# US 7,745,450 B2 · Pyrazolo[4,3-d]pyrimidines, processes for their preparation and methods for therapy

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- Number: US 7,745,450 B2
- Document ID: US7745450B2
- Status: Granted
- Kind: B2
- Application number: 10/952,087
- Filed: 2004-09-28
- Published: 2005-04-14
- Granted: 2010-06-29
- Earliest claimed: 2002-03-28
- Assignees: Institute of Experimental Botany; Univerzita Palackeho V Olomouci
- Inventors: Daniela Moravcová; Libor Havlicek; Vladimir Krystof; René Lenobel; Miroslav Strnad
- Web page: https://patentgrep.com/patent/US7745450B2

## CPC

- C07D 487/04: Ortho-condensed systems
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/08: Vasodilators for multiple indications
- A61P 11/06: Antiasthmatics
- A61P 13/12: of the kidneys
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/06: Antipsoriatics
- A61P 17/08: Antiseborrheics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/06: Antigout agents, e.g. antihyperuricemic or uricosuric agents
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 27/02: Ophthalmic agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/12: Antivirals
- A61P 33/00: Antiparasitic agents
- A61P 35/00: Antineoplastic agents
- A61P 35/04: specific for metastasis
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The invention relates to 3-, 5-, 7-trisubstituted pyrazolo[4,3-d]pyrimidines represented by the general formula I and pharmaceutically acceptable salts thereof, wherein R3 is an optionally substituted alkyl, cycloalkyl, cycloheteroalkyl, cycloalkyl alkyl, aryl or alkylaryl group; R5 is halogen, —NHNH2, —NHOH, NHCONH2, guanylo (NH—C(NH)NH2) an optionally substituted C1-C6 alkyl, alkenyl, alkynyl, C3-C15 cycloalkyl, Rf(C3-C15 cycloalkyl), heterocyclyl, heteroalkyl, aryl, heteroaryl, arylalkylene, arylalkenylene, arylalkynylene, cycloheteroalkyl, cycloheteroalkyl alkyl, heteroarylalkylene, heteroarylalkenylene, heteroarylalkynylene group, the group —C(O)—Ra, —C(O)NRbRc, —SO3Rd, or —NHC(O)Re, wherein Ra and Rf are an optionally substituted C1-C6 alkyl, alkenyl, or alkynyl group, Rb, Rc, and Rd are independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, alkenyl, or alkynyl group, and Re is a hydroxy, amino, alkoxy, alkylamino, optionally substituted C1-C6 alkyl, alkenyl or alkynyl group; or the group —X—R5′, wherein X is —NH—, —O—, —S— or —N(alkyl)- and R5′ is hydrogen, an optionally substituted C1-C6 alkyl, alkenyl, alkynyl, C3-C15 cycloalkyl, Rf(C3-C15 cycloalkyl), aryl, heterocyclyl, hetero C1-C6 alkyl, arylalkylene, arylalkenylene, arylalkynylene, heteroaryl, cycloheteroalkyl, cycloheteroalkyl alkyl, or heteroarylalkylene, heteroarylalkenylene, heteroarylalkynylene group, the group —C(O)—Ra, —C(O)NRbRc, —SO3Rd, or —NHC(O)Re, wherein Ra, Rb, Rc, Rd, Re and Rf have the above meaning, and R7 is halogen, —NHNH2, NHOH, NHCONH2, guanylo (NH—C(NH)NH2) or the group —X—R7′, wherein X has the above meaning and the meaning of R7′ is as defined for R5′.

## Claims

### Claim 1

A 3-, 5-, 7-trisubstituted pyrazolo[4,3-d]pyrimidine compound represented by the formula I
and a pharmaceutically acceptable salt thereof, wherein
R3 is selected from the group consisting of a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, cycloalkyl alkylene, cycloalkyl alkenylene, cycloalkyl alkynylene, aryl, arylalkylene, arylalkenylene, and arylalkynylene group;
R5 is selected from the group consisting of halogen, —NHNH2, —NHOH, NHCONH2, guanylo (NH—C(NH)NH2), —SO3Rd, —NHC(O)Re, and —X—R5′, wherein
Rd is H, a C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl group, and
Re is hydroxy, amino, alkoxy, alkylamino, a C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl group;
X is —NH—, —O—, —N(C1-C6 alkyl)-, —N(C2-C6 alkenyl)-, or —N(C2-C6 alkynyl)- and
R5′ is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C15 cycloalkyl, C3-C15 cycloalkenyl, Rf(C3-C15 cycloalkyl), Rf(C3-C15 cycloalkenyl), aryl, heterocyclyl, hetero C1-C6 alkyl, hetero C2-C6 alkenyl, hetero C2-C6 alkynyl, heteroaryl, arylalkylene, arylalkenylene, arylalkynylene, cycloheteroalkyl, cycloheteroalkenyl, cycloheteroalkyl alkylene, cycloheteroalkyl alkenylene, cycloheteroalkyl alkynylene, heteroarylalkylene, heteroarylalkenylene, heteroarylalkynylene, —C(O)—Ra, —C(O)NRbRc, —SO3Rd, or —NHC(O)Re, wherein
Ra is a C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl group,
Rf is a C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene group,
Rb, Rc, and Rd are independently H, a C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl group,
Re has independently the meaning as defined above,
R7 is selected from the group consisting of halogen, —NHNH2, NHOH, NHCONH2, guanylo (NH—C(NH)NH2) and —X′—R7′, wherein X′ is —NH—, —O—, —S—, —N(C1-C6 alkyl)-, —N(C2-C6 alkenyl)-, or —N(C2-C6 alkynyl), and R7′ has independently the same meaning as R5′, as defined above;
wherein in R5 and R7, each of the C1-C6 alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C15 cycloalkyl, C3-C15 cycloalkenyl, Rf(C3-C15 cycloalkyl), Rf(C3-C15 cycloalkenyl), aryl, heterocyclyl, hetero C1-C6 alkyl, hetero C2-C6alkenyl, hetero C2-C6alkynyl, heteroaryl, arylalkylene, arylalkenylene, arylalkynylene, cycloheteroalkyl, cycloheteroalkenyl, cycloheteroalkyl alkylene, cycloheteroalkyl alkenylene, cycloheteroalkyl alkynylene, heteroarylalkylene, heteroarylalkenylene, heteroarylalkynylene, C1-C6 alkylene, C2-C6 alkenylene, and C2-C6 alkynylene is independently optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, alkoxy, amino, hydrazo, mercapto, carboxyl, cyano, nitro, amido, sulfo, sulfamido, acylamino, acyloxy, alkylamino, dialkylamino, and alkylmercapto and carbamoyl group; and
wherein in R3, each of the alkyl, alkenyl, alkynyl, alkylene, alkenylene, and alkynylene is independently optionally substituted with one or more substituents selected from the group consisting of hydroxyl, mercapto, alkylmercapto, halogen, alkoxy, acyloxy, amino, acylamino, hydrazino, carbamoyl, amido, carboxyl, sulfo, acyl and guanidine; the aryl is optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, hydroxy, amino, acylamino, carbamoylamino, hydrazino, mercapto, alkoxy, alkylmercapto, alkylamino, amido, carboxyl, nitro and sulfo; the cycloalkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, cyano, nitro, mercapto, alkoxy, alkylamino, acylamino, carbamoylamino, acyloxy, dialkylamino, alkylmercapto, carboxyl, amido, sulfo and sulfamido; and the cycloheteroalkyl is optionally substituted or unsubstituted with one or more substituents selected from the group consisting of halogen, amino, hydroxy, cyano, nitro, mercapto, alkoxy, alkylamino, acylamino, carbamoylamino, acyloxy, dialkylamino, alkylmercapto, carboxyl, amido, sulfo and sulfamido.

### Claim 2 (depends on 1)

The 3-, 5-, 7-trisubstituted pyrazolo[4,3-d]pyrimidine compound according to claim 1, wherein
R3 is an unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, fluorine or chlorine substituted alkyl, fluorine or chlorine substituted alkenyl, fluorine or chlorine substituted alkynyl, fluorine or chlorine substituted cycloalkyl, fluorine or chlorine substituted cycloalkenyl, unsubstituted cycloheteroalkyl, unsubstituted cycloheteroalkenyl, fluorine or chlorine substituted cycloheteroalkyl, fluorine or chlorine substituted cycloheteroalkenyl, unsubstituted cycloalkyl alkylene, unsubstituted cycloalkyl alkenylene, unsubstituted cycloalkyl alkynylene, fluorine or chlorine substituted cycloalkyl alkylene, fluorine or chlorine substituted cycloalkyl alkenylene, fluorine or chlorine substituted cycloalkyl alkynylene, unsubstituted aryl, fluorine or chlorine substituted aryl, unsubstituted arylalkylene, unsubstituted arylalkenylene, unsubstituted arylalkynylene, fluorine or chlorine substituted arylalkylene, fluorine or chlorine substituted arylalkenylene, or fluorine or chlorine substituted arylalkynylene;
R5 is
—SO3Rd, wherein Rd is C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, selected from the group consisting of methyl, ethyl, isopropyl, butyl, isobutyl, vinyl, allyl, propenyl, propargyl, propynyl, isopentenyl, and isobutenyl, substituted independently at each occurrence with 0-5 substituents selected from the group consisting of halogen, hydroxy, alkoxy, amino, hydrazo, mercapto, carboxyl, cyano, nitro, amido, sulfo, sulfamido, acylamino, acyloxy, alkylamino, dialkylamino, alkylthio and carbamoyl group;
—NHC(O)Re, wherein Re is alkoxy, alkylamino, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, the C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl being independently selected from the group defined above for SO3Rd; or
—X—R5′, wherein
X is —N(C1-C6 alkyl)-, —N(C2-C6 alkenyl)-, or —N(C2-C6alkynyl)-, each C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl being selected from the group consisting of methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, allyl, propargyl, and isopentenyl; and
R5′ is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C15 cycloalkyl, C3-C15 cycloalkenyl, Rf(C3-C15 cycloalkyl), aryl, heterocyclyl, hetero C1-C6 alkyl, hetero C2-C6 alkenyl, or hetero C2-C6 alkynyl, heteroaryl, arylalkylene, arylalkenylene, arylalkynylene, cycloheteroalkyl, cycloheteroalkyl alkylene, cycloheteroalkyl alkenylene, cycloheteroalkyl alkynylene, heteroarylalkylene, heteroarylalkenylene, heteroarylalkynylene, —C(O)Ra, —C(O)NRbRc, —SO3Rd, or —NHC(O)Re, wherein
the C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is independently selected from the group defined above for SO3Rd;
the C3-C15 cycloalkyl or C3-C15 cycloalkenyl is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and adamantyl, substituted independently at each occurrence with 0-5 substituents selected from the group defined above for SO3Rd;
the Rf is a C1-C6 alkylene, C2-C6 alkenylene or C2-C6 alkynylene, independently selected from the group defined above for SO3Rd;
the aryl is selected from the group consisting of phenyl, biphenyl, naphthyl, tetrahydronaphthyl, fluorenyl, indenyl and phenanthrenyl, substituted independently at each occurrence with 0-5 substituents selected from the group defined above for SO3Rd;
the heterocyclyl is selected from the group consisting of thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isothiazolyl, and isoxazolyl, substituted independently at each occurrence with 0-5 substituents selected from the group defined above for SO3Rd;
the hetero C1-C6 alkyl, hetero C2-C6 alkenyl, or hetero C2-C6 alkynyl, is —Rg-Het, wherein
the Rg is a C1-C6 alkylene, C2-C6 alkenylene or C2-C6 alkynylene, independently selected from the group defined above for SO3Rd, and
the Het is heterocyclyl as defined above;
the heteroaryl is —Rh-HetAr, wherein
the Rh is selected from the group consisting of methylene, ethylene, propylene, isopropylene, vinylene, propynylene, and propenylene, and
the HetAr is selected from the group consisting of benzothienyl, naphthothienyl, benzofuranyl, chromenyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinolinyl, and quinazolinyl, substituted independently at each occurrence with 0-5 substituents selected from the group defined above for SO3Rd;
the arylalkyl, arylalkenyl, or arylalkynyl is —RiAr, wherein
the Ri is a C1-C6 alkylene, C2-C6 alkenylene or C2-C6 alkynylene independently selected from the group defined above for SO3Rd, and
Ar is aryl as defined above;
the cycloheteroalkyl is selected from the group consisting of piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, imidazolidinyl, substituted independently at each occurrence with 0-5 substituents selected from the group defined above for SO3Rd;
the cycloheteroalkyl alkylene, cycloheteroalkyl alkenylene, or cycloheteroalkyl alkynylene, is —Rj(cycloheteroalkyl), wherein
the Rj is RiAr, wherein
Ri is a C1-C6 alkylene, C2-C6 alkenylene or C2-C6 alkynylene independently selected from the group defined above for SO3Rd,
Ar is aryl as defined above, and
the cycloheteroalkyl is selected from the group consisting of piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, imidazolidinyl, substituted independently at each occurrence with 0-5 substituents selected from the group defined above for SO3Rd;
the heteroarylalkylene, heteroarylalkenylene, or heteroarylalkynylene is —Rk-HetAr, wherein
the Rk is a C1-C6 alkylene, C2-C6 alkenylene or C2-C6 alkynylene independently selected from the group defined above for SO3Rd, and
the HetAr is heteroaryl group as defined above;
R7 is —X′—R7′, wherein
X′ is —N(C1-C6 alkyl)-, —N(C2-C6 alkenyl)-, or —N(C2-C6 alkynyl), each C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl being selected from the group consisting of methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, allyl, propargyl, and isopentenyl; and
R7′ has independently the same meaning as R5′ as defined above.

### Claim 3 (depends on 1)

The 3-, 5-, 7-trisubstituted pyrazolo[4,3-d]pyrimidine compound according to claim 1, which has independent occurrence of (R) or (S) configuration in R3, R5, or R7.

### Claim 4 (depends on 1)

A method of preparing a 3, 5, 7-trisubstituted pyrazolo[4,3-d]pyrimidine compound of claim 1, comprising chlorination of a 3,5-disubstituted-7-hydroxypyrazolo[4,3-d]pyrimidine compound with a chlorination agent wherein the chlorination agent comprises SOCl2, dimethylformamide, and chloroform; or the chlorination agent comprises POCl3 and dimethylformamide; or the chlorination agent comprises POCl3, PCl5, and dimethylformamide; or the chlorination agent comprises Cl2P(O)OP(O)Cl2, to obtain a 3,5-disubstituted-7-chloropyrazolo[4,3-d]pyrimidine compound.

### Claim 5 (depends on 4)

The method according to claim 4, further comprising
substituting, by a nucleophilic substitution, the chlorine atom at position 7 of the 3,5-disubstituted-7-chloropyrazolo[4,3-d]pyrimidine compound with the substituent —X′R7′.

### Claim 6 (depends on 1)

A method of preparing a 3, 5, 7-trisubstituted pyrazolo[4,3-d]pyrimidine compound of claim 1, comprising chlorination of a 5,7-dihydroxy-3-substituted-pyrazolo[4,3-d]pyrimidine compound with diphosphoryldichloride (Cl2P(O)OP(O)Cl2) to obtain a 5,7-dichloro-3-substituted-pyrazolo[4,3-d]pyrimidine compound, and isolating the 5,7-dichloro-3-substituted pyrazolo[4,3-d]pyrimidine compound by extraction and subsequent crystallization.

### Claim 7 (depends on 6)

The method according to claim 6, further comprising
substituting, by a nucleophilic substitution, at least one of the chlorine atoms at positions 5 and 7 of the 5,7-dichloro-3-substituted pyrazolo[4,3-d]pyrimidine compound with the substituents —X—R5′ and —X′R7′, respectively.

### Claim 8 (depends on 1)

A method of preparing a 3,7-substituted-5-aminopyrazolo[4,3-d]pyrimidine compound of claim 1, comprising chlorination of a 5-amino-7-hydroxy-3-substituted-pyrazolo[4,3-d]pyrimidine compound with SOCl2, and substituting, by a nucleophilic substitution, the chlorine atom at position 7 of the chlorinated compound with the —X′R7′ substituent as defined in claims 1.

### Claim 9 (depends on 1)

A method of treating a hyperproliferative skin disease in a human subject comprising administering to the human subject a therapeutically effective amount of a 3-, 5-, 7-trisubstituted pyrazolo[4,3-d]pyrimidine compound according to claim 1 or a pharmaceutically acceptable salt thereof, together with a pharmaceutical carrier.

### Claim 10 (depends on 9)

The method according to claim 9, wherein the hyperproliferative skin disease is selected from the group consisting of actinic keratosis, Bowen's disease, papilloma, seborrheic keratosis, toxic eczema, atopic dermatitis and ichthyosis.

### Claim 11 (depends on 1)

A method of maintaining a mammalian oocyte at the germinal vesicle stage comprising administering to the mammalian oocyte an effective amount of a 3-, 5-, 7-trisubstituted pyrazolo[4,3-d]pyrimidine compound according to claim 1 or a pharmaceutically acceptable salt thereof.

### Claim 12 (depends on 11)

The method of claim 11, wherein the mammalian oocyte is used in an in vitro fertilization process.

### Claim 13 (depends on 1)

A pharmaceutical composition comprising a 3-, 5-, 7-trisubstituted pyrazolo[4,3-d]pyrimidine compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutical carrier.

### Claim 14 (depends on 1)

A method of treating a mammal that suffers from a disease or disorder selected from the group consisting of human cervical carcinoma, human breast carcinoma, human osteosarcoma, human colon carcinoma, murine fibroblast tumor, human melanoma, comprising administering to the mammal an effective amount of a 3-, 5-, 7-trisubstituted pyrazolo[4,3-d]pyrimidine compound according to claim 1 or a pharmaceutically acceptable salt thereof together with a pharmaceutical carrier.

### Claim 15 (depends on 1)

A method of treating a mammal that suffers from psoriasis comprising administering to the mammal an effective amount of a 3-, 5-, 7-trisubstituted pyrazolo[4,3-d]pyrimidine compound according to claim 1 or a pharmaceutically acceptable salt thereof together with a pharmaceutical carrier.

### Claim 16 (depends on 1)

The 3-, 5-, 7-trisubstituted pyrazolo[4,3-d]pyrimidine compound according to claim 1, wherein R3 is an isopropyl group.

### Claim 17 (depends on 1)

The 3-, 5-, 7-trisubstituted pyrazolo[4,3-d]pyrimidine compound according to claim 1, wherein R5 is an aminocyclohexylamino group or an optionally substituted benzylamino group.

### Claim 18 (depends on 17)

The 3-, 5-, 7-trisubstituted pyrazolo[4,3-d]pyrimidine compound according to claim 17, being selected from the group consisting of:

### Claim 19 (depends on 1)

The 3-, 5-, 7-trisubstituted pyrazolo[4,3-d]pyrimidine compound according to claim 1, wherein R7 is an optionally substituted benzylamino group.

### Claim 20 (depends on 19)

The 3-, 5-, 7-trisubstituted pyrazolo[4,3-d]pyrimidine compound according to claim 19, wherein R7 is an optionally substituted methoxybenzylamino group.

### Claim 21 (depends on 20)

The 3-, 5-, 7-trisubstituted pyrazolo[4,3-d]pyrimidine compound according to claim 20, being selected from the group consisting of: