Title of Invention

ADENOSINE A2A RECEPTOR ANTAGONISTS

Abstract Compounds having the structural formula (I) or a pharmaceutically acceptable salt thereof, wherein R is optionally substituted phenyl, cycloalkenyl, or heteroaryl; X is alkylene or -C(O)CH¿2?-;Y is -N(R?2¿)CH¿2?CH¿2?N(R?3¿)-, -OCH¿2?CH¿2?N(R?2¿)-, -O-, -S-, -CH¿2?S-, -(CH¿2?)¿2?-NH-, or optionally substituted,(Ia), m and n are 2-3, and Q is nitrogen or optionally substituted carbon; and Z is optionally substituted phenyl, phenylalkyl or heteroaryl, diphenylmethyl, R?6¿-C(O)-, R?6¿-SO¿2?-, R?6¿-OC(O)-, R?7¿-N(R?8¿)-C(O)-, R?7¿-N(R?8¿)-C(S)-, phenyl-CH(OH)-, or phenyl-C(=NOR?2¿)-; or when Q is CH, (Ib),phenylamino or pyridylamino; or Z and Y together are substituted piperidinyl or substituted phenyl; and R?2¿, R?3¿, R?6¿, R?7¿, and R?8¿ are as defined in the specification are disclosed, their use in the treatment of Parkinson's disease, alone or in combination with other agents for treating Parkinson's disease, and pharmaceutical compositions comprising them; also disclosed are a processes for preparing intermediates useful for preparing compounds of formula (I).
Full Text

ADENOSINE A.^ RECEPTOR ANTAGONISTS
BACKGROUND
The present invention relates to substituted 5-amino-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine adenosine A^ receptor antagonists, the use of said compounds in the treatment of central nervous system diseases, in particular Parkinson's disease, and to pharmaceutical compositions comprising said compounds. The invention also relates to a process for preparing 5-amino-2-(substituted)pyrazolo[4,3-e]-1,2,4-triazolo-[1,5"C]pyrimidines, intermediates useful in preparing the claimed compounds.
Adenosine is known to be an endogenous modulator of a number of physiological functions. At the cardiovascular system level, adenosine is a strong vasodilator and a cardiac depressor. On the central nervous system, adenosine induces sedative, anxiolytic and antiepileptic effects. On the respiratory system, adenosine induces bronchoconstriction. At the kidney level, it exerts a biphasic action, inducing vasoconstriction at low concentrations and vasodilation at high doses. Adenosine acts as a lipless inhibitor on fat cells and as an antiaggregant on platelets.
Adenosine action is mediated by the interaction with different membrane specific receptors which belong to the family of receptors coupled with G proteins. Biochemical and pharmacological studies, together with advances in molecular biology, have allowed the identification of at least four subtypes of adenosine receptors: and A3 are high-affinity, inhibiting the activity of the enzyme Aden late cycles, and P and A are low-affinity, stimulating the activity of the same enzyme. Analogs of adenosine able to interact as antagonists with the A,, A23 , and A3 receptors have also been identified.
Selective antagonists for the A receptor are of phannacological interest because of their reduced level of side affects. In the central nervous system, A antagonists can have antidepressant properties and stimulate cognitive functions.

Moreover, data has shown that P receptors are present in high density in the basal ganglia, known to be important in the control of movement. Hence, A , antagonists can improve motor impairment due to neurodegenerative diseases such as Parkinson's disease, senile dementia as in Alzheimer's disease, and psychoses of organic origin.
Some xanthine-related compounds have been found to be A, receptor selective antagonists, and xanthine and non-xanthine compounds have been found to have high A affinity with varying degrees of A vs. A, selectivity. Triazole-pyrimidine adenosine A receptor antagonists with different substitution at the 7-position have been disclosed previously, for example in WO 95/01356; US 5,565,460; WO 97/05138; and WO 98/52568.





Another aspect of the invention is a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I in a pharmaceutically acceptable carrier.
Yet another aspect of the invention is a method of treating central nervous system diseases such as depression, cognitive diseases and neurodegenerative diseases such as Parkinson's disease, senile dementia or psychoses of organic origin, and stroke, comprising administering a compound of funnels I to a mammal in need of such treatment. In particular, the invention is drawn to the method of treating Parkinson's disease comprising administering a compound of funnels 1 to a mammal in need of such treatment.
Another aspect of the invention is a process for preparing 5-amino-2-(R-substituted)-pyrazolo[4,3-e]-1,2.4-tria2olo-[1,5-c]pyrimidines of fonnula 11, which are intermediates useful in the preparation of compounds of formula I. The process of preparing compounds of fonnula II


A preferred aspect of the process is the dehydrative rearrangement of the intermediate of formula IX to obtain the 5-amino-2"(R-substituted)-pyrazolo[4,3-e]" 1,2,4-triazolo[1,5-c]pyrimidine of formula II. Preferred embodiments of the process use 2-furoic hydrazide or 2-thienoylhydrazide in step 2, thus preparing compounds of formula II wherein R is 2-fury! or 2-thienyl.
Another aspect of the invention is a process for preparing 7-bromoalkyl-5-amino-2-(R-substituted)-pyrazolo[4,3-e]-1,2,4-triazolo-[1,5-c]pyrimidine of fonnula Ilia, which are intermediates useful in the preparation of compounds of formula I. The process of preparing compounds of fonnula Ilia


Still another aspect of the invention is a method of treating Parkinson's disease with a combination of a compound of formula I and one or more agents known to be useful in the treatment of Parkinson's disease, for example dopamine; a dopaminergic agonist; an inhibitor of monoamine oxidase, type B (MAO-B); a DOPA dicarboxylic inhibitor (DO); or a catechol-0-methyltransferase (COMT) inhibitor. Also claimed is a pharmaceutical composition comprising a compound of formula I and one or more agents known to be useful in the treatment of Parkinson's in a pharmaceutically acceptable carrier.
DETAILED DESCRIPTION
As used herein, the term alkyl Includes straight or branched chains. Alkylene, referring to a divalent alkyl group, similarly refers to straight or branched chains. Cycloalkylene refers to a divalent cycloalkyi group. Cycloalkenyl refers to a C^-Cg cycloalkyl ring comprising one double bond.

Heteroaryl means a single ring, bicyclic or benzofused heteroaromatic group of 5 to 10 atoms comprised of 2 to 9 carbon atoms and 1 to 4 heteroatoms independently selected from the group consisting of N, 0 and S, provided that the rings do not include adjacent oxygen and/or sulfur atoms. N-oxides of the ring nitrogens are also included. Examples of single-ring heteroaryl groups are pyridyl, oxazolyl, isoxazolyl, oxadiazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrazinyl, pyrimidyl, pyridazinyl and triazolyl. Examples of bicyclic heteroaryl groups are naphthyridyl (e.g., 1, 5 or 1,7), imidazopyridyl, pyrido[2,3]imidazolyl, pyridopyrimidinyl and 7-azaindoIyl. Examples of benzofused heteroaryl groups are indolyl, quinolyl, isoquinolyl, phthalazinyl, benzothieny! (i.e., thionaphthenyl), benzimidazoiyi, benzofuranyl, benzoxazolyl and benzofurazanyl. All positional isomers are contemplated, e.g., 2-pyridyl, 3-pyridyl and 4-pyridyl. R -substituted heteroaryl refers to such groups wherein substitutable ring carbon atoms have a substituent as defined above.
Certain compounds of the invention may exist in different stereoisomeric forms (e.g., enantiomers, di stereoisomers and atropisomers). The invention contemplates all such stereoisomers both in pure form and in mixture, including racemic mixtures.
Certain compounds will be acidic In nature, e.g. those compounds which possess a carboxyl or phenol hydroxyl group. These compounds may form pharmaceutically acceptable salts. Examples of such salts may include sodium, potassium, calcium, aluminum, gold and silver salts. Also contemplated are salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine and the like.
Certain basic compounds also form pharmaceutically acceptable salts, e.g., acid addition salts. For example, pyrido-nitrogen atoms may form salts with strong acid, while compounds having basic substituents such as amino groups also fonn salts with weaker acids. Examples of suitable acids for salt fonn ation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those skilled in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. The free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate. The free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the acid and base salts are equivalent to their respective free base forms for purposes of the invention.

All such acid and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.
Compounds of fonnula ! can be prepared by known methods from starting materials either known in the art or prepared by methods known in the art; see, for example, WO 95/01356 and J, Med. Chem.. 39 (1996) 1164-1171,
Preferably, the compounds of formula I are prepared by the methods shown in the following reaction schemes. In Scheme 1, alkylation of a 5-aminO"pyrazolo[4,3-e]-[1,2,4Hriazolo[l ,5-c]pyrimidine of fomnula II is used to prepare compounds of formula 1:

Starting materials of formula II can be reacted with an alky I diol ditosylate and a base such as NaH in an inert solvent such as dimethylformamide (DMF), or with a chloro-bromo- or dibromo-alkyl compound under similar conditions, to obtain the alkyl-substituted intermediate of formula III. The compound of formula III is then reacted with an amine of the formula Z-Y-H in an inert solvent such as DMF at an elevated temperature to obtain a compound of fonnula la, i.e., a compound of formula I wherein X is alkylene.
Alternatively, staring materials of formula it can be reacted with a compound of formula Z-Y-X-CI and a base such as NaH in an inert solvent such as DMF to obtain a mixture of a 7-substituted compound of formula I and the corresponding 8-substituted compound.
To prepare compounds of formula I wherein Y is piperazlnyl and Z is R®-C(0)-, R'-SO -, R'-OC(O)-, R'-N(R>C(0)- or R'-N(RVC(S)", a compound of fonnula I wherein Z-Y is 4-t-butoxycarbonyl-l-piperazinyl is deprotected, for example by reaction with an acid such as HCl. The resultant free piperazinyl compound, IV, is treated according to procedures well known in the art to obtain the desired compounds. The following Scheme 2 summarizes such procedures:


In this procedure, chloropyrazolo-pyrimidine V is reacted with a compound of formula Z-Y-X-CI in a manner similar to the alkylation procedure of Scheme 1, and the resultant intermediate is reacted with a hydrazide of formula H2N-NH-C(0)-R (or with hydrazine hydrate, followed by a compound of formula CI-C(O)-R). The resultant hydrazide undergoes dehydrative rearrangement, e.g., by treatment with N,0-bis-

{trimethylsilyl)acetamide (BSA) or a combination of BSA and hexamethyldisilazane (HMDS) and at elevated temperatures.
Starting materials are known or can be prepared by processes known in the art. However, compounds of formula II are preferably prepared by the novel process disclosed above and described in further detail here.
In the first step of the process, 2-amino-4,6-dihydroxypyrimidine (VI) is converted to the corresponding 4,6-dichloro-5-carboxaldehyde by treatment with POCI3 roscoe in DMF as described in Helv. Chim. Act. 69 (1986), 1602-1613. The reaction is carried out at an elevated temperature, preferably about 100°C, for 2 to 8 hours, preferably about 5 hours.
In the second step, 2-amino-4,6-dichloropyrimidine-5-carboxaldehyde (VII) is treated with a hydrazide of the formula H2N-NH-C(0)-R, wherein R is as defined above, to obtain the compound of formula VIII; the compound of formula VI and the hydrazide are used in a molar ratio of approximately 1:1, with a slight excess of the hydrazide being preferred. The reaction is carried out at room temperature or up to about 80°C in a solvent such as CH3CN or DMF. The reaction time is about 16 hours (e.g., overnight).
In the third step, the compound of formula Val is heated at 60-100°C with 1-5 equivalents of hydrazine hydrate In a solvent such as CH3CN or DMF for 1-24 hours to obtain the compound of formula IX.
In the last step, the compound of formula IX undergoes dehydrative rearrangement by treatment with a mixture of HMDS and BSA or with BSA alone. The reaction is carried out at elevated temperatures, preferably about 120°C, for about 16 hours (e.g., overnight)
After each step of the process, the crude material is purified by conventional methods, e.g., extraction and/or recrystallisation.
Compared to previously published methods for preparing the intermediate of formula II, this method proceeds in fewer steps, under milder reaction conditions and with much higher yield.
The compounds of fondles V and VII are known (Helve. Chim. Act. 69 (1986), 1602-1613).
Another method for preparing compounds of formula I is illustrated in the following Scheme 4.



Chloride Val is treated with a hydroxyalkyl-hydrazine in an inert solvent such as ethanol at temperatures from ambient to 100°C to furnish derivative X. This is subjected to dehydrative Cyclization, similarly to IX, such as with BSA, to provide tricyclic XI. Tricyclic XI is then converted to bromide Ilia with Prig at elevated temperature from 80°C to 150°C for 1 to 24 hours. Intermediate XI can also be converted into the consulate analogous to Ilia by toluenesulfonic chloride and base. Bromide Ilia is converted to compounds of formula I as described above for III.
Another method for preparing compounds of formula i is illustrated in the
following Scheme 5: Scheme 5:


In analogy to Scheme 1, chloride V is converted into alkylated compound Xli, and this is further reacted with carbonate XIV, where R' is preferably f-butyl or benzyl:. to obtain derivative XIII. A solvent such as DMF may be employed at a temperature of 60-120°C. This is then reacted as in Scheme 1 to furnish XV. The R' group is next removed, such as removal of a f-butyl group with HCI aorta, furnishing hydrazine XVI. Acylation of XVI furnishes XVII, which is subjected to dehydrative cyclization as described above to provide desired la. Alternatively, XII may be reacted with a hydrazide XVIll to obtain XIX, which can be converted to XVII analogously to preparation of XV.

Step 1: Stir POCb (84 ml, 0.9 mol) and chill to 5-10°C while adding DMF (17.8 ml, 0.23 mol) drop-wise. Allow the mixture to warm to room temperature (RT) and add 2-amino-4,6-dihydroxypyrimidine VI (14 g, 0.11 mol) portion-wise. Heat at 100°C for 5 h. Strip off excess POCI3 under vacuum, pour the residue into ice water, and stir overnight. Collect solids by filtration and recrystallize the dried material from a filtered ethyl acetate (EtOAc) solution to give the aldehyde, VII, m.p. 230° (deck). Mass spectrum: M+=192. PMR (DMSO): 5 8.6(6,2H); 5 10.1 (s,1H). Step 2: Stir a mixture of the product of Step 1 (0.38 g, 2 mmol) and 2-furoic hydrazide (0.31 g, 2.5 mmol) in CH3CN (50 ml) containing N,N-dfisopropylethylamine (0.44 ml, 2.5 mmol) overnight at RT. Solvent strip the reaction mixture, and partition the residue between EtOAc and water. Dry the organic layer over MgSO , remove the solvent, and recrystallize the residue from CH3CN to give the desired compound .. Vlii. Mass spectrum: MH+ = 282.

step 3: Add hydrazine hydrate (75 mg, 1.5 mmol) to a hot CH3CN solution of the product of Step 2 (0.14 g, 0.5 mmol). Reflux 1 h. Cool to RT and collect the yellow product IX. Mass spectrum: MH+ = 260.
Step 4: Heat the product of Step 3 (5.4g, 0.021 mol) in a mixture of hexamethyl-disilazine (100 ml) and N,0-bis(trimethylsilyl) acetamide (35 ml) at 120°C overnight. Remove volatiles under vacuum and slurry the residue in hot water to give a solid precipitate. Recrystallize from 80% aqueous acetic acid to give the title compound. M.P. >300°C. Massspectmm: MH+ = 242.

Combine the product of Preparation 1 (6.0 g, 25 mmol), ethylene glycol ditosylate (11.1 g, 30 mmol), and NaH (60% in oil, 1.19 g, 30 mmol) in dry DMF (30 ml). Stir under N2 for 24 h and filter to obtain the title compound as a cream solid (PMR in DMSO: 54.47+4.51 triplets, 8.03s). Isolate additional material by chromatography of the filtrate.

In a similar manner to Preparation 2, but using the product of Preparation 3, prepare the title compound as a yellow solid, PMR (DMSO) 5 4.49+4.54 triplets, 8.05s.



1 -(5-Ethyl-2-pyrimidinyl)pipera2ine is prepared from 2-chloro-5-ethyIpyrimidine. Heat the chloride (2.0 g, 14 mmol) and piperazine (3.0 g, 35 mmol) in EtOH (70 ml) -d 90° C for 2h in a sealed vessel. Concentrate and partition between CH2CI2 and 2N NaOH. Dry the organic with MQSOA and concentrate. Chromatograph the crude product on silica (CH2CI2-CH3OH) to obtain the piperazine as a yellow oil.
In a similar fashion, prepare the following piperazines from the appropriate
1-(4-Cyano-2-fluorophenyl)piperazine is prepared from 3,4-difluorobenzonitrile, Heat the nitrile (2.0 g, 14.4 mmol), piperazine (6.2 g, 72 mmol) and K2CO3 (2.4 g, 17 mmol) in toluene (10 ml) at reflux for 22h. Allow to cool, and extract with 1N HCI. Basify with NaOH to pH=10. Extract with CH2CI2 and wash with water and then brine. Dry the organic with MgS04 and concentrate to give the piperazine as a white solid.
In a similar fashion, prepare the following piperazines from the appropriate

1-(4-(2-Methoxyethoxy)phenyl)pipera2ine is prepared from 4-(4-hydroxy-phenyl)-1-acetylplperazine. To NaH (60% in mineral oil, 0.79 g, 20 mmol) in DMF (25 ml) add the phenol (3.0 g, 13.6 mmol), followed by 2-bromoethyl methyl ether (2.27 g, 16.3 mmol). Stir at RT 18h, concentrate, and partition between EtOAc and 5% citric acid. Wash the organic with 1N NaOH, then brine. Dry over MgS04, and concentrate to obtain the alkylated product as a white solid. Heat this material (2.2 g, 7.9 mmol) in 6N HCI (30 ml) at reflux for 1 h. Allow to cool and basify to pH=10 with NaOH.

Extract with CH2CI2 and wash with water and then brine. Dry the organic with MgS04 and concentrate to give the piperazine as a yellow oil.
In a similar fashion (except basic hydrolysis is employed for the cyclopropyl-methyl ether) prepare the following pioerazines:
4-(2-Methylaminoethoxy)fluorobenzene is prepared from 4-(2-bromo-ethoxy)-fluorobenzene. Combine the bromide (1.0 g, 4.6 mmol) in CH3OH (5 ml) with CH3NH2 in CH3OH (2M, 46 ml, 92 mmol) in a sealed vessel. Heat at C for 18h, concentrate, and partition between EtOAc and sat. NaHCOs. Wash the organic with brine, dry with MgS04, and concentrate to obtain the amine as a yellow oil.
N-methyl-2-(4-(2-methoxyethoxy)phenoxy)ethylamine was prepared in two steps. Combine 4-(2-methoxyethoxy)phenol (1.68 g, 10.0 mmol), 1,2-dibromoethane (16.9 g, 90 mmol), and K2CO3 (2.76 g, 20 mmol) in CH3CN (20 ml) and DMF (10 ml). Heat at reflux 22 h, allow to cool, filter, and partition between ether (Et20) and 1N NaOH, Wash with brine, dry over MgS04, and concentrate to provide the bromoethyl ether as beige solid. Combine this (0.97 g, 3.5 mmol) with 2M CH3NH2/CH3OH (35 ml). Heat in a sealed tube (65°C, 18 h), concentrate, and partition between Et20 and 1N NaHCOs. Wash with brine, dry MgS04, and concentrate to provide the amine as an orange oil.
1 -Phenyl-2-piperazinone is prepared from 4-benzyloxycarbonyl-1 -phenyl-2-piperazinone. Combine this material (1.61 g, 5.2 mmol) with 10%Pd/C (0.4 g) in Eton (50 ml) and 1N HCI (6 ml). Hydrogenate at 45 psi for 2h and filter. Concentrate and chromatograph the residue on silica (eluting with CH2Cl2:CH30H:NH40H) to obtain the piperazine as a cream solid.


Step 1: Dissolve the product of Preparation 1, Step 2 (0.56 g, 2.0 mmol) in hot
CH3CN (200 ml). Add 2-hydroxyethylhydrazine (0.51 g, 6.0 mmol). Heat at reflux 2 h
and concentrate. Treat with 25 ml water and stir to give a solid. Collect and dry to
give the alcohol, MS: m/e= 304 (M+1).
Step 2: Heat the product of Step 1 (0.10 g, 0.33 mmol) in BSA (10 ml) for 4 h at
115°C. Concentrate in vacuo and warm with aqueous CH3OH. Collect and dry to
give the cyclization product, MS: m/e = 286 (M+1).
Step 3: Combine the product of Step 2 (0.285 g, 1.0 mmol) and PUT (2.0 ml, 21
mmol). Heat at 145°C for 2 h, cool, and pour onto ice. Filter and dry the solid,
Recrystallize from CH3OH to obtain the title compound, MS: m/e= 348+350 (M+1).

Combine 5-bromo-2-furoic acid (0.50 g, 2.6 mmol) and NaHCOa (0.44 g, 5.2 mmol) in hexane (6 ml) and water (5.2 ml). Add Selectfluor® (0.98 g, 2.8 mmol) and stir 2 h. Separate the hexane layer and dry over MgS04 to provide a solution of 2-bromo-5-fIuorofuran. Dilute with THF (6 ml) and cool to -TS^C. Add 2.5M n-Bali/ hexane (4.2 ml, 11 mmol). Stir 10 min., add excess dry ice, and stir 1 h additional. Treat with 1N HCI, extract with Chicly, and dry over MgS04. Concentrate and dry to obtain the title compound as a white solid, PMR (CDCI3) 56.70 + 7.28.


Combine the tessellate of Preparation 2 (0.55 g, 1.25 mmol) and 1-(2,4" difluorophenyOpiperazine (0.50 g, 2.5 mmol) in DMF (7 ml) and heat at 80°C for 20h. Concentrate and purify by flash column chromatography (CH2CI2, CH3OH+NH3) to obtain the title compound as a cream solid, mass spectrum m/e = 466 (M+H).
In similar fashion, prepare the following compounds:





















Combine the product of Preparation 1 (0.60g, 2.5mmol), 1,3-dibromopropane (0.60 g, 3.0 mmol), and NaH (60% in oil, 0.119 g, 3.0 mom!) in dry DMF (9 mi). Stir under Na for 2 h, concentrate and flasii chromatographic to obtain the title compound as a solid (PMR in CDCI3+CD3OD: 52.43 quint., 3.38+4.51 triplets, 8.09s), as well as 8-substituted isomer. Step 2:
Combine the product of Step 1 (0.050 g, 0.14 mmol) and 1-phenylpiperazine (0.045 g, 0.28 mmol) in DMF (2 m!) and heat at 80°C for 4h. Concentrate and purify by flash column chromatography (CH2CI2, CH3OH+NH3) to obtain the title compound as a cream solid, mass spectrum m/e = 443 (M+H).
Similarly prepare the following compounds:
Example 3 The compound of Example 1-2 was also prepared by the following procedure: Combine the product of Preparation 1 (0.15 g, 0.62 mmol), 1-phenyl-4-(2-chloroethyl)piperazine (0.17 g, 0.75 mmol), and NaH (60% in oil, 0.035 g, 0.87 mmol) in dry DMF (7 ml). Stir under N2 for 48 h, add additional chloride (0.03 g) and NaH (0.005 g) and stir another 72 h. Concentrate and purify by flash column chromatography (CH2CI2, CH3OH+NH3) to obtain the title compound as a cream solid, mass spectrum m/e = 429 (M+H).
The compound of Example 1-3 is similarly prepared, as are the following compounds:

























































Compounds having the structural formula

R' is 1 to 3 substituents independently selected from hydrogen, -alkyl, . Halogen, -NO1, - alkoxy. Alkyllithium, alkylsulfinyl, and -C. alkylsulfonyl;
R1 and R2are independently selected from the group consisting of hydrogen
Alkyl;







comprising
(1) treating 2-amino-4,6-dihydroxypyrimidine

with POCI3 in dimethylformamide to obtain 2-amino-4,6-dichloropyrimidine-5-carboxaldehyde

(2) treating carboxaldehyde VII with a hydrazide of the formula
H2N-NH-C(0)-R, wherein R is as defined above, to obtain

(3) treating the intermediate of formula Villa with hydrazine hydrate to form a
pyrazol ring, thus obtaining the intermediate of formula IX

(4) forming the desired compound of formula II by dehydrative rearrangement.
12. A process for preparing a compound of the formula II

wherein R is R -furan, R'-thienyl, R -pyridyl, R -pyridyl N-oxide, R -oxazolyl, R °-phenyl, R -pyrrolyl or cycloalkenyl; and
R is 1 to 3 substituents independently selected from hydrogen, -alkyl, "CF3, halogen, -NO , -NR 'R', alkoxy, alkyllithium, alkylsulfinyl. and alkylsulfonyl;
R is 1 to 5 substituents independently selected from the group consisting of hydrogen, halogen, C,-Cg alkyl, hydroxy, alkoxy, -CN, -NH2, alkylamino, di-((Cry,)alkyI)amino, -CF3, -OCF3 and -S(Outcries)alkyI;
R'is H or C,-CAE alkyl; and
R' is alkyI-C(0)- or (C,-C,)alkyl-S02-;

comprising converting a compound of formula IX

into the desired compound of formula 11 by dehydrative rearrangement. 13. A process for preparing a compound of formula cilia
kill

wherein R is R -furan, R -thienyl, R -pyridyl, R'-pyridyl N-oxide, R'-oxazolyl, R' phenyl, R -pyrrolyl or cycloalkenyl; and
R' is 1 to 3 substituents independently selected from hydrogen, -alkyi, -CF3, halogen, -NO2, -NR 'R', alkoxy, alkyllithium, aikylsulfinyl, and alkylsulfonyl;
R is 1 to 5 substituents independently selected from the group consisting of hydrogen, halogen, alkyl, hydroxy, alkoxy, -CN, -NH2, C,-Csalkylamino, di-((C,-C5)alkyl)amino, -CF3, -OCF3 and -S(0) 2(C1-C6)alkyl;
R^' is H or alkyl; and
R^' is (C,-C5)alkyl-C(0)- or (C,-C5)alkyl-S02-; comprising
(1) treating a chloride of formula Val

with a hydroxyalkyl hydrazine of the formulae HO"(CH2)rNHNH2, wherein r is 2-6, to obtain

(2) cyclizing the Intermediate of formula X by dehydrative rearrangement to •
obtain the tricyclic intermediate of formula XI


(3) converting the hydroxy compound of formula XI to the bromide of formula Iliad.
14. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 in combination with 1 to 3 other agents useful in the treatment of Parkinson's disease in a pharmaceutically acceptable carrier.
15. The use of a compound of claim 1 in combination with 1 to 3 other agents useful in the treatment of Parkinson's disease for the preparation of a medicament for treating Parkinson's disease.

16. A pharmaceutical composition substantially as herein described and exemplified.
17. A compounds having the structural formula substantially as herein described and
exemplified.


Documents:

in-pct-2002-1932-che-abstract.pdf

in-pct-2002-1932-che-assignement.pdf

in-pct-2002-1932-che-claims filed.pdf

in-pct-2002-1932-che-claims grand.pdf

in-pct-2002-1932-che-correspondnece-others.pdf

in-pct-2002-1932-che-correspondnece-po.pdf

in-pct-2002-1932-che-description(complete) filed.pdf

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in-pct-2002-1932-che-form 1.pdf

in-pct-2002-1932-che-form 19.pdf

in-pct-2002-1932-che-form 26.pdf

in-pct-2002-1932-che-form 3.pdf

in-pct-2002-1932-che-form 4.pdf

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in-pct-2002-1932-che-other documents.pdf

in-pct-2002-1932-che-pct.pdf

in-pct-2002-1932-che-priority documents.pdf


Patent Number 208630
Indian Patent Application Number IN/PCT/2002/1932/CHE
PG Journal Number 35/2007
Publication Date 31-Aug-2007
Grant Date 06-Aug-2007
Date of Filing 25-Nov-2002
Name of Patentee M/S. SCHERING CORPORATION
Applicant Address 2000 Galloping Hill Road Kenilworth, NJ 07033-0530
Inventors:
# Inventor's Name Inventor's Address
1 NEUSTADT, Bernard, R 24 Brook Place West Orange, NJ 07052
PCT International Classification Number C07D 487/14
PCT International Application Number PCT/US2001/016954
PCT International Filing date 2001-05-24
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/207,143 2000-05-26 U.S.A.