JPS61225184A - Novel compound, manufacture and medicinal composition - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a pyrazolopyridine having useful pharmacological activity, a process for its preparation, and its use as a pharmaceutical.

[Conventional technology]

European Patent Publication No. 119774 discloses a group of described pyrazolopyridine derivatives with potential use as anti-inflammatory agents.

[Summary of the invention]

A structurally distinct group of pyrazolopyridine derivatives has been found whose compounds have anti-inflammatory (including anti-rheumatic) and/or anti-allergic activity.

Therefore, the present invention provides the formula (1) [wherein X is NR (wherein R is hydrogen m C, ~6 alkyl or as defined below for R3); oxygen;
Sulfur; SO: or SO2; R2 is hydrogen or C
1-6 alkyl: and R2 is CN, CR,
5R6Y (wherein R5 and R6 are independently hydrogen and C
selected from 1 to 4 alkyl and Y is hydrogen, OR, or SR, where R7 is hydrogen, CI to 4 alkyl, or C1
~4 alkanoyl) and NR8R,9 (wherein R8
and R9 are independently hydrogen h CI~4alkyl, C2~
4 alkenyl or C2-4 alkanoyl or - taken together with 04-6 polymethylene), or ■R3° (wherein RIG is 01-4 alkyl), where R when Y is other than hydrogen; or R2 is hydrogen, 01-6 alkyl, or halogen;
CF3, phenyl optionally substituted by C1-4 alkoxy or C1-4 alkyl and R
, is the CN defined for R2 above.

CR5R,Y or COR+o: or R, and R2 together form a C3-C6 polymethylene optionally substituted by C1-04 alkyl; R3 is either hydroxy, 01-4 alkoxy,
Thiol, 01-4 alkylthio or NRII T1.
+*(In the formula, R11 and R12 are independently hydrogen a C1~
C! optionally substituted by 6 alkyl or 02-7 alkanoyl or - taken together are 03-6 polymethylene)! ~ ] 0 alkyl or 03-1o cycloalkyl; or C2-1o alkenyl; or 1
or two halogens, CF3. C, ~4 alkoxy,
C] ~4 alkyl, hydroxy, nitro, cyano, c2
~10 acyloxy, Ivl, 3R,,4 (in the formula R13
and R14 are independently hydrogen, C1-6 alkyl, C2-
7 alkanoyl or C1-6 alkylsulfonyl cara) or C0T (,, (wherein R, +5 is hydroxy).

C3-6 alkoxy): or NR, +e R, +7C where R76 and R, +7 are independently selected from hydrogen or 01-6 alkyl) ka: or together with R 0
4-6boJrimethylene; and R4 is hydrogen: or C]~4alkyl or one or two halogens, CF3. benzyl (optionally substituted on the phenyl ring by C1-4 alkoxy or C]-4 alkyl) and nitrogen atoms 1 or 2
and pharmaceutically acceptable salts and solvates thereof.

Suitable groups for X include those in which R in NR is hydrogen, methyl, ethyl, n-
and isopropyl, hydrogen and oxygen or sulfur. The favorite character is X is NH.

Suitable groups for R, /R2 are hydrogen, methyl, ethyl, n- and iso-propyl, optionally N-substituted aminomethyl and acetamidomethyl and acetyl or - taken together to form 09 or C4 polymethylene. Including those who do.

Suitable groups for T(, + are methyl, ethyl, n- and iso-propyl, n-, iso-1 secondary- and tertiary-butyl, n-pentyl (CT712)n CH3 (where n is 4- 7) or cyclohexyl (these groups are methyl, ethyl and/or hydroxy, methoxy).

n- or iso-propoxy, thiol, methylthio, or by amino optionally substituted by one or two methyl or acetyl groups or by C4 or C, polymethylene): vinyl , prop-1-enyl, prop-2-enyl, ■-methylvinyl, boudo-1-enyl, boudo-2-enyl, boudo-3
- Enil.

■-methylenepropyl, nimethylprop-1-enyl and l-methylprop-2-enyl, in their E and Z forms when stereoisomerism exists; or one or two chlorine, bromine, methoxy, ethoxy, n- and iso-propoxy, methyl, ethyl, n- and iso-propyl,
n-, iso-1 secondary- and tertiary-butyl, hydroxy,
Nitro, cyano, acetoxy, propionyloxy, benzyloxy, or NH+4"RI4"C R1 in the formula
3" and RI41 independently represent water volume, methyl, ethyl, n
- and iso-propyl, acetyl, propionyl, methylsulfonyl and ethylsulfonyl): C0RI
! ! ” (wherein R351 is hydroxy, methoxy, ethoxy): or NR+a” Rtt” (wherein R,,1 and R47” are independently hydrogen, methyl, n-
and iso-propyl). Particularly suitable groups for R3 are n-butyl, n-pentyl, allyl or prop-2-enyl, 2-methylallyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 3 - diethylaminopropyl, phenyl and phenyl substituted in the 3- or 4-position by one hydroxy, nitro, cyano, carboxy, t-butyl and ethoxycarbonyl. Preferred groups for R3 include n-butyl, prop-2-enyl and 2-hydroxyethyl, 3-dimethylaminopropyl and 3-diethylaminopropyl.

Suitable groups for R4 include hydrogen, methyl, ethyl, n- and iso-propyl and benzyl. More suitably R4 is hydrogen or 2-methyl. Preferably R4 is hydrogen.

It will be appreciated that when R4 is hydrogen, compounds of formula (1) exist as tautomers, ie the R4 hydrogen is unstable. Compounds in which R4 is hydrogen are expressed as (Ila) and (
Ilb).

(Ila') (Ilb)
Compounds of formula (1) can be added with acids such as conventional pharmaceutically acceptable acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, acetic acid, fumaric acid, salicylic acid, citric acid, lactic acid, mandelic acid, tartaric acid and methanesulfonic acid. Vine that forms salt. Such compounds form part of the invention as well as solvates such as hydrates of the compound of formula CI) or a salt thereof.

R] is hydrogen or C]~6 alkyl; and R2
is CN, CRsR,aY' (where Y' is OR7
, SR7 or NR8R, or C0RIo): or R2 is as defined for R1 or has the formula (
is optionally substituted phenyl as defined in 1): and R1 is CN, CR11R6Y or Co
R, , and Y, R5・R6・R7・R8・
There are some compounds within formula (I) in which R9.R, IO and the remaining substituents are as defined in formula (1).

RI is hydrogen, R2 is CN, C0RI. or CR11R6Y' or R5 is CN, CO
R+o or CR5R4Y where R2 is hydrogen and the remaining substituents are 1 as defined in formula (1)
There are other groups of compounds within formula (I).

When R4 is other than hydrogen it is preferably bonded to nitrogen atom 2.

Formula (Ift) (In the formula, R11 is CN, ■RIG or CR,, R6Y'
Yes.

There is a preferred group of compounds within formula (1) where R' is hydrogen or methyl, R41 is hydrogen or 2-methyl and R3 is as defined in formula (1).

R4'aR'% Appropriate and preferred groups for R41 and R3 are as described for the related substituents in formula (1).

Another subgroup of compounds within formula (III) are those of formula (IV)c in which RIg is hydrogen, chlorine, bromine, methoxy, ethoxy, hydroxy, cyano, carboxyl, ethoxycarbonyl, nitro or t-butyl. There are compounds.

Preferably when RI8 is other than hydrogen it is 3- or 4-
The moiety is also preferably bonded in the 4-position.

A preferred subgroup of compounds within formula (I[l) is formula (V) (
In the formula 1 (31 is n-butyl, iso-butyl, allyl.

2-hydroxyethyl, 3-dimethylaminopropyl or 3-diethylaminopropyl, and R, 1 and R41 are as defined in formula (III).

Suitable and preferred groups of substituents are as described for the relevant substituents for formula (1).

Other groups of compounds within formula (1) are represented by formula (Vl) (wherein R21
is CN%ctt as specified! iRe Y' or COR, , and the remaining substituents are of formula (III)
It is a compound with a general υ defined by .

Suitable and preferred groups for T(2'', R', R,3 and R41 are as described for the relevant substituents in formula (1).

A preferred subgroup of compounds within formula (Vl) is formula (■) 1 (
Nrl, 31 (wherein R31 and R41 are as defined in formula (V), and R21 is as defined in formula (■)).

Suitable and convenient groups of substituents are as described for the relevant substituents in formula (1).

Compounds of other subgroups within formula (1) are represented by formula [■] (wherein XI
is oxygen or sulfur and R, 1''& R3 and 1 (41 is as defined in subsection I).

Suitable and preferred groups for Xi, R, 1* R3 and R41 are as described for the relevant groups in formula (1).

Other groups of compounds within formula (1) are represented by formula (IX) (wherein n is 3
~8, R19 is hydrogen or C1-C4 alkyl, and X, R, and R4 are as defined in formula (1).

A preferred subgroup of compounds within formula (X) are compounds of formula (X)C in which 31 and R41 are as defined for formula (V) and m is 1 or 2.

Regarding the substituents of formulas (IX) and (X) -JmW and preferred groups are as described for formula (1).

The present invention is based on the following formula: is R4 defined in formula (1) or an atom or group convertible thereto) and a compound of formula (Xll) T(X2R,3' (X[l) (wherein X2 is defined in formula (1) NR, oxygen or sulfur and R3' is R3 or a group or atom convertible thereto) and then optionally and optionally convert to R1, R2' to L, R
A compound of formula (1) or a pharmaceutically acceptable salt thereof, consisting of converting 3' to R3 and/or R4' to R4 and/or forming a pharmaceutically acceptable salt or solvate thereof; A method of making a solvate is provided.

It will be understood that one compound of formula (1) may be converted to another compound of formula (1) by interconversion of appropriate substituents. Compounds of formula (1) are therefore useful intermediates for forming other compounds of the invention. Salts or solvates of compounds of formula CI) which are not pharmaceutically acceptable are therefore pharmaceutically acceptable salts. or may be useful as an intermediate in the preparation of solvates. Such salts or solvates therefore also form part of the invention.

Suitable leaving groups Q include halogens such as chlorine and bromine, preferably chlorine.

The reaction is carried out using an excess of reagent (aniline when X is NR) as a solvent or at elevated temperatures in an inert solvent such as toluene, ethanol, dimethylformamide, dimethyl sulfoxide, dioxane or water as conventionally used for nucleophilic aromatic displacements. It will be carried out under the following conditions. The reaction is preferably if H
If X, T(,' have low boiling points, they will occur in a sealed tube.

When X2 is oxygen or sulfur, the reaction can be carried out in the presence of a base such as sodium hydride, potassium, t-butoxide or sodium t-butoxide.

Compounds of formula (1) in which X is SO or SO2 can be prepared by conventional oxidation methods such as using sodium periodate or by 1 equivalent of m-chloroperbenzoic acid (compounds of formula (1) in which X is SO). or 2 equivalents of m-chloroperbenzoic acid (forming the compound of formula (1) where X is SO2) from the corresponding compound where X is S.

Conversion of the R hydrogen of X to an RC, ~6 alkyl group may be accomplished by conventional amine alkylation or acylation (eg, formylation) followed by reduction.

Conversion of R,'/R,,' to R,/FL, may be accomplished by conventional functional group interchange. Therefore, for example;
(1) The CN group will preferably be provided by dehydration of the amide group with phosphorus pentoxide.

(11) The hydroxymethyl group is preferably a metal hydride such as: [, iA/! This would result from reduction of the alkoxycarbonyl group with H4. In this case, pyrazole N
-H needs to be protected.

(111)Alkanoyl groups may be provided by reaction of the CN group with organometallic reagents such as Grignard reagents.

(1) Secondary alcohol groups may be provided by reduction of alkanoyl groups, preferably with metal hydrides.

(V) Tertiary alcohol groups may be provided by reaction of an organometallic reagent such as a Grignard reagent with an alkanoyl group.

The (Vl)-grade aminomethyl group will preferably be provided by metal hydride or by reduction of the CN group using PtO2/HCg-R2.

The (V++)aminomethyl group will preferably be provided by reduction of the corresponding amide with a metal hydride.

(vIID alkanoyloxyalkyl groups will preferably be provided by acylation of the corresponding alcohol with a suitable acid anhydride in trifluoroacetic acid at elevated temperature.

The (1×)alkanoylaminoalkyl group will preferably be provided by acylation of the corresponding aminoalkyl group using a suitable acid anhydride under mild conditions.

(x) The methyl group, especially at position 6, will preferably be provided by reduction of the alkoxycarbonyl group with lithium aluminum hydride.

(XD Aminoalkyl groups may be generated by converting the hydroxy of the corresponding alcohol to a leaving group and reacting with a suitable amine nucleophile.

(xii) The aminoalkyl group of Wenmu Ct ((Rs ) NRs Re is preferably reduced by reaction with a suitable amine and the corresponding keto group COT'L, by hydrogenation or by reaction with an amine and sodium cyanoborohydride. may be brought about by amination.

The (X++1)alkoxyalkyl group will preferably be provided by alkylation of the corresponding alcohol by reaction of the alcohol's sodium salt with a suitable alkyl iodide.

(X+V')alkylthioalkyl groups may be provided by reaction of the corresponding derivatized hydroxyalkyl or haloalkyl group with an appropriate alkylthiol.

When R1' or R2' is methyl it can be converted to Co, T by conventional oxidation with an oxidizing agent such as potassium permanganate.
- It will be converted to one unit. This transformation is preferably carried out, however, on the intermediate of formula (XI) or at an early stage.

The CO,H group of I(,/or l(2/) may be converted to an alkoxycarbonyl group by conventional esterification or to an amide group in the presence of condensation and a dehydrating agent such as dicyclohexylcarbodiimide.

When the R, z or R21 group is an amide it will be converted to an ester group by conventional hydrolysis/esterification in ethanolic HCe. When H, + or R2' is an ester group, the reaction of a compound of formula (Xll) with a compound of formula (XI) will also replace the ester to give an amide.

Transformations of R3 phenyl substituents are generally well known in the art of aromatic chemistry. An example of this conversion is as follows.

(a) Hydroxy groups may be converted to acyloxy by conventional acylation methods using acid anhydrides in trifluoroacetic acid, preferably at elevated temperatures.

The cyano group may be converted to carboxy by base-catalyzed hydrolysis, preferably with sodium hydroxide in ethanol followed by acid neutralization.

(C) An alkoxycarbonyl group may be converted to C0NT(,+sR+s) by heating with a suitable amine.

(dl The nitro group will be converted to an amine group by reduction, preferably by catalytic reduction with palladium on charcoal.

(e) Amino groups may be converted to alkylamino or acylamino groups by conventional amine acylation or alkylation. Acylation is preferably carried out using an acid anhydride and alkylation is carried out using an alkyl halogenide.

(f) Amino groups will preferably be converted to alkylsulfonylamino groups by reaction with a suitable alkylsulfonyl chloride using an acid acceptor such as triethylamine in an inert solvent such as dichloromethane.

R4 hydrogen atom is converted into R4C1 by conventional alkylation)
6 will be converted to an alkyl group.

It will be understood that these transformations may occur in any desired or necessary order. In particular, transformations involving amine substitutions also include R4
The hydrogen is replaced and it will therefore need to be protected using an amine protecting group such as para-methoxypendinoyl, which is then removed by heating in the presence of an acid such as trifluoroacetic acid. Pharmaceutically acceptable salts of compounds of ) may be conventionally formed by reaction with a suitable acid and solvates by crystallization from a suitable solvent.

The compounds of formula (XI) are known compounds or can be prepared by analogy with methods for preparing structurally similar compounds.

For example, a compound of formula (XI) where Q is chlorine is a compound of formula (Xll
l) It may be prepared by chlorination of phosphorus oxychloride of the compound T4.

A compound of formula (Xlll) in which R4 is hydrogen is a compound of formula (Xlll) where R4 is hydrogen.
It will be appreciated that a) exists in the major tautomeric form.

Compounds of formula (XII[) can be obtained from [J, Chem, Soc, Perkin trans.
'I'rans,) Jl, 1976(5), 507
or by a similar method.

In another aspect, the invention provides a pharmaceutical composition comprising a compound of formula (1) or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier.

The compositions may be suitable for administration via topical, oral, rectal or injection routes. The compositions of the present invention are prepared by combining the active ingredient with carriers such as diluents, binders, etc. in the conventional manner.
It may be prepared by mixing fillers, disintegrants, flavors, colorants, lubricants, and preservatives. These conventional additives may be used in a conventional manner, such as in the manufacture of ketoprofen, indomethacin, naproxen, acetylsalicylic acid or other anti-inflammatory agents.

The compounds of this invention have topical anti-inflammatory activity and therefore will normally be made into compositions that are creams, lotions, liniments, gels, gel sticks, ointments, sprays or aerosols for topical administration to the skin.

Creams, lotions for use with compounds of formula (I),
The formulations of liniments, gels, gel sticks, ointments, sprays and aerosols are conventional formulations well known to those skilled in the art1 and are described, for example, in standard textbooks of medicine and cosmetics, such as by Leonard Hill B.
``Harry's Cosmeticolo-'' published by Harry's Cosmeticolo
gy) J, r Remington's Pharmaceutical
Sciences (Remingtons Pharmac
eutical Sciences)j and the British Pharmacopoeia and the United States Pharmacopoeia. Standard emulsifying ointment bases or anhydrous polyethylene glycols are simple examples of such suitable formulations.

Examples of oils suitable for inclusion in standard emulsifying ointment bases include mineral oils, vegetable oils, synthetic fatty acid esters, fatty alcohols, lanolin and its derivatives.

These compositions usually contain suitable emulsifiers. The compositions range from liquid to semi-liquid or gel types depending on the type of emulsion and the amount of naturalizing agent that may be present.

Examples of emulsifiers include polyhydric alcohol esters such as sorbitan monostearate, fatty acid esters such as glyceryl monostearate, and polyester derivatives of fatty acids or fatty alcohols.

The composition also contains antioxidants and other conventional ingredients such as preservatives,
It may also contain fragrance and alcohol. Advantageously, penetrants such as AZONB will also be included.

Compositions for topical treatment may also contain other therapeutic agents such as anti-infective and/or
Or it may contain an antiviral agent. Suitable anti-infective agents include anti-bacterial, anti-yeast, anti-fungal and anti-herpetic agents that can be applied topically.

These compositions are suitable for atopic and contact dermatitis, psoriasis, acne, eczema and other inflammatory skin diseases and eyes.

It may be used for topical treatment of inflammatory conditions of the ear, nose and throat. However, treatment of skin inflammation may also be carried out using the oral compositions of the present invention, such as manure.

It will be appreciated that the amount of compound of formula (1) employed will depend on a number of factors, including the nature and extent of the disorder being treated and the particular compound employed.

However, by way of example, it is believed that effective treatment will be achieved using an amount of the compound of formula (1) that is approximately similar to the amount used of hydrocortiscin. A typical prescription is O.1 for proper flame.
It will contain a compound of formula (1) of between .about.20 and more suitably between 0.5 and 5.

The compositions of the present invention are useful for the treatment of rheumatism and arthritis and for the treatment of pain and other inflammatory conditions, as well as for the treatment of bronchial asthma, rhinitis,
It is useful for the prevention and treatment of hay fever and allergic eczema. Suitably, the oral ready-to-use preparation of the invention will be in the form of a reconstituted powder in a unit dose such as a tablet, capsule or pack. Such unit doses generally have an iQ~1000
and more suitably from about 30 mg to
500m? For example 5 ##i~250 m9. For example 5
(1, I n (].

150, 2 [10, 250, 3+10, 35 (
1, 4 (1, 450 or 50 (1 mg). These compositions may be administered more than once a day, such as 2, 3 or 4 times a day, and the total daily dose for a 70 kg adult is Normally 20~3000■ And even more usually 40~
It will be within the range of 1000■. Also, the unit dose is 2~
It contains 20 ml of active ingredient and, if desired, may be administered in multiple doses to give the aforementioned daily dosage jt'(r).

For use in the treatment or prevention of allergic disorders, suitable dosage units for all of the above formulations are 0.0 L to 500 L for use by the oral route, more suitably 1 to 500 L.
Contains active ingredients of ~0.0 for inhalation (this is 0.
It will include 1 to IO ■. The effective dosage of a compound will depend on the particular compound employed.

Depending on the patient's symptoms and the frequency and route of administration, generally the patient's weight is 1! <9A90.001119/day ~ 1O0
It is within the range of Tn9/day.

No toxicological side effects are observed at all of the above dosage ranges.

If appropriate, small amounts of other anti-asthmatic agents and bronchodilators such as sympathomimetic amines such as inbrenaline, isoethaline, salbutamol, phenylephrine and ephedrine; xanthine derivatives such as theophylline and aminophylline and corticosteroids such as prednisolone and adrenal stimulants such as ACTH will be included.

A preferred form of oral compositions of the invention is a tablet containing the active agent. The active agent may be in the form of recompacted granules of the active ingredient intimately mixed with a lubricant such as magnesium stearate, a filler such as microcrystalline cellulose, and a disintegrant such as sodium starch glycolate.

A special composition of the invention for inflammatory diseases comprises a compound of the invention in the form of a powder or granules intimately mixed with a lubricant such as magnesium stearate, a filler such as microcrystalline cellulose and a disintegrant such as sodium starch glycolate. It is a hard gelatin capsule containing the required amount.

Products specifically designed for administration into the respiratory tract are e.g.
Aerosols, nebulizer solutions or finely divided powders for inhalation, alone or in combination with inert carriers such as lactose. In such cases the particles of active compound suitably have a diameter of less than 50 microns, preferably less than 10 microns.

For parenteral administration, liquid unit dosage forms are prepared using a compound of formula (1) or a pharmaceutically acceptable salt thereof and a sterile medium. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions, the compound is dissolved and sterilized for injection and then placed in a suitable vial or ampoule and sealed. Advantageously, auxiliary agents such as local anesthetics, preservatives and buffers are dissolved in the vehicle.

Parenteral suspensions are prepared in substantially the same manner, but
However, instead of being dissolved, the compound is in the medium! I! ! It is sterilized by exposure to ethylene oxide before being clouded and suspended in a sterilizing medium. First, a surfactant or wetting agent is included in the composition to aid in uniform distribution of the compound.

The present invention further provides a method for treating or preventing inflammatory and/or allergic symptoms in mammals, including humans, which comprises administering to a subject a compound of formula (H) or a pharmaceutically acceptable salt or solvate thereof. I will provide a.

The present invention also provides a compound of formula (1) or a pharmaceutically acceptable salt or solvate thereof for use in treating disorders and particularly inflammatory and/or allergic conditions in mammals.

The present invention also provides the use of a compound of formula (1) or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of inflammatory and/or allergic symptoms.

Mammals treated include humans and domestic animals such as dogs.

Including cats or horses.

Most suitably the medicament will be administered orally at the aforementioned dosages 1.3 or 4 times per day.

〔Example〕

The detailed examples below provide a detailed explanation of the invention and the reference examples illustrate the preparation of intermediates.

Reference Example 1 Ethyl 7-chloro-I B-pyrazoloC4,3-bl pyridine-6-carboxylate e Ethyl 4,7-sihydro 7-oxo IH-pyrazolo(4,3-b)pyridine- in phosphorus oxychloride 6-carboxylate [H.E. Foster (H,E,
Foster) and J. Burst (J.

Hurst) rJ, Chem, Soc, *Perkin Tr
ans, ) J l *1978.507] was heated under reflux for 45 minutes.

After removing excess reagent under vacuum, the residue was made basic with saturated sodium bicarbonate solution. The precipitated solid was washed with water and then extracted with ethyl acetate to give the crude title compound.

δ (DMSOd6) 1.4 (3H, t, J=7Hz
)4.3 (2H,q, J=7Hz)8.4(I
H,s) 8.8(IH,s) Much improved yield of the title compound ('67%
) was obtained by keeping the reaction mixture at 70-80° C. above the reflux temperature.

Reference Example 2 Ethyl 7-allylamino-IH-pyrazolo (4,3-b
)-Pyridine-6-carboxylate ethyl 7-chloro-IH pyrazolo C4,3-b) Pyridine-6-carboxylate C2,259゜0.01 mol) and allylamine (20me) were combined overnight at room temperature. Stirred. Excess allylamine was removed under reduced pressure. The residue was dissolved in a minimum volume of aqueous ethanol and enough 10% sodium carbonate was added to bring the pH to 8.

The resulting solid was collected and dried to give a yellow solid which was recrystallized from ether pentane containing a few drops of methanol (to increase solubility) to give the free base (1,09
, 42 Section) to obtain the title compound.

Melting point 218-222'C.

(Actual measurements: C, 58, 32: H, 5, 72: N, 22
．． 85°Cl2H14N402 as C,58,53:
) 1,5.73:N, 22.75%).

δ(CDC(?s)1.4 (3H,t, J=7Hz
)4.3 (2H, q, J=7 Hz)4,.
7-4.85 (2H, m) 5, r+5-s, 5 (zH, rn) 5.75-6.41 (LH, m) 8.15 (IT-1, s) 8.8 (IH, s) Reference Example 3 7-allylamino=lH-pyrazoloC4,3-bl pyridine-6-carboxylic acid (D3) Ethyl 7-allylamino-IFI-pyrazolo[4,3-
b) Pyridine-6-carboxylate (5,0 g, 2
0 mmol) was added to a solution of sodium hydroxide (2,49, RO mmol) in water (10 (l rnl) and 60
Heated under reflux for minutes. solution? Filtered, diluted with water (200d) and made neutral with 5N hydrochloric acid. The solid was washed with water and dried to give the title compound C4,259,98.
) was obtained.

Melting point: 240-242°C.

δ (DMS Od6/TFA): 0.92 (3H, t, J 7Hz) 1.1- t, sn (4H, m) 4.20 (LH,, nl) 8°55 (IH, 8) 8 .85 (11-J, 8) Reference Example 4 7-allylamino-L H-pyrazolo[4,3-b]pyridine-6-carboxamide (D4) 7-allylamino-IH-pyrazolo(4,3-b)pyridine A mixture of -6-carboxylic acid (3,8'3, 17.4 mmol) and thionyl chloride (10 mg) was heated under reflux for a total of 10 minutes.

Excess thionyl chloride was removed under vacuum and the remaining solid was added with stirring to a water-cooled solution of o,ssn ammonia (20d) in water (10d). The mixture was thoroughly shaken and then made strongly basic with 40% sodium hydroxide solution. The pH was returned to pH f3 with 5N hydrochloric acid, and the product was extracted into ethyl acetate. The extract was washed with brine and then dried (M'
7SO4) and evaporated in vacuo. T the remaining solid
Recrystallization from HF/ethanol/pentane gave the title compound as yellow needles (1,819,48).

Melting point: 254-258°C 0 Actual value: C, 55, 41: H, 5, 13: N, 31.
83:C as CloHnN50, 55, 29:)
], 5. lO:N, 32.24% δ(DMSOd6): 4.6(](2H,br' t) 5, n5-5.4n(2H,m)s, 6o-6,30c tH,m) 7. 55 (replaced with 2H1b r s r D20)
8.25 (IF-1, s) 8.57 (II-Ls) 9.95 (IH, br t, replaced with D20) 13.7
0 (IH, br 8. Replaced with D20) Reference Example 5 Ethyl-7-allylamino-2-(2-methoxy-2-
Propyl-2d-pyrazolo[4,3-b]pyridine-
6-Calphodylate (D5) 7/ゝ\i2-IN (D5) Ethyl 7-allylamino-I in acetone (200d)
H-pyrazoloC4,3-b]pyridine-6-carphokidylate (3,69 g - 15 mmol).

2.2-dimethoxypropane (9.2ml, 75
mmol) and 4-toluenesulfonic acid (142~,07
5 mmol) was heated under reflux for 48 hours. The solution was cooled and stirred with solid potassium carbonate, then filtered and evaporated under vacuum. Column chromatography of the residue on basic alumina (1110!?) eluting with ethyl acetate gave a white (1) solid C3, n79.
The title compound was obtained as (64%).

Melting point: 102-103°C Actual value: C, 60, 31: H, 6, 78: N, 17.
60:C]6H22N40! l as C, [+, 36:
H, 6, 97: N, 17.60 circulation δ (CDCe3): 1.40 (3H, t, J 7Hz) 1.83 (6H, s) 3.08 (3H, s) 4.30 (2) (, q, J 7Hz) 4.73 (2H
, t, J flHz) 5.05-5.50 (2H, m
) 5.7 (1-6,30 (lH, m) 8.15 (IF (,8) 8.73 (1,)], s ) 9.30 (IH, br s) Reference Example 6 Tourylamino -6-hydroxymethyl-2-(2-
methoxy-2-propyl)-2H-pyrazolo(4,3-
b] Pyridine (D6) (D6) Ethyl 7-allylamino-2-(2-methoxy-2-propyl)-2H-pyrazoloC4,3-b) Pyridine-6-carboxy in dry THF (25,,t) A solution of the compound (2,389, 7,5 mmol) was dried in THF.
(15 mt) of lithium aluminum hydride (28
5+7.5 mmol) was added dropwise to a water-cooled suspension. The mixture was stirred for 24 hours at room temperature under nitrogen, then water (o3y), tn
n iced sodium hydroxide solution 0.3 d) and water (0.85 d)
rnl)'. The mixture was filtered through Kieselguhr, the solvent was evaporated under vacuum and the remaining solid was recrystallized from ethyl acetate to give needles (1,87!9.90
%) to obtain the title compound.

Melting point: 152-154°C.

Actual value: C, Ro, 58:H, 7, 21:N, 2
0.2ftC14H2I, N40□ as C, Ro, 8
4:H, 7,29:N, 20.27 coefficient δ (CDCe3)
: 1.82 (6H, s) 3.00 (3H, s) 4.56 (2H, s) 4.67 (2H, t, J 8H, z) 4.90-5.
40 (3H, m) 5.65-6.30 (2B, m) 7.60 (1'H, s) 8.00 (IH, s) Reference Example 7 Ethyl 2-(pyrazol-4-ylamino)cyclohexene -1-carboxylate (D7) ethanol (150
4-nitropyrazole (5,2 g, 0.046
mol) solution at atmospheric pressure and room temperature in a trench where hydrogen absorption stops.
(1% Pd/C catalyst (7.3 ml, 0.046 mol) and evaporated to dryness. A few drops of concentrated hydrochloric acid (o,
A 1 ml aliquot was added to the yellow oil and then heated in a steam bath under 109+ heat.

The mixture was dissolved in ethyl acetate, washed with aqueous sodium bicarbonate solution and water, then dried (M9SO<) and concentrated to give a yellow solid. This is ether/60~
Recrystallized from 800 petroleum ether to give a white solid (9,
The title compound was obtained as (79.9n%).

Melting point 92-94°C.

Actual value: C, full, 20:) 1.7.35: N, 1
8.00%Cl2l-117N! C as +02, 81
, 25:) 1, 7.30: N, 17.85 coefficient δ (CDC
h): 1.25 (3-1, t, J 7Hz) 1.40
-1.75 (4H, m) 20o-2,40 (4H, m) 4, In (2H, q, J 7) 1z) 7,, +rB2
H, 5) 10.2+1(11-1,br 5)11.15(l
libr s) Reference Example 8 4.5. LL8.9-hexahydro-9-oxo-1H
-Pyrazolo[4,3-b]quinoline(D8)H(D8
) Ethyl 2-(pyrazoli-4-ylamino)cyclohexene-1-carboxylate (8.5 g.

0.03f1 mol) was refluxed under nitrogen.
)owtherrn)A (250 ml, ) was added quickly and the mixture was heated under reflux for a period of VC15+ and then allowed to cool to room temperature. The mixture fR+1~80° was diluted with petroleum ether (2nOrn!) and the solid was then stripped off.The petroleum ether was then thoroughly washed with ethanol and dried in vacuo to give a white solid (6,2f[.

92 width) to obtain the title compound.

Melting point>325°C9 Actual value: C, fi3.20:)1.5.85:N,2
2.2i1 C+oHn NhO as C, R3,5(
1:11.5.85:N, 22.20 coefficient δ(CDCes
/DMSOd6) :1.50-1.9(1(4H,
m) 2.30-2.8+1 (41-1, m)7.6o(x
H, 5) 11.40 (114, bs) Reference Example 9 9-chloro-5,6,7,8-tetrahydro-11''-
Pyrazolo[4,,'1-b)quinoline (D9) 4.5.
fi,7,L9-hexahythro9-oxo-IH-
Pyrazolo(4,3-b)quinoline(5,n!?.

0.026 mol) of phosphoryl chloride (4(l me )
and the mixture was heated under reflux for 30 minutes.

Excess reagent was evaporated and the residue was treated with water (30ml) and made basic by addition of sodium carbonate solution. The solid was removed, washed with water, dried, and recrystallized from ethyl acetate to give a yellow solid (4, 85, 9, 88 width).
As the title compound′! i- got it.

Melting point: 190-193°C.

Actual measurement: C, 57, 85SR, 4, 95:N, 20
．． nO:Cd, 16.95 ratio (-+oH+oCgN
3 as C, 57, 85: r-1, 4, 85: N, 20
．． 25: CCl2.20% δ(CDC(?s/DMSOd6): 1.70-2.
0n(4'F-1,,m)2.65-3.15(4T-
Lm) 8, n n (IH,,s) Reference Example 10 Ethyl 2-(pyrazol-4-ylamino)cyclopenten-1-sulfoxylate (Dl(1)) The title compound was converted to ethyl 2-cyclopentanonecarboxylate ( The product was obtained as a white solid (9.8 g, 94 parts) as in Reference Example 7 from 4-nitropyrazole (5,2&,0. Ta.

Melting point 121-123"C.

δ(CDCe3):], , 25(3H,t, J=7H
z)],,R(1-2,(H)(2H,rn)2.40
-2.75 (4F-1, rn) 4.15 (2H, q, J
=7Hz) 7.35 (2H, s) 8.80 (l)], br s ) 11.40 (IH,, br s ) Reference Example 11 4.5. fi, 7.8-pentahydro-8-oxo-I
H-cyclopenta[b]pyrazolo[: 3.4-e
]Pyridine (Dll) The title compound was prepared from ethyl 2-(pyrazoli-4-ylamino)cyclopenten-1-rupoxylate C9,49,0,042 mol) using the method of Reference Example 8.

The product was obtained as a beige solid (6, 29, 84 cycles).

Melting point>310°C.

δ (TFA) 1.952.50 (2H, m) 2.8
0-3.30 (4) T, m) 8.20 (IH, s) Reference Example 12 8-chloro-5,6,7-dolihydro I H-cyclopenta(b) pyrazolo-(3,4-e ) Pyridine (D
l2) Ce (Dl2) Using the method of Reference Example 9, the title compound was treated with 4,5. L7.8-
Pentahydro-8-oxo-IF-1-cyclopenta
b] PyrazoOC3,4-e) Pyridine (6, (1゜0
, (134 mol). The product is a white solid (
5.9 g, 89%).

Melting point: 210-213°C.

δ(CDCes/DMSOd, ): 1.90-2
．． 40 (2H, m) 2.80-3.20 (4H, m) 8.00 (1'H, s) Reference Example 13 Ethyl 2-acetyl-3-(4-pyrazolylamino)acrylate (Dl3) Ethanol ( A solution of 4-nitropyrazole (5,69,50 mmol) in 200 rnl) was hydrogenated over 10% palladium (0,59) on charcoal at room temperature for 3.5 hours. Catalyst &F removed and ethyl 2-acetyl-3
-ethoxy acrylate (9,3!ii' * 50m
mol) was added to the solution under nitrogen. After 5 minutes the solution was evaporated under vacuum and the remaining solid was dissolved in ethyl acetate/pentane (charcoal).
Recrystallization was performed to obtain the title compound C7,79,69).

Melting point: 126-128°C.

Actual value: C, 49, 9f5:H, 6, 28:N, 17
．． Section 34.

C1oH+aNaOs -C as H2O, 49,78
:H, 6, 27:N.

17.41 section.

δ(CDCis): 1,. 35 (3H,t, J=8T-1z)2.
55 (3H, s) 4.20 (2H, q, J=8Hz) 7.65 (
2H, s) 8.25 (IH, d, J = 12Hz) 12.55 (1, Hlbr d, I') Replaced with 20) Reference Chemical Engineering 4 6-acetyl-4,7-sihydro 7-oxo IH-
Pyrazolo[4,3-b]pyridine (DI4.) Ethyl 2-acetyl-3-(4-pyrazolylamino)acrylate (DI3.1.09.4.5 mmol) was added to boiling Dowsum A and the solution was stirred for 20 minutes. Heated under reflux for minutes. The mixture was cooled by 1 light and heated to 60-80° petroleum ether (10
0 ml, ) was added. The solid was removed and washed thoroughly with petroleum ether to give the title compound (5901 Zeng, section 74).
I got it.

Melting point>320°C δ(TFA): 2.95(3)1. ,s)8.8(1
(lH,s) 9.45 (IT-1,s) M+, actual value: 177,05,'IO,Cl1
177°0538° as H7N302 Reference Example 15 6-acetyl-7-chloro-I T-1-pyrazolo (4
,3-b) Pyridine (DI5) 6-acetyl-4,7-sihydro-7-oxo IH-
Pyrazolo[4,3-b]pyridine (DI4.

1.6'7.9 mmol) and phosphorus oxychloride (15 mg
) mixture was heated at 80° C. for 30 minutes. Excess reagent was removed under vacuum, water was added and the mixture was adjusted to pH 9 with 10% sodium carbonate solution. The resulting mixture was extracted with ethyl acetate (4xsoy) and the extracts were washed with brine and evaporated under vacuum to dry CM9SOa) to give the title compound as a yellow solid, which was used without further purification.

δ (CDCd3): 2.75 (3H, s) 8.25 (N
-1,s) 8.7+1(IH,8) Example 1 7-n-butylamino-6-methyl-IH-pyrazolo(
4,3-b) Pyridine (El) Ethyl 7-chloro-I
T(-pyrazoloC4,3-43 pyridine-6-carboxylate (3,59: 15.5 mmol)' was dissolved in f-n-butylamine (25 m) and stirred for 3 hours at room temperature. Excess butylamine was removed in vacuo. and the remaining solid was thoroughly washed with water and recrystallized from ethyl acetate to give ethyl 7-n-butylamino-IH-pyrazolo[4,3-
b) Pyridine-6-carboxylate (2,75g,
67th cycle) was obtained.

Melting point 1f14-170°C.

A solution of ethyl 7-n-butylamino-17-1-pyrazolo(4,3-b]pyridine-6-carboxylate (524 m9, 2 mmol) in dry T)(F (15 Tnl) was dissolved in T)1F ( was added dropwise to a stirred suspension of lithium aluminum hydride (152 m 9.4 mmol) in 15 d). The mixture was heated under reflux under nitrogen for 90 min and then cooled. Ether (30 d), water (0.15 d)
), 10% sodium hydroxide solution (0.15 mg) and water (0.45 d ) were added sequentially with stirring and the mixture was filtered and then evaporated under vacuum. Crow-like residue (30
0 mg) was recrystallized from ethyl acetate/ether to obtain a white solid.

Melting point 86-95°C.

δ (CDCga): 0.95 (3H, t, J=7H
z) 1.15-2.0 (4H, m) 2.25 (3H, s) 3.80 (2H, t, J=7Hz) 7.90 (replaced by IH, brs, D20) 8.12
(IT-1,s) 8.17(IH,s) Example 2 7-allylamino-6-cyano-I H-pyrazolo[4
,3-b) Pyridine (E2) Trifluoroacetic anhydride (1,91m, 13.5mmol) was mixed with dry dioxane (10mg) and pyridine (1,6m.

7-allylamino-IH-(
4,3-b) Pyridine-6-carboxamide (1-4
9*6.45 mmol) was added dropwise to the stirred suspension in a water-cooled tank. The mixture was stirred overnight at room temperature, water was added and the pH
was adjusted to pH 9 with 10% sodium carbonate solution.

The solid was removed and the aqueous solution was extracted with ethyl acetate. The extracts were washed with brine, dried (M9SO<) and evaporated under vacuum. The residue was crystallized from ethanol/ethyl acetate to give the title compound (26 o m, 20 width).

Melting point 249-252JC8 δ (DMSOd6): 4.55 (2[-1, m) 5.10-5.35 (2H, m) 5.80-6.30 (It-1, m)? ,90(1)(,brs) 8.20(IH,s) 8.40(lH,s) Example 3 7-allylamino-6-hydroxymethyl-2-methyl-2H-pyrazolo[4,3- b ] Pyridine (E3) Dry'! 1(Ethyl 7-allylamino-2-methyl-2T4-pyrazoloC4,3-b in F(2me))
Pyridine-6-carboxylate (100u&, 0.
Water-accumulated lithium aluminum (15Wy, 0.39 mmol) in solution tTE (F (iml)) of 38 mmol)
was added dropwise to an ice-cooled suspension. The mixture was stirred for 16 h at room temperature and then dissolved in water (0, (13 m), l O% sodium hydroxide solution i (o, ai) and water (0, I) 9 m
l) were added sequentially. The solid IF' was removed and washed with ethyl acetate. The solution was evaporated under vacuum to obtain a solid, which was recrystallized from ethyl acetate to give needle-shaped crystals (40m9°48).
The title compound was obtained as .

Melting point: 151-159°C.

δ (DMSOa6): 4.10 (3H, s) 4.52
(2) J, s) 4.50-4.70 (2H, m) 4.90-5.35 (2H, m) 5.70-6.10 (IH, m) 6.3o (+H, m ) 7.90(IH,s) 8.17DH,s) Example 4 7-arylamino-6-hydroxymethyl-IH-pyrazolo(4,3-b)pyridine (E4) 7-allylamino-6-hydroxy Methyl-2-(2-methoxy-2-
Propyl)-2H-pyrazolo(4,3-b)pyridine (1,30 mmol) was suspended in water (15 m) and acidified with 6N hydrochloric acid. After 45 minutes solution'
fr10tlI was adjusted to p1]9 with sodium carbonate solution. The precipitated solid fP was removed and dried to give the title compound (0.899°93 width).

Melting point 19C] to 192C.

Actual value: C, 58, 58:H, 5, f'12SN, 2
7.25CIO) lI2N40 as C,58,8
1:I-(,5,92:N, 27.43% δ(DMSO
da): 4,. 35(2H,t,J [(z) 4,.57(2H,s) 4.9s-s,2o(2)],m) 5.3+1(IT(,s) 5.7(1-6 ,3(1(2H,m) 8,(15(N(,s) 8,Hl(N(,s) Example 5 9-(2-hydroxyethylamino) -5,8°7.
8-tetrahydro-I H-pyrazolo[4,3-bl quinoline (E5) 9-chloro-5, fi, 7,8-tetrahydro-I H
-pyrazolo(4,3-b )quinoline (2,45 g.

0, f) 12 mol) and ethanolamine (2,2 m
/.

xylene (25d) dried for 24 hours
The mixture was heated under reflux. The solvent was evaporated and the residue was dissolved in water/methanol. The pH'of the solution was adjusted to 1.9 by addition of sodium 4 acid solution. The precipitate formed was removed, washed with water, dried and recrystallized from ethyl acetate to yield a beige solid (0.55 g).

The title compound was obtained as Section 20).

Melting point 205-210°C Actual value: C, 62,05:H, 6°95:N, 24.
C, 62, 05 as 00 Cl2H16N40:
H, 6, 95:N, 24.10 coefficient δ (DMSOda)
: x, 6n-t, 9o (4H, m) 2.40-2.9 (1 (4H, m) a, 5o-a, 9o (4H, m) 5.35-5.6 (1 (lH) , rn) s, nn (tH, s) Example 6 9-Inbutylamino-5,6,7,8-tetrahydro-IT-1-pyrazolo[4,3-b)quinoline (E6
)9-chloro-5,6,7,8-tetrahydro-IH-
Pyrazolo[4,3-b]quinoline (4,90!?.

0.024 mol) and isobutylamine (11,7 me
O, 1.18 mol) was dissolved in dry xylene (50 ml) for 6 days.
) under nitrogen at reflux. The solution was concentrated to dryness, the residue was dissolved in water/methanol and the solution was adjusted to pH 9-10 by addition of 10% sodium carbonate solution. The precipitate was removed, washed with water, dried, and recrystallized from ethyl acetate to obtain the title compound as a beige solid (0.859.15).

Melting point 124 ml 27'C.

Actual value: C, fi8.45:T-1,8,55:N,
C, 68, 80 as 22.80 Cl4I42ON4
SH, 8,25SN, 22.95% δ (CDCes):
1.05 (6H, d, J=8Hz) 1.85-2.
00 (5B, m) 2, '50-2.55 (21-1, m) 2.95-3
．． (10(2Hsm) 3.55-3.60(2H,m) 4.10-4.20(lH,m) 8.0R(IH,s) Measured mass = 244, 1688, Cl4H2
244.1881° as 0N4 Example 7 8-(2-hydroxyethylamino) -5,6,7-
dolihydro IH-cyclopenta[b) pyrazolo[3,
4-e) Pyridine (E7) The title compound was prepared using the method of Example 5 as 8-chloro-5,
8,7-trihydro-IH-cyclopenta[1)]pyrazoloC3+4- e) viridi> (3,n 9jO,
016 mol). The product was recrystallized from ethyl acetate/methanol to give a beige solid (1.27 g,
38φ) f was obtained.

Melting point 232-235°C.

δ(DMSOda): 1.90-2.10 (2H
, m) 2.70-2.95 (4FLm) 3.50-3.75 (4H, rn) 5.80-5.95 (IT(, m) 7.90 (1, H, 5) 12. 75 (IH, br 8 ) Measured mass = 218.1168.Co[-114
218 as N40. , Li2Q.

Actual sister example 8 8-inbutylamino-5,fi,7-dolihydro I
H-cyclopenta[b) pyrazolo(3,4-b)pyridine[E8] 8-chloro-5,6°7-dolihydro IH-cyclopenta[b]pyrazolo C in dry xylene (90 ml)
3,4,-e) Pyridine (2,70P, O,nl
4 mol) and isobutylamine (17 tJl, 0
．． 2.17 mol) solution for 44 hours. Lyu/crl
(30psi) and 150°C for an additional 45 hours at approximately 2.8 kg/cdt (40psi) and 175
Heated in a pressurized vessel at °C. The solution was evaporated to dryness and the residue was dissolved in water/methanol. pHf of solution
The concentration was adjusted to 9-10 by addition of 10% sodium carbonate solution and then extracted with chloroform. The organic extracts were washed with brine, dried (MgSO4) and evaporated to dryness.

The product was purified by column chromatography on basic alumina, eluting with 20% methanol/ethyl acetate. The title compound was obtained as a beige solid (1,209,37%) after recrystallization from ethyl acetate.

Melting point 148-150°C 6 δ (CDCN3): 0.92 (38, d, J=8H
z)1,,fl O-2,00(IH,rn)2,Oo
-2,35 (2n, m) 2.8 +1-3.15 (4H, m) 3.30-3.
55 (2F-1, m) 5.35-5. fl O(IH
, m) 8.00 (IH, 5) 10.0 n (IH, brs) Actual mass = 23011532 , 0,3H,8
230.1523° as N4 Example 9 6-aminomethyl-7-broby-IH-pyrazolo[4
,3-b) Pyridine (E9) ethanol cio
oy) and 7-allylamino-6-cyano-IH-pyrazoloC4,3-b in ethanolic hydrogen chloride (2,d)
) Pyridine (E2゜487 m'j, 2.4 m
A solution of 10% palladium (200 mL) on ice charcoal was hydrogenated for 48 hours at 40° C. and atmospheric pressure. The catalyst was removed and the solution was evaporated in vacuo. The resulting solid was dissolved in water (15d) and the solution was adjusted to pH 3 with 10% sodium carbonate solution. The condensate solution washed with ethyl acetate was cooled at 4° C. for 2 days. A white solid separated, was removed and dried to give the title compound (1857 ng, 3
Section 7) was obtained.

Melting point 97-100゛C8 δ (DM'SOda): 1.0 (3) 1. t, J
=6) 1z) 1.65 (2H, m) 3.7 (2H, t, J = 7Hz) 3.8-4.3 (3H, m) 6.85 (Replace with T8, br s +D20) 7
．． 4 (THI br s * Replaced with D20) 7.9
5 (N-], s) 8.1 (IH, s) M+, actual value: 205.1323. C,,H,5N6
as 205° 1327° Example 10 6-acetyl-7-allylamino-I H-pyran 0
(4,3-b)pyridi:/(EIO)allylamine(
6-acetyl-7-chloro-1'[(-pyrazolo[4,3-b]pyridine (DI5, 340
m'i, 1.7 mmol) was stirred at room temperature for 16 hours. Excess allylamine was removed in vacuo and the residue was dissolved in aqueous methanol. The solution was adjusted to pH 8 with 10% sodium carbonate solution and diluted with ethyl acetate (4X5[1d
) was extracted. Wash the extract with brine (50d)
Dry (Mg5O4)'L.

Evaporation under vacuum gave a sticky solid. This was crystallized from ethyl acetate/ethanol to give the title compound C280m9.7
5 width) was obtained.

Melting point: 211-213°C.

Actual value: C+ 60.49: T'l + 5.81
:N*25.55, C'BH12N40 as C,81,1O:H,5,59:N,25.91 section.

δ (CDC6s): 2.70 (3H, s) 4.7
0 (2H, m) 5.2-5.55 (2H, m) 5.85-6.40 (IT (+m) 6.95 (IH, br s ) 8.25 (lH, s,) 8. 85 (IH,s) [Efficacy] Pharmacological Data Representative compounds of the present invention were tested on various related diseases as described below.

α) Mouse cantharidin
)Screen compound by K.F.Swingle,M.G.Reiter,D.K.Schwartzmiller(K.F.Swingee*M.J.R.Eiter,
D. H. Schwartzmi-(ller)r
Arch, Int.
Pharmacodyn) J (1981), 2
A modified cantharidin mouse ear screen of 54 e168-176 was tested for local anti-inflammatory activity.

(a) 25μs canthalizin (zOμg THF
The compound in the same solvent was applied simultaneously to the left ear only. Ears were weighed 24 hours after application of kanchelidin. Inhibition of acute inflammatory swelling O Compound Dose Inhibition Percentage Example Nα for the increase in weight of the left ear (canthalizin plus ψ compound) compared to the vehicle-treated negative control as a percentage of the increase in the amount of N in the right ear (canthalizin only) relative to the control (μ9/ear) (circulation) 1
5 n 0 95 “75 500
91""76 500 97"1
18 500 97°1 9 500 91"" + Sac P<0.001 (2) This model of carrageenin-induced pleuritic monocyte accumulation in rats was developed by R. Binger, G.F.
Trau, G.L. Self, F.N., Bonilcar (R+Vinegar+, T+F+Traux.

J, L, Se/ph, F, A. Voeeker ) r
Federation Proceedings (:Feder)
ation Proceedings) J41.258
8-2595 (1982).

λ-Carrageenin [Viscarin (Vis) in physiological saline
carin) 402)'s 2.0 melt i0.2rn
lffi anesthetized rats (weighing approximately 175-20Q&
) was injected into the breast meat. compound 1 hour before carrageenin,
Administered 24 and 48 hours later. Carrageenin injection 72
After an hour, EDTA m solution (add 325η of phenol red to 59 EDTA in 0.9% physiological saline and 100 green onions, and then add raw barley saline to make 16) 4.0 m
l'j (Injected into the womb after killing the animal (2) The exudate was removed with a needle through Guiaflam. Volume of exudate jt? Spectral spectrum (5ROnm) calculated from the dilution of the injected phenol red. i and cell content #DN
A Quantitative [née Carsten.

Knee 〇Hollenbell force - (U, 1carsten + A,
Wo/gen-berger) rana/L-Biohem (Anad, Biochem, )j77.4f1
4-47M1.1977).

The compound of Example 5 at a dose of 25 ml)/ki7 p, Oo decreased the amount of DNA-containing 31
36% reduction in exudate volume.

(p<0.ns).

(3) Mouse fist oxacilone screen compound Dietrich, Hess (less)
Indian Arc Allergy (Int, Arch.

Aeeergy) 38, 248 (1970)
) was tested for local anti-inflammatory activity in a screen using mice sensitized to oxacilone.

Oxacylone (
Sensitization was carried out with 2■) in 20 μe OEtOH. After 5 days, inject 10 μe of TFIF/MeO into the right ear of the animal.
A test compound in the same solvent was applied to the left ear using a 1:1 v/v solution. One hour later, all animals were placed in each ear. The suppressor of inflammatory swelling was found in the right ear (T) relative to similar controls.
Regarding the weight increase of the left ear (oxacilone plus compound in THF/Me OH) compared to the untreated negative control as a percentage of the weight increase of HF/MeOT (oxacilone only in THF/MeOT).

Compound Dosage Inhibitor 8 200 49'' Mouth P (0,01 Meal + +p (0,001) No toxicity was observed for the exemplified compounds in the tests described above.

Agent Patent Attorney Masaaki Akizawa 1 other person

Claims (24)

[Claims] (1) Formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, ; sulfur; SO; or SO_2; R_1 is hydrogen or C_1_-_6 alkyl; and R_2 is CN, CR_5R_6Y, where R_5 and R_6 are independently selected from hydrogen and C_1_-_4 alkyl and Y is hydrogen , OR_7 or SR_7 (wherein R_7 is hydrogen, C_1_~_4 alkyl or C_2_~
_4 alkanoyl) and NR_8R_9 (wherein R
_8 and R_9 are independently selected from hydrogen, C_1__4 alkyl, C_2___4 alkenyl or C_2__4_4 alkanoyl or together are C_4__6 polymethylene) or COR_1_0 (wherein R_
or R_2 is hydrogen, C_1_-_6 alkyl, or halogen, CF_3, C_1_-_4 alkoxy or C_
is phenyl optionally substituted by 1_-_4 alkyl and R_1 is CN, CR_5R_6Y or COR_1_0 as defined for R_2 above;
or R_1 and R_2 together form C_3-C_6 polymethylene optionally substituted by C_1-C_4 alkyl; R_3 is either hydroxy, C_1_-_4 alkoxy, thiol, C_1_-_4 alkylthio or N
R_1_1R_1_2 (R_1_1 and R_1_2 in the formula
are independently hydrogen, C_1_-_6 alkyl or C_2_
C_1 optionally substituted by ~_7 alkanoyl or together with C_3_-_6 polymethylene)
~_1_0 alkyl or C_3_1_0 cycloalkyl; or C_2__1_0 alkenyl; or one or two halogens, CF_3, C_1_-_
4 alkoxy, C_1_~_4 alkyl, hydroxy,
Nitro, cyano, C_1_～_1_0 acyloxy, N
R_1_3R_1_4 (R_1_3 and R_1_4 in the formula
are independently hydrogen, C_1_~_6 alkyl, C_2_~
_7 alkanoyl or C_1_-_6 alkylsulfonyl) or COR_1_5 (in the formula R_1_5
or NR_1_6R_1_7 (wherein R_1_6 and R_
1_7 is independently selected from hydrogen or C_1_-_6 alkyl); or together with R, C_4_-
_6 polymethylene; and R_4 is hydrogen; or C_1_-_4 alkyl or one or two halogens, CF_3, C_1_-_4
benzyl optionally substituted on the phenyl ring by alkoxy or C_1_-_4 alkyl and attached to one or two nitrogen atoms. (2) X is NR (wherein R is hydrogen, methyl, ethyl, n-
and iso-propyl); oxygen or sulfur. (3) R_1 and R_2 are hydrogen, methyl, ethyl, n-
and iso-propyl, aminomethyl, N-substituted aminomethyl and acetamidomethyl or taken together to form a C_3 or C_4 polymethylene. (4) R_3 is methyl, ethyl, n- and iso-propyl, n-, iso-, secondary- and tertiary-butyl, n-pentyl, (CH_2)nCH_3 (wherein n is 4 to 7) or cyclohexyl (these groups may be substituted by methyl, ethyl and/or hydroxy, methoxy, n- or iso-propoxy, thiol, methylthio, or by amino which may be substituted by one or two methyl or acetyl groups or by C_4 or C_5 polymethylene); or vinyl, prop-1-enyl, prop-2-enyl, 1-methylvinyl, but-
1-enyl, but-2-enyl, but-3-enyl, 1
- methylenepropyl, 1-methylprop-1-enyl and 1-methylprop-2-enyl in their E and Z forms when stereoisomerism exists; or one or two chlorine, bromine, methoxy , ethoxy, n- and iso-fropoxy, methyl, ethyl, n- and iso-propyl, n-iso-mono-, sec- and tertiary-butyl, hydroxy, nitro, cyano, acetoxy, propionyloxy, benzyloxy, NR_1_3 ^1R_1_4^1(
where R_1_3^1 and R_1_4^1 are independently selected from hydrogen, methyl, ethyl, n- and iso-propyl, acetyl, propionyl, methylsulfonyl and ethylsulfonyl) or COR_1_5^1 (wherein R_1
_5^1 is phenyl optionally substituted with hydroxy, methoxy, ethoxy; or NR
Claim No.
) to (3). (5) R_3 is iso-butyl, n-butyl, n-pentyl, allyl or prop-2-enyl, 2-methylallyl, 2-hydroxyethyl, 3-hydroxypropyl, 2
- selected from dimethylaminoethyl, 3-dimethylaminopropyl, 3-diethylaminopropyl, phenyl and phenyl substituted in the 3- or 4-position by one hydroxy, nitro, cyano, carboxy, t-butyl or ethoxycarbonyl Claim No. (4)
Compounds described in Section. (6) R_4 is hydrogen, methyl, ethyl, n- and iso-
Claim No. selected from propyl and benzyl (
A compound described in any one of items 1) to (5). (7) The compound according to claim (6), wherein R_4 is hydrogen or 2-methyl. (8) R_1 is hydrogen or C_1_-_6 alkyl; and R_2 is CN, CR_5R_6Y' (in the formula Y'
is OR_7, SR_7 or NR_8R_9 or COR_
or R_2 is phenyl as defined for R_1 or optionally substituted as defined for formula (I); and R_1 is CN, CR_5R_6Y or COR_1_0 ; and Y, R_5, R_6, R_7, R_8, R
The compound according to claim (1), wherein _9, R_1_0 and the remaining substituents are as defined in formula (I). (9) R_1 is hydrogen, R_2 is CN, COR_1
_0 or CR_5R_6Y' or R_1 is CN
, COR_1_0 or CR_5R_6Y and R_2
is hydrogen and the remaining substituents are as defined in formula (I). (10) Formula (III) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(III) (In the formula, R_1^1 is CN, COR_1_0 or CR_5
R_6Y, R' is hydrogen or methyl, R_4
^1 is hydrogen or 2-methyl and R_3 has the formula (
The compound according to claim (1) (as defined in I). (11) Formula (IV) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (IV) (In the formula, R_1_8 is hydrogen, chlorine, bromine, methoxy, ethoxy, hydroxy, cyano, carboxyl, ethoxycarbonyl, nitro, or t-butyl. Compounds according to claim (10) of (selected). (12) Formula (V) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(V) (In the formula, R_3^1 is n-butyl, iso-butyl, allyl, 2-hydroxyethyl, 3-dimethylaminopropyl, or 3- Diethylaminopropyl and R_1^
1 and R_4^1 are as defined in formula (III).) The compound according to claim (10). (13) Formula (VI) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (VI) (In the formula, R_2^1 is CN as specified, CR_5R
_6Y' or COR_1_0 and the remaining substituents are as defined in formula (III). (14) Formula (VII) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (VII) (In the formula, R_3^1 and R_4^1 are as specified in formula (V), and R_2^1 is the formula (VI) The compound according to claim (13), which is as defined in . (15) Formula (VIII) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(VIII) (In the formula, X^1 is oxygen or sulfur, and R_1^1,
A compound according to claim (1), wherein R_3 and R_4^1 are as defined for formula (III). (16) Formula (IX) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(IX) (In the formula, n is 3 to 8 and R_1_9 is hydrogen or C
_1_-_4 alkyl and X, R_3 and R_
4 is as defined for formula (I).) The compound according to claim (1). (17) Formula (X) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(X) (In the formula, R_3^1 and R_4^1 are as specified for formula (V), and m is 1 or 2) The compound according to claim (16). (18) The compound is 7-n-butylamino-6-methyl-1H-pyrazolo [
4,3-b]pyridine, 7-allylamino-6-cyano-1H-pyrazolo[4,
3-b]pyridine, 7-allylamino-6-hydroxymethyl-2-methyl-2H-pyrazolo[4,3-b]pyridine, 7-allylamino-6-hydroxymethyl-1H-pyrazolo[4,
3-b] Pyridine, 9-(2-hydroxyethylamino)-5,6,7,8
-tetrahydro-1H-pyrazolo[4,3-b]quinolone, 9-isobutylamino-5,6,7,8-tetrahydro-1H-pyrazolo[4,3-b]quinolone, 8-(2-
hydroxyethylamino)-5,6,7-trihydro-
1H-cyclopenta[b]-pyrazolo[3,4-e]pyridine, 8-isobutylamino-5,6,7-trihydro-1H
-cyclopenta[b]pyrazolo[3,4-e]pyridine, 6-aminomethyl-7-propyl-1H-pyrazolo[4
,3-b]pyridine or 6-acetyl-7-allylamino-1H-pyrazolo[4
, 3-b] The compound according to claim (1), which is pyridine. (19) X is NR (wherein R is hydrogen, C_1_-_6 alkyl or as defined below for R_3)
; oxygen, sulfur; SO; or SO_2; R_1 is hydrogen or C_1_-_6 alkyl; and R_2 is CN, CR_5R_6Y [wherein R_5 and R_6 are independently selected from hydrogen and C_1_-_4 alkyl and Y is hydrogen, OR_7 or SR_7 (wherein R_7 is hydrogen, C_1_~_4 alkyl or C_2_~
_4 alkanoyl) and NR_8R_9 (wherein R
COR_1_0(
where R_1_0 is C_1___4 alkyl); R_2 is hydrogen, C_1___6 alkyl or halogen, CF_3, C_1___4 alkoxy or C_
is phenyl optionally substituted with 1_-_4 alkyl; and R_1 is CN, CR_5R_6Y, or COR_1_0 as defined for R_2 above; R_3 is hydroxy, C_1_-_4 alkoxy, thiol, C_1_-_4 alkylthio, or NR_1
_1R_1_2 (in the formula, R_1_1 and R_1_2 are independently hydrogen, C_1_-_6 alkyl, or C_2_-_7
Alkanoyl or together C_3_～_6
C_ which is optionally substituted by polymethylene)
1_-_1_0 alkyl or C_3_-_1_0 cycloalkyl; C_2_-_1_0 alkenyl; or 1 or 2 halogens, CF_3, C_1
___~_4 alkoxy, C_1_~_4 alkyl, hydroxy, nitro, cyano, C_2_~_1_0 acyloxy, NR_1_3R_1_4 (in the formula R_1_3 and R_
1_4 is independently hydrogen, C_1_ to_6 alkyl, C_
COR_1_5 (in which R_
1_5 is phenyl optionally substituted by hydroxy, C_1_ to_6 alkoxy; or NR_1_6R_1_7 (wherein R_1_6 and R_1_
7 is independently selected from hydrogen or C_1_-_6 alkyl); or together with R is C_4_-_6
and R_4 is hydrogen; or C_1_-_4 alkyl or one or two halogens, CF_3, C_1_-_4
benzyl optionally substituted on the phenyl ring by alkoxy or C_1_-_4 alkyl and bonded to nitrogen atom 1 or 2; provided that Y is other than hydrogen when R_1 is hydrogen; ) Compounds described in section 2. (20) A pharmaceutically acceptable salt or solvate of the compound described in any one of claims (1) to (19). (21) A pharmaceutical composition comprising a compound according to any one of claims (1) to (20) and a pharmaceutically acceptable carrier. (22) Formula (X I ) ▲Mathematical formulas, chemical formulas, tables, etc.▼(X I) (In the formula, Q is a leaving group, R_1' and R_2' are the formula (
R_1 and R_2 defined in formula (I) or a group convertible thereto, and R_4' is R_4 defined in formula (I) or an atom or group convertible thereto) and a compound of formula (XII) HX^ 2R_3'(XII) (wherein X^2 is NR, oxygen or sulfur as defined in formula (I) and R_3' is R_3 or a group or atom convertible thereto), Then, arbitrarily and if necessary, change X^2 to X, R_1' to R_1, and R_2' to R.
to _2, R_3' to R_3 and/or R_4' to R_
4 and/or forming a pharmaceutically acceptable salt or solvate thereof. (23) Claim No. 1 in which the leaving group Q is a halogen (
22) The method described in section 22). (24) The compound of formula (X I) is ethyl 7-chloro-1H-pyrazolo[4,3-b]pyridine-6-carboxylate, 9-chloro-5,6,7,8-tetrahydro-1H-pyrazolo [4,3-b]quinoline, 8-chloro-5,6,7-trihydro-1H-cyclopenta[b]pyrazolo-[3,4-e]pyridine, or 6-acetyl-7-chloro-1H-pyrazolo [4,3-
b] The method according to claim (22) or (23), which is pyridine.