阅读说明：本技术 一氧化氮释放第5型磷酸二酯酶抑制剂 (Nitric oxide releasing phosphodiesterase type 5 inhibitors ) 是由 N·阿尔米兰特 S·布兰比拉 L·斯托洛尼 F·因派纳提洛 E·巴斯蒂亚 于 2019-07-31 设计创作，主要内容包括：本发明涉及式(I)或(Ib)或(II)的一氧化氮释放第5型磷酸二酯酶(PDE5)抑制剂或其立体异构体或药学上可接受的盐,其可用于治疗与眼内压升高相关的眼病症诸如高眼压、青光眼或视网膜病变。本发明进一步涉及3-[(2S)-2,3-双(硝氧基)丙氧基]丙酸和6-(硝氧基)己酸,其用于治疗与眼内压升高相关的眼病症诸如高眼压、青光眼或视网膜病变。(The present invention relates to nitric oxide releasing phosphodiesterase type 5 (PDE5) inhibitors of formula (I) or (Ib) or (II) or a stereoisomer or pharmaceutically acceptable salt thereof, which are useful for the treatment of ocular disorders associated with elevated intraocular pressure such as ocular hypertension, glaucoma or retinopathy. The invention further relates to 3- [ (2S) -2, 3-bis (nitrooxy) propoxy]Propionic acid and 6- (nitrooxy) hexanoic acid for use in the treatment of ocular disorders associated with elevated intraocular pressure such as ocular hypertension, glaucoma or retinopathy.)

1. A compound of formula (I) or (II) or a stereoisomer or pharmaceutically acceptable salt thereof,

wherein:

R₁is a residue of a nitric oxide-releasing molecule of the formula:

R₁＝-C(O)-(O-CH₂)_y(CH₂)_m-[O-(CH₂)_n]_p-(CH-ONO₂)_q-CH₂-ONO₂

wherein:

y is 1 or 0;

p is 1 or 0;

q is 1 or 0;

m is an integer ranging from 1 to 10; preferably m is 1 to 6;

n is an integer ranging from 1 to 6; preferably n is 1 or 2;

R₂is ethyl or n-propyl;

R₃is methyl or ethyl;

with the proviso that when in formula (I), R₂When is ethyl, R₃Is methyl, or when R₂When it is n-propyl, R₃Is ethyl.

2. A compound of formula (I) or (II) according to claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein y is 0.

3. A compound of formula (I) or (II) according to claim 2, wherein R is R or a stereoisomer or pharmaceutically acceptable salt thereof₁Selected from:

4. a compound of formula (I) or (II) according to claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein y is 1.

5. A compound of formula (I) or (II) according to claim 4 or a stereoisomer or a drug thereofA pharmaceutically acceptable salt, wherein R₁Selected from:

6. a compound of formula (I) according to any one of claims 1 to 5, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R₂Is n-propyl, and R₃Is ethyl.

7. A compound of formula (I) according to any one of claims 1 to 5, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R₂Is ethyl, R₃Is methyl.

8. A stereoisomer or salt of a compound of formula (Ib), said compound having the formula

Wherein:

R₁is a residue of a nitric oxide-releasing molecule of the formula:

R₁＝-C(O)-(O-CH₂)_y(CH₂)_m-[O-(CH₂)_n]_p-(CH-ONO₂)_q-CH₂-ONO₂

wherein:

y is 1 or 0;

p is 1 or 0;

q is 1 or 0;

m is an integer ranging from 1 to 10;

n is an integer ranging from 1 to 6;

R₂is ethyl or n-propyl;

R₃is methyl or ethyl;

with the proviso that when R₂When is ethyl, then R₃Is methyl; when R is₂When it is n-propyl, then R₃Is an ethyl group; and is

With the proviso that when R₂Is ethyl, and R₃When y is 0 and p and q are 0, then m is not 2.

9. A compound of formula (Ib) according to claim 8, wherein R₁A group selected from formulas (IIIa) - (IIIh):

10. a compound of formula (Ib) according to claim 8, wherein R₁A group selected from formulas (IVa) to (IVh):

11. a compound of formula (Ib) according to claim 8, wherein R₂Is ethyl, and R₃Is methyl, or R₂Is n-propyl, and R₃Is ethyl.

12. A compound of formula (Ib) according to claim 9 or 10, wherein R₂Is ethyl, and R₃Is methyl.

13. A compound of formula (Ib) according to claim 9 or 10, wherein R₂Is n-propyl, and R₃Is ethyl.

14. The compound of claim 8 of formula (Ib) wherein y is 1.

15. A compound of formula (I) according to claim 1 or a stereoisomer or pharmaceutically acceptable salt thereof, selected from:

2- (4- (3- (5-ethyl-4-oxo-7-propyl-4, 5-dihydro-3H-pyrrolo [3,2-d ] pyrimidin-2-yl) -4-propoxyphenylsulfonyl) piperazin-1-yl) ethyl 3- (2, 3-bis (nitrooxy) propoxy) propionate (compound (1));

2- (2- (nitrooxy) ethoxy) acetic acid 2- (4- ((3- (5-ethyl-4-oxo-7-propyl-4, 5-dihydro-3H-pyrrolo [3,2-d ] pyrimidin-2-yl) -4-propoxyphenyl) sulfonyl) piperazin-1-yl) ethyl ester (compound (2));

2- (4- (3- (5-ethyl-4-oxo-7-propyl-4, 5-dihydro-3H-pyrrolo [3,2-d ] pyrimidin-2-yl) -4-propoxyphenylsulfonyl) piperazin-1-yl) ethyl 5, 6-bis (nitrooxy) hexanoate (compound (3));

2- (4- ((3- (5-ethyl-4-oxo-7-propyl-4, 5-dihydro-3H-pyrrolo [3,2-d ] pyrimidin-2-yl) -4-propoxyphenyl) sulfonyl) piperazin-1-yl) ethyl 6- (nitrooxy) hexanoate (compound (4));

2- (4- (3- (5-ethyl-4-oxo-7-propyl-4, 5-dihydro-3H-pyrrolo [3,2-d ] pyrimidin-2-yl) -4-propoxyphenylsulfonyl) piperazin-1-yl) ethyl carbonate 6- (nitrooxy) hexyl ester (compound (5));

2- (4- (3- (5-ethyl-4-oxo-7-propyl-4, 5-dihydro-3H-pyrrolo [3,2-d ] pyrimidin-2-yl) -4-propoxyphenylsulfonyl) piperazin-1-yl) ethyl carbonate 5, 6-bis (nitrooxy) hexyl ester (compound (6));

2- {4- [ 4-ethoxy-3- (5-methyl-4-oxo-7-propyl-4, 5-dihydro-1H-pyrrolo [3,2-d ] pyrimidin-2-yl) benzene-1-sulfonyl ] piperazin-1-yl } ethyl 5, 6-bis (nitrooxy) hexanoate (compound (7));

2- {4- [ 4-ethoxy-3- (5-methyl-4-oxo-7-propyl-4, 5-dihydro-1H-pyrrolo [3,2-d ] pyrimidin-2-yl) benzene-1-sulfonyl ] piperazin-1-yl } ethyl 6- (nitrooxy) hexanoate (Compound (8)).

16. A compound of formula (II) according to claim 1 or a stereoisomer or pharmaceutically acceptable salt thereof, selected from:

(S) - (1- (4- (3-chloro-4-methoxybenzylamino) -5- (pyrimidin-2-ylmethylcarbamoyl) pyrimidin-2-yl) pyrrolidin-2-yl) methyl 6- (nitrooxy) hexanoate (compound (9));

5, 6-bis (nitrooxy) hexanoic acid [ (2S) -1- (4- { [ (3-chloro-4-methoxyphenyl) methyl ] amino } -5- { [ (pyrimidin-2-yl) methyl ] carbamoyl } pyrimidin-2-yl) pyrrolidin-2-yl ] methyl ester (compound (10));

(S) - (1- (4- (3-chloro-4-methoxybenzylamino) -5- (pyrimidin-2-ylmethylcarbamoyl) pyrimidin-2-yl) pyrrolidin-2-yl) methyl 2- (2- (nitrooxy) ethoxy) acetate (Compound (11));

3- [2, 3-bis (nitrooxy) propoxy ] propanoic acid [ (2S) -1- (4- { [ (3-chloro-4-methoxyphenyl) methyl ] amino } -5- { [ (pyrimidin-2-yl) methyl ] carbamoyl } pyrimidin-2-yl) pyrrolidin-2-yl ] methyl ester (compound (12));

(S) - (1- (4- (3-chloro-4-methoxybenzylamino) -5- (pyrimidin-2-ylmethylcarbamoyl) pyrimidin-2-yl) pyrrolidin-2-yl) methyl carbonate 6- (nitrooxy) hexyl ester (compound (13));

carbonic acid ((S) -1- (4- (3-chloro-4-methoxybenzylamino) -5- (pyrimidin-2-ylmethylcarbamoyl) pyrimidin-2-yl) pyrrolidin-2-yl) methyl ester 5, 6-bis (nitrooxy) hexyl ester (compound (14)).

17. A compound of formula (I) or (II) according to claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, selected from:

(5S) -5, 6-bis (nitrooxy) hexanoic acid [ (2S) -1- (4- { [ (3-chloro-4-methoxyphenyl) methyl ] amino } -5- { [ (pyrimidin-2-yl) methyl ] carbamoyl } pyrimidin-2-yl) pyrrolidin-2-yl ] methyl ester (compound (10) - (5S));

3- [ (2S) -2, 3-bis (nitrooxy) propoxy ] propanoic acid [ (2S) -1- (4- { [ (3-chloro-4-methoxyphenyl) methyl ] amino } -5- { [ (pyrimidin-2-yl) methyl ] carbamoyl } pyrimidin-2-yl) pyrrolidin-2-yl ] methyl ester (compound (12) - (2S));

(S) - (1- (4- (3-chloro-4-methoxybenzylamino) -5- (pyrimidin-2-ylmethylcarbamoyl) pyrimidin-2-yl) pyrrolidin-2-yl) methyl 6- (nitrooxy) hexanoate 2-hydroxypropane-1, 2, 3-tricarboxylate ((compound (9) -citrate);

(5S) -5, 6-bis (nitrooxy) hexanoic acid ((S) -1- (4- (3-chloro-4-methoxybenzylamino) -5- (pyrimidin-2-ylmethylcarbamoyl) pyrimidin-2-yl) pyrrolidin-2-yl) methyl ester 2-hydroxypropane-1, 2, 3-tricarboxylate ((compound (10) - (5S) citrate);

2- (2- (nitrooxy) ethoxy) acetic acid (S) - (1- (4- (3-chloro-4-methoxybenzylamino) -5- (pyrimidin-2-ylmethylcarbamoyl) pyrimidin-2-yl) pyrrolidin-2-yl) methyl ester 2-hydroxypropane-1, 2, 3-tricarboxylate ((compound (11) citrate);

(ii) 3- ((S) -2, 3-bis (nitrooxy) propoxy) propionic acid ((S) -1- (4- (3-chloro-4-methoxybenzylamino) -5- (pyrimidin-2-ylmethylcarbamoyl) pyrimidin-2-yl) pyrrolidin-2-yl) methyl ester 2-hydroxypropane-1, 2, 3-tricarboxylate ((compound (12) - (2S) citrate);

3- [2, 3-bis- (nitrooxy) propoxy) ] propionic acid (S) -2- (4- (3- (5-ethyl-4-oxo-7-propyl-4, 5-dihydro-3H-pyrrolo [3,2-d ] pyrimidin-2-yl) -4-propoxyphenylsulfonyl) piperazin-1-yl) ethyl ester citrate (compounds (1) - (2S) citrate);

citrate salt of 2- (4- (3- (5-ethyl-4-oxo-7-propyl-4, 5-dihydro-3H-pyrrolo [3,2-d ] pyrimidin-2-yl) -4-propoxyphenylsulfonyl) piperazin-1-yl) ethyl 6- (nitrooxy) hexanoate (compound (4) citrate salt);

2-hydroxypropane-1, 2, 3-tricarboxylic acid [2- (nitrooxy) ethoxy ] acetic acid 2- {4- [3- (5-ethyl-4-oxo-7-propyl-4, 5-dihydro-3H-pyrrolo [3,2-d ] pyrimidin-2-yl) -4-propoxybenzene-1-sulfonyl ] piperazin-1-yl } ethyl ester (compound (2) citrate);

5, 6-bis (nitrooxy) hexanoic acid (S) -2- (4- (3- (5-ethyl-4-oxo-7-propyl-4, 5-dihydro-3H-pyrrolo [3,2-d ] pyrimidin-2-yl) -4-propoxyphenylsulfonyl) piperazin-1-yl) ethyl ester citrate (compound (3) - (5S) citrate);

(S) -2- (4- (3- (5-ethyl-4-oxo-7-propyl-4, 5-dihydro-3H-pyrrolo [3,2-d ] pyrimidin-2-yl) -4-propoxyphenylsulfonyl) piperazin-1-yl) 3- (2, 3-bis (nitrooxy) propoxy) propionic acid (S) -dihydrochloride (compound (1) - (2S) HCl salt);

carbonic acid ((S) -1- (4- (3-chloro-4-methoxybenzylamino) -5- (pyrimidin-2-ylmethylcarbamoyl) pyrimidin-2-yl) pyrrolidin-2-yl) methyl ester (S) -5, 6-bis (nitrooxy) hexyl ester (compounds (14) - (5S));

carbonic acid (S) - (1- (4- (3-chloro-4-methoxybenzylamino) -5- (pyrimidin-2-ylmethylcarbamoyl) pyrimidin-2-yl) pyrrolidin-2-yl) methyl ester 6- (nitrooxy) hexyl ester 2-hydroxypropane-1, 2, 3-tricarboxylate ((compound (13) citrate);

(S) - (1- (4- (3-chloro-4-methoxybenzylamino) -5- (pyrimidin-2-ylmethylcarbamoyl) pyrimidin-2-yl) pyrrolidin-2-yl) methyl 6- (nitrooxy) hexanoate fumarate (compound (9) fumarate);

6- (Nitropoxy) hexanoic acid (S) - (1- (4- (3-chloro-4-methoxybenzylamino) -5- (pyrimidin-2-ylmethylcarbamoyl) pyrimidin-2-yl) pyrrolidin-2-yl) methyl ester maleate (Compound (9) maleate).

18. A compound of formula (Ib) according to claim 8 selected from:

2- {4- [ 4-ethoxy-3- (1-methyl-7-oxo-3-propyl-6, 7-dihydro-1H-pyrazolo [4,3-d ] pyrimidin-5-yl) benzene-1-sulfonyl ] piperazin-1-yl } ethyl 5, 6-bis (nitrooxy) hexanoate (compound (7 b));

(S) -5, 6-bis (nitrooxy) hexanoic acid (S) -2- (4- ((4-ethoxy-3- (1-methyl-7-oxo-3-propyl-6, 7-dihydro-1H-pyrazolo [4,3-d ] pyrimidin-5-yl) phenyl) sulfonyl) piperazin-1-yl) ethyl ester (compound (7b) - (5S));

2- {4- [ 4-ethoxy-3- (1-methyl-7-oxo-3-propyl-6, 7-dihydro-1H-pyrazolo [4,3-d ] pyrimidin-5-yl) benzene-1-sulfonyl ] piperazin-1-yl } ethyl 6- (nitrooxy) hexanoate (compound (8 b));

2- {4- [ 4-ethoxy-3- (1-methyl-7-oxo-3-propyl-6, 7-dihydro-1H-pyrazolo [4,3-d ] pyrimidin-5-yl) benzene-1-sulfonyl ] piperazin-1-yl } ethyl 3- [2, 3-bis (nitrooxy) propoxy ] propionate (compound 15);

(S) -3- (2, 3-bis (nitrooxy) propoxy) propionic acid (S) -2- (4- ((4-ethoxy-3- (1-methyl-7-oxo-3-propyl-6, 7-dihydro-1H-pyrazolo [4,3-d ] pyrimidin-5-yl) phenyl) sulfonyl) piperazin-1-yl) ethyl ester (compound (15), (S) isomer).

19. A compound of formula (I) or formula (Ib) or formula (II) as claimed in any one of claims 1 to 18 or a stereoisomer or pharmaceutically acceptable salt thereof, for use as a medicament.

20. A compound of formula (I) or (Ib) or (II) as defined in any one of claims 1 to 18 or a stereoisomer or pharmaceutically acceptable salt thereof, for use in a method of treating a disease or disorder associated with elevated intraocular pressure.

21. A compound of formula (I) or (Ib) or (II) or a stereoisomer or pharmaceutically acceptable salt thereof, for use according to claim 20, wherein the disease or disorder is selected from ocular hypertension, glaucoma, open angle glaucoma, normal ocular tension glaucoma, pigmentary glaucoma, pseudoexfoliation glaucoma and drug-induced glaucoma.

22. A compound of formula (I) or (Ib) or (II) or a stereoisomer or pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 18 for use in a method of treating retinopathy including retinopathy of prematurity, retinal vein occlusion or diabetic macular edema.

23. An ophthalmic pharmaceutical composition comprising a compound of formula (I) or formula (Ib) or formula (II) according to any one of claims 1 to 18, or a stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

24. A composition comprising a compound of formula (I) or formula (Ib) or formula (II) according to any one of claims 1 to 18 and at least one further active agent selected from the following pharmaceutical classes: a beta-adrenergic antagonist, a prostaglandin analog, an adrenergic agonist, a carbonic anhydrase inhibitor, a cholinergic agonist, a steroid, a cholinesterase inhibitor, a soluble guanylate cyclase activator, a Rho-kinase inhibitor or cinaxiguat.

25. The composition of claim 24 in the form of a kit comprising a dosage form comprising a compound of formula (I) or formula (Ib) or formula (II) and a dosage form comprising another active agent selected from the following pharmaceutical classes: beta-adrenergic antagonists, prostaglandin analogs, adrenergic agonists, carbonic anhydrase inhibitors, cholinergic agonists, steroid and cholinesterase inhibitors, soluble guanylate cyclase activators, Rho-kinase inhibitors or cinaciguat.

26. The compound 3- [ (2S) -2, 3-bis (nitrooxy) propoxy ] propanoic acid for use in treating elevated intraocular pressure, ocular hypertension or a condition associated with elevated intraocular pressure.

27. The compound 6- (nitrooxy) hexanoic acid for use in treating elevated intraocular pressure, ocular hypertension, or a condition associated with elevated intraocular pressure or retinopathy.

28. The compound 3- [ (2S) -2, 3-bis (nitrooxy) propoxy ] propanoic acid or 6- (nitrooxy) hexanoic acid for use in a method of treating retinopathy including retinopathy of prematurity, retinal vein occlusion or diabetic macular edema.