# US 7,745,433 B2 · 2-Substituted phenyl-5, 7-dihydrocarbyl-3, 7-dihydropyrrolo [2, 3-D] pyrimidin-4-one derivatives, the preparation and the pharmaceutical use thereof

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- Number: US 7,745,433 B2
- Document ID: US7745433B2
- Status: Granted
- Kind: B2
- Application number: 10/559,516
- Filed: 2004-05-14
- Published: 2006-08-03
- Granted: 2010-06-29
- Earliest claimed: 2004-05-14
- Assignees: Yangtze River Pharmacuetical (Group) Co., Ltd.; Tianjin North Pharma Sci-Tech Co., Ltd.
- Inventors: Yongfeng Wang; Kejun Zhao
- Web page: https://patentgrep.com/patent/US7745433B2

## CPC

- C07D 487/04: Ortho-condensed systems
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/14: Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 9/12: Antihypertensives
- A61P 11/06: Antiasthmatics
- A61P 13/02: of urine or of the urinary tract, e.g. urine acidifiers
- A61P 13/08: of the prostate
- A61P 13/10: of the bladder
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 15/08: for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
- A61P 15/10: for impotence
- A61P 15/14: for lactation disorders, e.g. galactorrhoea
- A61P 15/18: Feminine contraceptives
- A61P 17/06: Antipsoriatics
- A61P 17/14: for baldness or alopecia
- 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 27/06: Antiglaucoma agents or miotics
- A61P 35/00: Antineoplastic agents
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- C07C 65/21: containing ether groups, [IMAGE cpc-sch-C07C-0958.gif] groups,[IMAGE cpc-sch-C07C-0959.gif] groups, or[IMAGE cpc-sch-C07C-0960.gif] groups
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS

## Abstract

The invention relates to the compounds of formula I, their preparation and the pharmaceutical compositions containing the compounds. The invention also relates to the use of the compounds of formula I in preparing medicines, which can treat sexual dysfunction of animals including human (male and female), especially erectile dysfunction of male and the diseases in which the function of phospholipase 5 (cGMP PDE5) is involved.

## Claims

### Claim 1

A compound of the formula I:
wherein R1 is C1-C4 branched or straight chain alkyl;
R2 is H;
R3 is H; C1-C6 branched or straight chain alkyl; C2-C4 alkenyl; or C2-C4 alkynyl;
R4 is H; C1-C6 branched or straight chain alkyl; or C2-C4 alkenyl;
R5 is SO2NR10R11;
R8 is H; or C1-C6 branched or straight chain alkyl;
R10 and R11 are each independently H; C1-C12 branched or straight chain alkyl; C1-C3 halogenated branched or straight chain alkyl; C2-C6 alkenyl; C2-C6 alkynyl or C3-C6 cycloalkyl; or R10 and R11 together with their attached nitrogen atom form a pyrrolinyl, pyrrolinone group, piperidyl, morpholinyl, or 4-N(R8)-piperazinyl; the said groups are optionally substituted with OH, CN, CO2R8, C1-C4 branched or straight chain alkyl, or C1-C3 alkoxyl;
or their pharmaceutically acceptable salts.

### Claim 2

The compound selected from the group consisting of:
2-[2-ethoxyl-5-(4-ethylpiperazinyl-1-sulfonyl)phenyl]-5-methyl-7-n-propyl-3,7-dihydropyrrolo[2,3-d]pyrimidin-4-one, the monohydrochloride, dihydrochloride and other possible hydrochloride thereof;
2-[2-methoxyl-5-(4-ethylpiperazinyl-1-sulfonyl)phenyl]-5-methyl-7-n-propyl-3,7-dihydropyrrolo[2,3-d]pyrimidin-4-one, and the hydrochloride thereof;
2-[2-n-propoxy-5-(4-ethylpiperazinyl-1-sulfonyl)phenyl]-5-methyl-7-n-propyl-3,7-dihydropyrrolo[2,3-d]pyrimidin-4-one, and the hydrochloride thereof;
2-[2-allyloxy-5-(4-ethylpiperazinyl-1-sulfonyl)phenyl]-5-methyl-7-n-propyl-3,7-dihydropyrrolo[2,3-d]pyrimidin-4-one, and the monohydrochloride, dihydrochloride and other possible hydrochloride thereof;
2-[2-n-propoxy-5-(4-ethylpiperazinyl-1-sulfonyl)phenyl]-5-ethyl-7-n-propyl-3,7-dihydropyrrolo[2,3-d]pyrimidin-4-one, the monohydrochloride, dihydrochloride and other possible hydrochloride thereof;
2-[2-ethoxyl-5-(4-methylpiperazinyl-1-sulfonyl)phenyl]-5-methyl-7-n-propyl-3,7-dihydropyrrolo[2,3-d]pyrimidin-4-one, the monohydrochloride, dihydrochloride and other possible hydrochloride thereof;
2-[2-ethoxyl-5-(4-methylpiperazinyl-1-sulfonyl)phenyl]-5-ethyl-7-n-propyl-3,7-dihydropyrrolo[2,3-d]pyrimidin-4-one, the monohydrochloride, dihydrochloride and other possible hydrochloride thereof;
2-[2-ethoxyl-5-(4-ethoxycarbonylpiperazinyl-1-sulfonyl)phenyl]-5-methyl-7-n-propyl-3,7-dihydropyrrolo[2,3-d]pyrimidin-4-one, the monohydrochloride, dihydrochloride and other possible hydrochloride thereof;
2-{2-ethoxyl-5-[4-(2-hydroxyethyl)piperazinyl-1-sulfonyl]phenyl}-5-methyl-7-n-propyl-3,7-dihydropyrrolo[2,3-d]pyrimidin-4-one, the monohydrochloride, dihydrochloride and other possible hydrochloride thereof;
2-[2-ethoxyl-5-(pyrrolidinyl-1-sulfonyl)phenyl]-5-methyl-7-n-propyl-3,7-dihydropyrrolo[2,3-d]pyrimidin-4-one, the monohydrochloride, dihydrochloride and other possible hydrochloride thereof;
2-{2-ethoxyl-5-[3-(2-oxy-pyrrolidin-1-yl)-n-propylamino-N-sulfonyl]phenyl}-5-methyl-7-n-propyl-3,7-dihydropyrrolo[2,3-d]pyrimidin-4-one, the monohydrochloride, dihydrochloride and other possible hydrochloride thereof;
2-{2-ethoxyl-5-[2-(pyrrolidin-1-yl)-ethylamino-N-sulfonyl]phenyl}-5-methyl-7-n-propyl-3,7-dihydropyrrolo[2,3-d]pyrimidin-4-one, the monohydrochloride, dihydrochloride and other possible hydrochloride thereof;
2-[2-ethoxyl-5-(morpholino-4-sulfonyl)phenyl]-5-methyl-7-n-propyl-3,7-dihydropyrrolo[2,3-d]pyrimidin-4-one, the monohydrochloride, dihydrochloride and other possible hydrochloride thereof;
2-{2-ethoxyl-5-[3-(morpholin-4-yl)-n-propylamino-N-sulfonyl]phenyl}-5-methyl-7-n-propyl-3,7-dihydropyrrolo[2,3-d]pyrimidin-4-one, the monohydrochloride, dihydrochloride and other possible hydrochloride thereof;
2-{2-ethoxyl-5-[2-(morpholin-4-yl)-ethylamino-N-sulfonyl]phenyl}-5-methyl-7-n-propyl-3,7-dihydropyrrolo[2,3-d]pyrimidin-4-one, the monohydrochloride, dihydrochloride and other possible hydrochloride thereof;
2-[2-ethoxyl-5-(2,6-dimethylmorpholino-N-sulfonyl)phenyl]-5-methyl-7-n-propyl-3,7-dihydropyrrolo[2,3-d]pyrimidin-4-one, the monohydrochloride, dihydrochloride and other possible hydrochloride thereof;
2-[2-ethoxyl-5-(1-benzylpiperidyl-4-aminosulfonyl)phenyl]-5-methyl-7-n-propyl-3,7-dihydropyrrolo[2,3-d]pyrimidin-4-one, the monohydrochloride, dihydrochloride and other possible hydrochloride thereof;
2-{2-ethoxyl-5-[2-(piperidin-1-yl)ethylamino-1-sulfonyl]phenyl}-5-methyl-7-n-propyl-3,7-dihydropyrrolo[2,3-d]pyrimidin-4-one, the monohydrochloride, dihydrochloride and other possible hydrochloride thereof;
2-[2-ethoxyl-5-(4-benzylpiperazinyl-1-sulfonyl)phenyl]-5-methyl-7-n-propyl-3,7-dihydropyrrolo[2,3-d]pyrimidin-4-one, the monohydrochloride, dihydrochloride and other possible hydrochloride thereof;
2-[2-ethoxyl-5-(4-phenylpiperazinyl-1-sulfonyl)phenyl]-5-methyl-7-n-propyl-3,7-dihydropyrrolo[2,3-d]pyrimidin-4-one, the monohydrochloride, dihydrochloride and other possible hydrochloride thereof;
2-[2-ethoxyl-5-(piperazinyl-1-sulfonyl)phenyl]-5-methyl-7-n-propyl-3,7-dihydropyrrolo[2,3-d]pyrimidin-4-one, the monohydrochloride, dihydrochloride and other possible hydrochloride thereof;
2-[2-ethoxyl-5-(4-benzo[1,3]-dioxol-5-yl-methylpiperazinyl-1-sulfonyl)phenyl]-5-methyl-7-n-propyl-3,7-dihydropyrrolo[2,3-d]pyrimidin-4-one, the monohydrochloride, dihydrochloride and other possible hydrochloride thereof;
2-{2-ethoxyl-5-[4-(3-phenyl-n-propan-1-yl)piperidyl-1-sulfonyl]phenyl}-5-methyl-7-n-propyl-3,7-dihydropyrrolo[2,3-d]pyrimidin-4-one, the monohydrochloride, dihydrochloride and other possible hydrochloride thereof;
2-[2-ethoxyl-5-(n-propylamino-1-sulfonyl)phenyl]-5-methyl-7-n-propyl-3,7-dihydropyrrolo[2,3-d]pyrimidin-4-one, the monohydrochloride, dihydrochloride and other possible hydrochloride thereof;
2-{2-ethoxyl-5-[N,N-di(2-hydroxyethyl)aminosulfonyl]phenyl}-5-methyl-7-n-propyl-3,7-dihydropyrrolo[2,3-d]pyrimidin-4-one, the monohydrochloride, dihydrochloride and other possible hydrochloride thereof;
2-{2-ethoxyl-5-[N-(2-hydroxyethyl)-N-methylaminosulfonyl]phenyl}-5-methyl-7-n-propyl-3,7-dihydropyrrolo[2,3-d]pyrimidin-4-one, the monohydrochloride, dihydrochloride and other possible hydrochloride thereof;
2-{2-ethoxyl-5-[N-(2-hydroxyethyl)-N-ethylaminosulfonyl]phenyl}-5-methyl-7-n-propyl-3,7-dihydropyrrolo[2,3-d]pyrimidin-4-one, the monohydrochloride, dihydrochloride and other possible hydrochloride thereof;
2-{2-ethoxyl-5-[N-(2-hydroxyethyl)-N-n-butylaminosulfonyl]phenyl}-5-methyl-7-n-propyl-3,7-dihydropyrrolo[2,3-d]pyrimidin-4-one, the monohydrochloride, dihydrochloride and other possible hydrochloride thereof;
2-[2-ethoxyl-5-(p-ethoxylcarboxylphenylamino-N-sulfonyl)phenyl]-5-methyl-7-n-propyl-3,7-dihydropyrrolo[2,3-d]pyrimidin-4-one, the monohydrochloride, dihydrochloride and other possible hydrochloride thereof;
2-[2-ethoxyl-5-(o-benzoylphenylamino-N-sulfonyl)phenyl]-5-methyl-7-n-propyl-3,7-dihydropyrrolo[2,3-d]pyrimidin-4-one, the monohydro chloride, dihydro chloride and other possible hydrochloride thereof;
2-[2-ethoxyl-5-(N2-acethydrazido-N1-sulfonyl)phenyl]-5-methyl-7-n-propyl-3,7-dihydropyrrolo[2,3-d]pyrimidin-4-one, the monohydrochloride and dihydrochloride and other possible hydrochloride thereof;
2-[2-ethoxyl-5-(2-dimethylaminoethylamino-N-sulfonyl)phenyl]-5-methyl-7-n-propyl-3,7-dihydropyrrolo[2,3-d]pyrimidin-4-one, the monohydrochloride, dihydrochloride and other possible hydrochloride thereof;
2-[2-ethoxyl-5-(4-ethylpiperazinyl-1-sulfonyl)phenyl]-5-ethyl-7-n-propyl-3,7-dihydropyrrolo[2,3-d]pyrimidin-4-one, the monohydrochloride, dihydrochloride and other possible hydrochloride thereof;
2-[2-ethoxyl-5-(4-ethylpiperazinyl-1-sulfonyl)phenyl]-5-morpholinomethyl-7-n-propyl-3,7-dihydropyrrolo[2,3-d]pyrimidin-4-one, the monohydrochloride, dihydrochloride and other possible hydrochloride thereof;
2-[2-ethoxyl-5-(4-ethylpiperazinyl-1-sulfonyl)phenyl]-5-(pyrimidinyl-2)-methyl-7-n-propyl-3,7-dihydropyrrolo[2,3-d]pyrimidin-4-one, the monohydrochloride, dihydrochloride and other possible hydrochloride thereof; and
2-[2-ethoxyl-5-(4-ethylpiperazinyl-1-sulfonyl)phenyl]-5-methyl-7-allyl-3,7-dihydropyrrolo[2,3-d]pyrimidin-4-one, the monohydrochloride, dihydrochloride and other possible hydrochloride thereof.

### Claim 3 (depends on 1, 2)

A pharmaceutical composition containing the compound according to claims 1 or 2 as an active ingredient and a pharmaceutically acceptable excipient.

### Claim 4 (depends on 1, 2)

A veterinary drug composition containing the compound according to claims 1 or 2 as an active ingredient and a veterinarily acceptable excipient.

### Claim 5 (depends on 1)

Intermediates for the manufacture of a compound of formula I according to claim 1 having the Formulae IB, IC and IG:
wherein R1 is C1-C4 branched or straight chain alkyl;
R2 is H;
R3 is H; C1-C6 branched or straight chain alkyl; C2-C4 alkenyl; or C2-C4 alkynyl;
R4 is H; C1-C6 branched or straight chain alkyl; or C2-C4 alkenyl;
R5 is SO2NR10R11;
R8 is H; or C1-C6 branched or straight chain alkyl;
R10 and R11 are each independently H; C1-C12 branched or straight chain alkyl; C1-C3 halogenated branched or straight chain alkyl; C2-C6 alkenyl; C2-C6 alkynyl or C3-C6 cycloalkyl; or R10 and R11 together with their attached nitrogen atom form a pyrrolinyl, pyrrolinone group, piperidyl, morpholinyl, or 4-N(R8)-piperazinyl; the said groups are optionally substituted with OH, CN, CO2R8, C1-C4 branched or straight chain alkyl, or C1-C3 alkoxyl.