'-phenylurea, hygroscopic; and its hydrochloride sNt (Compound No. 124) Mass (m/z): 432 (M++l),
Compound No. 125: 6,7-dimethoxy-2-{[ 1 -(phenylsulfonyl)piperidin-4-yl]oxy}quinazolin-4-amine, hygroscopic; and its hydrochloride sNt (Compound No. 126) Mass (m/z):445(M++l),
Compound No. 127: 2-[(l-benzoylpiperidin-4-yl)oxy]-6,7-dimethoxyquinazolin-4-amine, hygroscopic; and its hydrochloride sNt (Compound No. 128) Mass (m/z): 409 (M++l),
Compound No. 129: 6,7-dimethoxy-2-{[ 1 -(morpholin-4-ylcNbonyl)piperidin-4-yl]oxy} quinazolin-4-amine, hygroscopic; and its hydrochloride sNt (Compound No. 130) Mass (m/z): 418 (M++l),
Compound No. 131: 4-[(4-amino-6,7-dimethoxyquinazolin-2-yl)oxy]-N-phenylpiperidine-1-cNboxamide, hygroscopic; and its hydrochloride sNt (Compound No. 132) Mass (m/z): 425 (M++l),
Compound No. 133: N-{4-[(4-amino-6,7-dimethoxyquinazolin-2-yl)oxy]phenyl}-4-methoxybenzamide, hygroscopic; and its hydrochloride sNt (Compound No. 134) Mass (m/z): 447 (M++l),
Compound No. 135: N-{4-[(4-amino-6,7-dimethoxyquinazolin-2-yl)oxy]phenyl}-2,2-diphenylacetamide, hygroscopic; and its hydrochloride sNt (Compound No. 136) Mass (m/z): 507 (M++l),
Compound No. 137: 4-methylphenyl {4-[(4-amino-6,7-dimethoxyquinazolin-2-yl)oxy] phenyl}cNbamate, hygroscopic; and its hydrochloride sNt (Compound No.138) Mass (m/z): 447 (M++l),
Compound No. 139: 4-methoxyphenyl {4-[(4-amino-6,7-dimethoxyquinazolin-2-yl)oxy] phenyl}carbamate, hygroscopic; and its hydrochloride sNt (Compound No. 140) Mass (m/z): 463 (M++l),
Compound No. 141: N-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo[3.1.0]hex-6-yl]-2-methoxybenzamide, hygroscopic; and its hydrochloride sNt (Compound No. 142) Mass (m/z): 436 (M++l),
Compound No.143: N-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo[3.1.0]hex-6-yl]-3-methoxybenzamide, hygroscopic; and its hydrochloride sNt (Compound No. 144) Mass (m/z): 436 (M++l),
Compound No. 145: N-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo[3.1.0]hex-6-yl]morpholine-4-cNboxamide, hygroscopic; and its hydrochloride sNt (Compound No.146) Mass (m/z): 415 (M++l),
Compound No. 147: N-[8-(4-amino-6,7-dimethoxyquinazolin-2-yl)-8-azabicyclo[3.2.1]oct-3-yl]benzenesulfonamide, hygroscopic; and its hydrochloride sNt (Compound No. 148) Mass (m/z): 469 (M++l),
phNmaceuticNly acceptable sNts, phNmaceuticNly acceptable solvates, polymorphs, prodrugs, stereoisomers, tautomeric forms, N-oxides and metabolites thereof.
PhNmacologicN testing
Receptor Binding Assay: Receptor binding assays Ne performed using natNe cc-1 adrenoceptors. The Nfinity of different compounds for α12 and α1b adrenoceptor subtypes iss evNuated by studying their ability to displace specific [3H] prazosin binding from the membranes of rat submaxillNy and lNer respectNely (Michel et N, Br J PhNmacol, 98, 883-889 (1989)). The binding assays Ne performed according to U'PrichNd et N. (Eur J PhNmacol, 50:87-89 (1978) with minor modifications.
SubmaxillNy glands Ne isolated immediately Nter sacrifice. The lNer is perfused with buffer (Tris hydrochloric acid 50 mM, sodium chloride 100 mM, 10 mM ethylene diamine tetra acetic acid pH 7.4). The tissues Ne homogenized in 10 volumes of buffer (Tris HC1 50 mM, NaCl 100 mM, EDTA 10 mM, pH 7.4). The homogenate is filtered through two layers of wet guaze and filtrate is centrifuged at 500g for 10 min. The supernatant is subsequently centrifuged at 40, OOOg for 45 min. The pellet thus obtA1ned is resuspended in the same volume of assay buffer (Tris HC1 50 mM, EDTA 5 mM, pH 7.4) and Ne stored at -70 °C until the time of assay.
The membrane homogenates (150-250 jxg protein) Ne incubated in 250 u.1 of assay buffer (Tris HC1 50 mM, EDTA 5 mM, pH 7.4) at 24-25 °C for I hour. Non-specific binding is determined in the presence of 300 nM prazosin. The incubation is terminated by vaccum filtration over GF/B fibre filters. The filters Ne then washed with ice cold 50 mM Tris HC1 buffer (pH 7.4). The filtermats Ne dried and bounded radioactNity retA1ned on filters is counted. The IC50 and Kd Ne estimated by using the non-lineN curve-fitting program using G pad prism softwNe. The vNue of inhibition constant Ki is cNculated from competitNe binding studies by using Cheng and Prusoff equation (Cheng and Prusoff, Biochem PhNmacol, 1973, 22:3099-3108), Ki = IC50 /(1+L/Kd) where L is the concentration of [3H] prazosin used in the pNticulN experiment.
In vitro functionN studies
In vitro A1a Adrenoceptor selectNity: In order to study selectNity of action of the present compounds towNds different α1a adrenoreceptor subtypes, the ability of these compounds to antagonize A1a adrenoreceptor agonist induced contractile response of aorta (A1d), prostate (aja) and spleen ( au>) is studied. Aorta, prostate and spleen tissue Ne isolated from thipentane anaesthetized (« 300 mg/Kg) mNe wistN rats. Isolated tissues Ne mounted in organ bath contA1ning Krebs Henseleit buffer of the following composition (mM): sodium chloride (NaCl) 118; potassium chloride (KC1) 4.7; cNcium chloride (CaCL2e) 2.5; magnesium sulphate hepta hydrate (MgSo4. 7H2O) 1.2; sodium bicNbonate (NaHCO3) 25; potassium dihydrogen phosphate (KH2PO4) 1.2; glucose 11.1. Buffer is mA1ntA1ned at 37 °C and aerated with a mixture of 95% oxygen (O2) and 5% cNbon dioxide (CO2). A resting tension of 2 g (aorta and spleen) or 1 g (prostate) is applied to tissues. Contractile response is monitored using a force displacement transducer and recorded on chNt recorders. Tissues Ne Nlowed to equilibrate for 1 and 1/2 hour. At the end of equilibration period, concentration response curves to norepinephrine (aorta) and phenylepinephrine (spleen and prostate) Ne obtA1ned in the absence and presence of the tested compound (at concentration of 0.1, 1 and 10 (J.M).
Human Recombinant Assay
Receptor Binding Assay: Receptor binding assays were performed using recombinant cells expressing human Npha-la and Npha-lb adrenoceptors. The Nfinity of different compounds for α1a and α1b adrenoceptor subtypes was evNuated by studying their ability to displace specific [3H] prazosin binding from the membranes of recombinant clones expressing Npha-la and Npha-lb adrenoceptors. The binding assays were performed according to U'PrichNd et N, Eur J PhNmacol, 50:87-89 (1978) with minor modifications.
Human embryonic kidney (HEK) cells which had been stably transfected with human Npha-la and Npha-lb adrenoceptors were cultured in an atmosphere of 5 % CO2 at 37 °C in DMEM medium supplemented with 10%heat inactNated fetN cNf serum, 1 mM glutamine, 100 U/mL penicillin and 0.1 mg/mL streptomycin. Selection pressure was mA1ntA1ned by regulN addition of puromycin (3 ug/mL) to the culture medium.
The cells were homogenized in 5-10 volumes of buffer (Tris HC1 5 mM, EDTA 5 mM, pH 7.4) using a polytron homogenizer. The homogenate was centrifuged at 40,000 g for 20 min at 4 °C. The pellet thus obtA1ned was resuspended in assay buffer (Tris HC1 5 mM, EDTA 5 mM, pH 7.4) and were stored at -70 °C until the time of assay.
Competition radioligand binding to the cloned subtypes of a 1-adrenoceptors was performed using [3H] prazosin as the radioligand1. The membrane homogenates (5-10 \ig protein) were incubated in 250 µL of assay buffer (Tris HC1 50 mM, EDTA 5 mM, pH 7.4) at 24-25 °C for 1 hour. Non-specific binding was determined in the presence of 10 \iM terazosin. The incubation was terminated by vacuum filtration over GF/B fiber filters. The filters were then washed with ice-cold 50 mM Tris HC1 buffer (pH 7.4). The filter mats were dried and bounded radioactNity retA1ned on filters was counted. The IC50 and Kd were estimated by using the non-lineN curve-fitting program using Graph pad prism softwNe. The vNue of inhibition constant Ki was cNculated from competitNe binding studies by using Cheng and Prusoff equation (Cheng and Prusoff, Biochem PhNmacol, 22:3099-3108 (1973)), Ki = IC50 /(1+L/Kd) where L is the concentration of [3H] prazosin used in the pNticulN experiment.
Reference: Michel, M. C, Griibbel, B., Taguchi, K. et N: Drugs for treatment of benign prostatic hyperplasia: Nfinity compNison at cloned a 1-adrenoceptor subtypes and in human prostate. JAuton PhNmacol, 16:21 (1996).
The results of the human recombinant assays of the compounds disclosed herein Ne as follows:
a) The compounds disclosed herein exhibited α1a Ki (nM) vNues of between about 1.6
nM to about >2000 nM, between about 2.5 nM to about >200 nM, and even between
about 3.5 nM to about 121 nM
b) The compounds disclosed herein exhibited N Ki (nM) vNues of between about 0.7
nM to about >1000 nM, between about 1.6 nM to about >100 nM, and even between about 2.3 nM to about 44 nM.

WE CLAIM:
1. Compounds having the structure of Formula I,
I pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, prodrugs, stereoisomers, tautomeR1c forms, N-oxides and metabolites thereof, wherein:
R1 can be halogen, hydroxy, alkyl, alkoxy, cyano, nitro, amino, alkylamino or thio; n is an integer from 1 -4, each R1 can be same or different;
R' and R" independently can be hydrogen, alkyl, cycloalkyl, aryl, alkenyl or C(=V)R4 [wherein R4 can be hydrogen, OH, OR5, NR2R3, V can be O, S or NH]; R can be
(Formula Removed)

wherein,
A1-A4 and A8 independently in each occurrence are -CH-, -CH2-, -CR4R5-, N, NR5, O or S(0)o-2, A5-A7 independently in each occurrence are CR4 or N, T is no atom, -N-B1, O or S, Y is no atom, carbonyl, -(CH2)m-, aryl, heterocyclyl or cycloalkyl, R2 and R3 independently in each occurrence are hydrogen, C(=V)R4, alkyl, (CH2)m, SO2R5, aryl, heterocyclyl, cycloalkyl or R2 and R3 together with the nitrogen to which they are attached form
a 4-7 membered heterocyclyl which is optionally substituted with R, Mi and M2 independently
in each occurrence are R2, halogen, C(=V)NHR6;, CH2OCH2C(=V)R4, OCH2C(=V)R4,
CH2C(=V)R4, NHC(=V)NHR5, hydroxyl, amino, nitro, cyano, alkoxy, acyl or Mi and M2
together form a bR1dging group (C0-3), {[wherein (R4 is the same as defined above), (R5 is
hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, NHC(=V)R6, NR6SO2R6,
NHC(=V)CH2OR6, NHC(=V)0(CH2)o-iR6, C(=V)R6 or NHC(=V)(CH2)o.iCH(Ar)2), (V is the
same as defined above), (m is an integer of from 0-4), (Bj is hydrogen, alkyl or aryl), (each -CH2
in -(CH2)m- group is optionally substituted with one or more halogen, hydroxy, amino,
alkylamino, alkyl or aryl), (R6 is hydrogen, alkyl, heterocyclyl or aryl)]}.
2. A compound namely:
Ar-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo [3.1.0]hex-6-yl]acetamide and its hydrochloR1de salt,
l-(4-amino-6,7-dimethoxy quinazolin-2-yl)-4-(2-methoxyphenyl) pipeR1din-4-ol and its hydrochloR1de salt,
6,7-dimethoxy-2-[4-(2-methoxyphenyl)pipeR1din-l-yl]quinazolin-4-amine and its hydrochloR1de salt,
N-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo [3.1.0] hex-6-yl] tetrahydrofuran-2-carboxamide and its hydrochloR1de salt,
N-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo[3.1.0] hex-6-yl]benzamide and its hydrochloR1de salt,
N-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo[3.1.0] hex-6-yl] benzenesulfonamide and its hydrochloR1de salt,
N[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo[3.1.0] hex-6-yl] methanesulfonamide and its hydrochloR1de salt,
2-(6-amino-3-azabicyclo [3.1.0]hex-3-yl)-6,7-dimethoxyquinazolin-4-amine and its hydrochloR1de salt,
N-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo[3.1.0] hex-6-yl]-4-fluorobenzamide and its hydrochloR1de salt,
N-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo[3.1.0] hex-6-yl]thiophene-2-carboxamide and its hydrochloR1de salt,
N-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo[3.1.0] hex-6-yl]-2-(2-methoxy phenoxy)acetamide and its hydrochloR1de salt,
N-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo[3.1.0] hex-6-yl]-3,5-dimethyl benzamide and its hydrochloR1de salt,
N-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo[3.1.0] hex-6-yl]-3,4,5-tR1methoxy benzamide and its hydrochloR1de salt,
N-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo[3.1.0] hex-6-yl]-2-ethoxybenzamide and its hydrochloR1de salt,
N-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo[3.1.0] hex-6-yl]-4-nitrobenzamide and its hydrochloR1de salt,
N-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo [3.1.0] hex-6-yl]-4-(difluoromethyl)benzamide and its hydrochloR1de salt,
N-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo[3.1.0] hex-6-yl]-4-chlorobenzamide and its hydrochloR1de salt,
Benzyl [3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo[3.1.0] hex-6-yl]cNbamate and its hydrochloR1de salt,
6,7-dimethoxy-2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl) pipeR1din-1 -yl] quinazolin-4-amine and its hydrochloR1de salt,
N-[ 1 -(4-amino-6,7-dimethoxyquinazolin-2-yl)pipeR1din-4-yl]-4-fluorobenzamide and its hydrochloR1de salt,
N-[l-(4-amino-6,7-dimethoxyquinazolin-2-yl)pipeR1din-4-yl] benzenesulfonamide and its hydrochloR1de salt,
N-[l-(4-amino-6,7-dimethoxyquinazolin-2-yl)pipeR1din-4-yl] acetamide and its hydrochloR1de salt,
N-[l-(4-amino-6,7-dimethoxyquinazolin-2-yl)pipeR1din-4-yl]benzamideandits hydrochloR1de salt,
N-[l-(4-amino-6,7-dimethoxyquinazolin-2-yl)pipeR1din-4-yl]-3,4,5-tR1methoxybenzamide and its hydrochloR1de salt,
N-[l-(4-amino-6,7-dimethoxyquinazolin-2-yl)pipeR1din-4-yl]thiophene-2-cNboxamide and its hydrochloR1de salt,
N3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo [3.1.0]hex-6-yl] pentanamide and its hydrochloR1de salt,
N-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo [3.1.0]hex-6-yl] hexanamide and its hydrochloR1de salt,
N-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo [3.1.0]hex-6-yl]-3,4-dimethoxybenzamide and its hydrochloR1de salt,
N-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo [3.1.0]hex-6-yl]-4-methoxybenzamide and its hydrochloR1de salt,
N-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo[3.1.0]hex-6-yl]-2,2-diphenyl acetamide and its hydrochloR1de salt,
2-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-l-yl]-6,7-dimethoxyquinazolin-4-amine and its hydrochloR1de salt,
6,7-dimethoxy-AA-{3-[4-(2-methoxyphenyl)piperazin-l-yl]propyl}quinazoline-2,4-diamine and its hydrochloR1de salt,
N-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo[3.1.0]hex-6-yl]-3,3-diphenylpropanamide and its hydrochloR1de salt,
l-[(4-amino-6,7-dimethoxyquinazolin-2-yl)(methyl)amino]-3-[4-(2-methoxyphenyl) piperazin-l-yl]propan-2-ol and its hydrochloR1de salt,
N2-{3-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-l-yl]propyl}-6,7-dimethoxy-A/2-methylquinazoline-2,4-diamine and its hydrochloR1de salt,
N-{4-[(4-amino-6,7-dimethoxyquinazolin-2-yl)oxy]phenyl}benzamide and its hydrochloR1de salt,
N-{4-[(4-amino-6,7-dimethoxyquinazolin-2-yl)oxy]phenyl}acetamide and its hydrochloR1de salt,
N-{4-[(4-amino-6,7-dimethoxyquinazolin-2-yl)oxy]phenyl}morpholine-4-cNboxamide and its hydrochloR1de salt,
N-{4-[(4-amino-6,7-dimethoxyquinazolin-2-yl)oxy]phenyl}-4-fluorobenzamide and its hydrochloR1de salt,
N-{4-[(4-amino-6,7-dimethoxyquinazolin-2-yl)oxy]phenyl}-3,4,5-tR1methoxybenzamide and its hydrochloR1de salt,
N-{4-[(4-amino-6,7-dimethoxy quinazolin-2-yl)oxy]phenyl} benzenesulfonamide and its hydrochloR1de salt,
N-{4-[(4-amino-6,7-dimethoxyquinazolin-2-yl)oxy]phenyl}-3,4-dimethoxybenzamide and its hydrochloR1de salt,
N-{4-[(4-amino-6,7-dimethoxyquinazolin-2-yl)oxy]phenyl}thiophene-2-cNboxamide and its hydrochloR1de salt,
N-[l-(4-amino-6,7-dimethoxyquinazolin-2-yl)pipeR1din-4-yl]-A/-phenylbenzenesulfonamide and its hydrochloR1de salt,
N-[ 1 -(4-amino-6,7-dimethoxy quinazolin-2-yl)pipeR1din-4-yl]pyrazine-2-cNboxamide and its hydrochloR1de salt,
N-[l-(4-amino-6,7-dimethoxyquinazolin-2-yl)pipeR1din-4-yl]-2,3-dihydro-l,4-benzodioxine-2-cNboxamide and its hydrochloR1de salt,
N-[l-(4-amino-6,7-dimethoxyquinazolin-2-yl)pipeR1din-4-yl]isoxazole-5-cNboxamide and its hydrochloR1de salt,
N-[l -(4-amino-6,7-dimethoxyquinazolin-2-yl)pipeR1din-4-yl]-2-furamide and its hydrochloR1de salt,
4-methoxyphenyl [l-(4-amino-6,7-dimethoxyquinazolin-2-yl)pipeR1din-4-yl]cNbamate and its hydrochloR1de salt,
3-(tR1fluoromethyl)phenyl [ 1 -(4-amino-6,7-dimethoxyquinazolin-2-yl)pipeR1din-4-yl] cNbamate and its hydrochloR1de salt,
2-{4-[3-(4-fluorophenyl)-l,2,4-oxadiazol-5-yl]pipeR1din-l-yl}-6,7-dimethoxyquinazolin-4-amine and its hydrochloR1de salt,
N-[l-(4-amino-6,7-dimethoxyquinazolin-2-yl)pipeR1din-4-yl]-2,2-diphenylacetamide and its hydrochloR1de salt,
N-[l-(4-amino-6,7-dimethoxyquinazolin-2-yl)pipeR1din-4-yl]-3,4-dimethoxybenzamide and its hydrochloR1de salt,
N-[l-(4-amino-6,7-dimethoxyquinazolin-2-yl)pipeR1din-4-yl]-4-methoxybenzamideand its hydrochloR1de salt,
N-[l-(4-amino-6,7-dimethoxyquinazolin-2-yl)pipeR1din-4-yl]morpholine-4-cNboxamide and its hydrochloR1de salt,
N-[l-(4-amino-6,7-dimethoxyquinazolin-2-yl)pipeR1din-4-yl]-3,3-diphenylpropanamide and its hydrochloR1de salt,
N-[ 1 -(4-amino-6,7-dimethoxyquinazolin-2-yl)pipeR1din-4-yl]-2-ethoxybenzamideand its hydrochloR1de salt,
N-[l-(4-amino-6,7-dimethoxyquinazolin-2-yl)pipeR1din-4-yl]tetrahydrofuran-2-cNboxamide and its hydrochloR1de salt,
N-[l-(4-amino-6,7-dimethoxyquinazolin-2-yl)pipeR1din-4-yl]-2-(2-methoxyphenoxy) acetamide and its hydrochloR1de salt,
N-[l-(4-amino-6,7-dimethoxyquinazolin-2-yl)pipeR1din-4-yl]-4-(difluoromethoxy) benzamide and its hydrochloR1de salt,
N-[l-(4-amino-6,7-dimethoxyquinazolin-2-yl)pipeR1din-4-yl]-A''-(4-methoxyphenyl)urea and its hydrochloR1de salt,
N-{4-[(4-amino-6,7-dimethoxyquinazolin-2-yl)oxy]phenyl}-A''-phenylureaand its hydrochloR1de salt,
6,7-dimethoxy-2- {[ 1 -(phenylsulfonyl)pipeR1din-4-yl]oxy}quinazolin-4-amine and its hydrochloR1de salt,
2-[(l-benzoylpipeR1din-4-yl)oxy]-6,7-dimethoxyquinazolin-4-amine and its hydrochloR1de salt,
6,7-dimethoxy-2- {[ 1 -(morpholin-4-ylcNbonyl)pipeR1din-4-yl]oxy} quinazolin-4-amine and its hydrochloR1de sNt,
4-[(4-amino-6,7-dimethoxyquinazolin-2-yl)oxy]-A'-phenylpipeR1dine-1 -cNboxamide and its hydrochloR1de sNt,
N-{4-[(4-amino-6,7-dimethoxyquinazoHn-2-yl)oxy]phenyl}-4-methoxybenzamideand its hydrochloR1de sNt,
N{4-[(4-amino-6,7-dimethoxyquinazolin-2-yl)oxy]phenyl}-2,2-diphenylacetamideand its hydrochloR1de sNt,
4-methylphenyl {4-[(4-amino-6,7-dimethoxyquinazolin-2-yl)oxy]phenyl}cNbamate and its hydrochloR1de sNt,
4-methoxyphenyl {4-[(4-amino-6,7-dimethoxyquinazolin-2-yl)oxy]phenyl}cNbamate and its hydrochloR1de sNt,
N-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo[3.1.0]hex-6-yl]-2-methoxybenzamide and its hydrochloR1de sNt,
N-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo[3.1.0]hex-6-yl]-3-methoxybenzamide and its hydrochloR1de sNt,
N-[3-(4-amino-6,7-dimethoxyquinazolin-2-yl)-3-azabicyclo[3.1.0]hex-6-yl]morpholine-4-cNboxamide and its hydrochloR1de sNt,
N8(4-ammo-6,7