Methods and compositions for treating retinal-related diseases using CCR3 inhibitors

文档序号：1590360 发布日期：2020-01-03 浏览：13次中文

阅读说明：本技术 使用ccr3抑制剂治疗视网膜相关疾病的方法和组合物 (Methods and compositions for treating retinal-related diseases using CCR3 inhibitors ) 是由 L.科拉迪尼 S.杰克逊 K.尼科利奇于 2018-04-04 设计创作，主要内容包括：提供用CCR3调节剂改善与视网膜相关疾病相关的视觉终点的方法。这类终点的实例是视敏度。可以改善视敏度和其它视觉终点的视网膜相关疾病包括早产儿视网膜病、年龄相关性黄斑变性、视网膜中央静脉阻塞和糖尿病性视网膜病。(Methods of using modulators of CCR3 to improve visual endpoints associated with retinal related diseases are provided. An example of such an endpoint is visual acuity. Retinal related diseases that can improve visual acuity and other visual endpoints include retinopathy of prematurity, age-related macular degeneration, central retinal vein occlusion, and diabetic retinopathy.)

1. A method of improving visual acuity in a subject diagnosed with a retinal related disease comprising administering a therapeutically effective amount of a compound of formula 1,

wherein

A is CH₂O or N-C_1-6An alkyl group;

R¹is selected from

NHR^1.1、NMeR^1.1；

NHR^1.2、NMeR^1.2；

NHCH₂-R^1.3；

NH-C_3-6Cycloalkyl, and optionally one carbon atom replaced by a nitrogen atom, and said ring being optionally substituted by one or two residues selected from the group consisting of: c_1-6Alkyl, O-C_1-6Alkyl, NHSO₂Phenyl, NHCONH-phenyl, halogen, CN, SO₂-C_1-6Alkyl, COO-C_1-6An alkyl group;

C_{9 or 10}Bicyclic ring, with one or two carbon atoms replaced by nitrogen atoms, and the ring system is bonded to the basic structure of formula 1 through nitrogen atoms, and the ring system is optionally substituted with one or two residues selected from the group consisting of: c_1-6Alkyl, COO-C_1-6Alkyl radical, C_1-6Haloalkyl, O-C_1-6Alkyl radical, NO₂Halogen, CN, NHSO₂-C_1-6Alkyl, methoxy-phenyl;

selected from NHCH (pyridyl) CH₂COO-C_1-6Alkyl, NHCH (CH)₂O-C_1-6Alkyl) -benzimidazolyl, optionally substituted with halogen or CN;

or 1-aminocyclopentyl optionally substituted with methyl-oxadiazole;

R^1.1is phenyl, optionally substituted with one or two residues selected from the group consisting of: c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Haloalkyl, C_1-6alkylene-OH, C_2-6alkenylene-OH, C_2-6alkynylene-OH, CH₂CON(C_1-6Alkyl radical)₂、CH₂NHCONH-C_3-6Cycloalkyl, CN, CO-pyridyl, CONR^1.1.1R^1.1.2、COO-C_1-6Alkyl, N (SO)₂-C_1-6Alkyl) (CH₂CON(C_1-4Alkyl radical)₂)O-C_1-6Alkyl, O-pyridyl, SO₂-C_1-6Alkyl, SO₂-C_1-6alkylene-OH, SO₂-C_3-6Cycloalkyl, SO₂Piperidinyl, SO₂NH-C_1-6Alkyl, SO₂N(C_1-6Alkyl radical)₂Halogen, CN, CO-morpholinyl, CH₂-a pyridyl or heterocyclic ring, said heterocyclic ring being optionally substituted by one or two groups selected from C_1-6Alkyl, NHC_1-6Alkyl and ═ O;

R^1.1.1selected from H, C_1-6Alkyl radical, C_3-6Cycloalkyl radical, C_1-6Haloalkyl, CH₂CON(C_1-6Alkyl radicals)₂、CH₂CO-azetidinyl, C_1-6alkylene-C_3-6Cycloalkyl radical, CH₂-pyranyl, CH₂-tetrahydrofuranyl, CH₂-furyl, C_1-6alkylene-OH or thiadiazolyl, optionally substituted by C_1-6Alkyl substitution selected from;

R^1.1.2H、C_1-6alkyl, SO₂C_1-6An alkyl group;

or R^1.1.1And R^1.1.2Together form a four-, five-or six-membered carbocyclic ring, optionally containing one N or O replacing a carbon atom of the ring, optionally selected from C_1-6Alkyl radical, C_1-4alkylene-OH, ═ O, and substitution of one or two residues;

R^1.1Is phenyl, wherein two adjacent residues together form a five-or six-membered carbocyclic aromatic or nonaromatic ring, which optionally independently of one another contains one or two N, S or SO replacing carbon atoms of the ring₂Wherein said ring is optionally substituted with C_1-4Alkyl or ═ O substitution;

R^1.2is selected from

Heteroaryl optionally substituted with one or two residues selected from the group consisting of: c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl radical, CH₂COO-C_1-6Alkyl, aryl, heteroaryl, and heteroaryl,CONR^1.2.1R^1.2.2、COR^1.2.3、COO-C_1-6Alkyl, CONH₂、O-C_1-6Alkyl, halogen, CN, SO₂N(C_1-6Alkyl radical)₂Or optionally selected from C_1-6Heteroaryl substituted with one or two residues of the group consisting of alkyl;

heteroaryl optionally substituted with a five-or six-membered carbocyclic non-aromatic ring containing, independently of each other, two N, O, S or SO replacing carbon atoms of the ring₂；

Aromatic or non-aromatic C_{9 or 10}Bicyclic, with one or two carbon atoms replaced by N, O or S, each optionally selected from N (C)_1-6Alkyl radical)₂、CONH-C_1-6Alkyl, ═ O, and one or two residue substitutions;

a heterocyclic non-aromatic ring optionally substituted with pyridyl; or

4, 5-dihydro-naphtho [2,1-d ]]Thiazole, optionally substituted with NHCO-C_1-6Alkyl substitution;

R^1.2.1selected from H, C_1-6Alkyl radical, C_1-6alkylene-C_3-6Cycloalkyl radical, C_1-4Alkylene-phenyl, C_1-4Alkylene-furyl group, C_3-6Cycloalkyl radical, C_1-4alkylene-O-C_1-4Alkyl radical, C_1-6Haloalkyl or a five-or six-membered carbocyclic non-aromatic ring, optionally containing, independently of one another, one or two N, O, S or SO replacing carbon atoms of the ring₂Optionally substituted by 4-cyclopropylmethyl-piperazinyl

R^1.2.2Selected from H, C_1-6An alkyl group;

R^1.2.3selected from five-or six-membered carbocyclic non-aromatic rings optionally containing, independently of each other, one or two N, O, S or SO replacing carbon atoms of said rings₂；

R^1.3Selected from phenyl, heteroaryl or indolyl, each of which is optionally substituted by one or two residues selected from the group consisting of: c_1-6Alkyl radical, C_3-6Cycloalkyl, O-C_1-6Alkyl, O-C_1-6A haloalkyl group,Phenyl, heteroaryl;

R²selected from the group consisting of: c_1-6Alkylene-phenyl, C_1-6Alkylene-naphthyl and C_1-6An alkylene-heteroaryl group; each of which is optionally substituted with one, two or three residues selected from the group consisting of: c_1-6Alkyl radical, C_1-6Haloalkyl, O-C_1-6Alkyl, O-C_1-6Haloalkyl, halogen;

R³is selected from H or C_1-6An alkyl group;

R⁴selected from H, or C_1-6An alkyl group;

or R³And R⁴Together form CH₂-CH₂A group;

to improve the visual acuity of the subject.

2. The method of claim 1, wherein the retinal-related disease is from the group consisting of: dry age-related macular degeneration, wet age-related macular degeneration, central retinal vein occlusion, retinopathy of prematurity, and diabetic retinopathy.

3. The method of claim 1 or 2, wherein the compound of formula 1, wherein

A is CH₂O or N-C_1-4An alkyl group;

R¹is selected from

NHR^1.1、NMeR^1.1；

NHR^1.2、NMeR^1.2；

NHCH₂-R^1.3；

C_{9 or 10}Bicyclic ring, with one or two carbon atoms replaced by a nitrogen atom and the ring system is bonded to the basic structure of formula 1 through a nitrogen atom, and the ring system is optionally substituted with one or two residues selected from the group consisting of: c_1-6Alkyl, COO-C_1-6Alkyl radical, C_1-6Haloalkyl, O-C_1-6Alkyl radical, NO₂Halogen, CN, NHSO₂-C_1-6Alkyl, m-methoxyphenyl;

selected from NHCH (pyridyl) CH₂COO-C_1-6Alkyl, NHCH (CH)₂O-C_1-6Alkyl) -benzimidazolyl, optionally substituted with Cl;

or 1-aminocyclopentyl optionally substituted with methyl-oxadiazolyl;

R^1.1is phenyl, optionally substituted with one or two residues selected from the group consisting of: c_1-6Alkyl radical, C_1-6Haloalkyl, CH₂CON(C_1-6Alkyl radical)₂、CH₂NHCONH-C_3-6Cycloalkyl, CN, CONR^1.1.1R^1.1.2、COO-C_1-6Alkyl, O-C_1-6Alkyl, SO₂-C_1-6Alkyl, SO₂-C_1-6alkylene-OH, SO₂-C_3-6Cycloalkyl, SO₂Piperidinyl, SO₂NH-C_1-6Alkyl, SO₂N(C_1-6Alkyl radical)₂Halogen, CN, CO-morpholinyl, CH₂-pyridyl or optionally selected from the group consisting of C_1-6Alkyl, NHC_1-6Alkyl, heterocycle substituted with one or two residues of the group consisting of O;

R^1.1.2selected from H, C_1-6Alkyl or SO₂C_1-6An alkyl group;

or R^1.1.1And R^1.1.2Together form a four-, five-or six-membered carbocyclic ring, optionally containing one O replacing a carbon atom of the ring, optionally selected from CH₂Substitution of one or two residues of the group consisting of OH

R^1.2Is selected from

Heteroaryl optionally substituted with one or two residues selected from the group consisting of: c_1-6Alkyl radical, C_3-6Cycloalkyl radical, CH₂COO-C_1-6Alkyl, CONR^1.2.1R^1.2.2、COO-C_1-6Alkyl, CONH₂、O-C_1-6Alkyl, halogen, CN, CO-pyrrolidinyl, CO-morpholinyl or optionally selected from C_1-6Heteroaryl substituted with one or two residues of the group consisting of alkyl;

benzothiazolyl, indazolyl, dihydro-indolyl, indanyl, tetrahydro-quinolinyl, each of which is optionally selected from the group consisting of N (C)_1-6Alkyl radical)₂、CONH-C_1-6Alkyl, ═ O, and one or two residue substitutions;

piperidinyl, optionally substituted with pyridinyl; or

4, 5-dihydro-naphtho [2,1-d ]]Thiazole, optionally substituted with NHCO-C_1-6Alkyl is substituted, wherein

R^1.2.1Is H or C_1-6An alkyl group;

R^1.2.2is H, or C_1-6An alkyl group;

R^1.3selected from phenyl, pyrazolyl, isoxazolyl, pyrimidinyl, indolyl or oxadiazolyl, each of which is optionally substituted with one or two residues selected from the group consisting of: c_1-6Alkyl radical, C_3-6Cycloalkyl, O-C_1-6Alkyl, O-C_1-6A haloalkyl group;

R²is selected from CH₂-phenyl or CH₂-naphthyl, both optionally substituted by one or two residues selected from the group consisting of: c_1-6Alkyl radical, C_1-6Haloalkyl, O-C_1-6Alkyl, O-C_1-6Haloalkyl, halogen; or CH₂-thienyl, optionally substituted with one or two residues selected from the group consisting of halogen;

R³is H or C_1-4An alkyl group;

R⁴is H or C_1-4An alkyl group;

or R³And R⁴Together form CH₂-CH₂A group.

4. The method of claim 1 or 2, wherein the compound of formula 1 is

A is CH₂O or NMe;

R¹is selected from

NHR^1.1、NMeR^1.1；

NHR^1.2、NMeR^1.2；

NHCH₂-R^1.3；

NH-cyclohexyl optionally substituted with one or two residues selected from the group consisting of: c_1-4Alkyl, NHSO₂-phenyl, NHCONH-phenyl, halogen;

NH-pyrrolidinyl, optionally selected from SO₂-C_1-4Alkyl, COO-C_1-4Alkyl, substituted with one or two residues of the group;

piperidinyl, optionally selected from NHSO₂-C_1-4Alkyl, m-methoxyphenyl, or one or two residues of the group;

an dihydro-indolyl, dihydro-isoindolyl, tetrahydro-quinolinyl, or tetrahydro-isoquinolinyl group, optionally substituted with one or two residues selected from the group consisting of: c_1-4Alkyl, COO-C_1-4Alkyl radical, C_1-4Haloalkyl, O-C_1-4Alkyl radical, NO₂A halogen;

selected from NHCH (pyridyl) CH₂COO-C_1-4Alkyl, NHCH (CH)₂O-C_1-4Alkyl) -benzimidazolyl, optionally substituted with Cl;

or 1-aminocyclopentyl optionally substituted with methyl-oxadiazolyl; wherein

R^1.1Is phenyl, optionally substituted with one or two residues selected from the group consisting of: c_1-4Alkyl radical, C_1-4Haloalkyl, CH₂CON(C_1-4Alkyl radical)₂、CH₂NHCONH-C_3-6Cycloalkyl, CN, CONR^1.1.1R^1.1.2、COO-C_1-4Alkyl, O-C_1-4Alkyl, SO₂-C_1-4Alkyl, SO₂-C_1-4alkylene-OH, SO₂-C_3-6Cycloalkyl, SO₂Piperidinyl, SO₂NH-C_1-4Alkyl, SO₂N(C_1-4Alkyl radical)₂Halogen, CO-morpholinyl, CH₂-pyridyl or imidazolidinyl, piperidinyl, oxazacyclohexanyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyridyl, pyrimidinyl, each of which is optionally substituted with one or two residues selected from the group consisting of: c_1-4Alkyl, NHC_1-4Alkyl, ═ O;

R^1.1.1selected from H, C_1-6Alkyl radical, C_3-6Cycloalkyl radical, C_1-4Haloalkyl, CH₂CON(C_1-4Alkyl radicals)₂、CH₂CO-azetidinyl, C_1-4alkylene-C_3-6Cycloalkyl radical, CH₂-pyranyl, CH₂-tetrahydrofuranyl, CH₂-furyl, C_1-4alkylene-OH or thiadiazolyl, optionally substituted by C_1-4Alkyl substitution;

R^1.1.2selected from H, C_1-4Alkyl, SO₂C_1-4An alkyl group;

R^1.2Is selected from

Pyridyl, pyridazinyl, pyrrolesA group selected from the group consisting of pyrazolyl, isoxazolyl, thiazolyl, thiadiazolyl, optionally substituted with one or two residues selected from the group consisting of: c_1-4Alkyl radical, C_3-6Cycloalkyl radical, CH₂COO-C_1-4Alkyl, CONR^1.2.1R^1.2.2、COO-C_1-4Alkyl, CONH₂、O-C_1-4Alkyl, halogen, CO-pyrrolidinyl, CO-morpholinyl or pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, each optionally selected from C_1-4Alkyl, substituted with one or two residues of the group;

benzothiazolyl, indazolyl, dihydro-indolyl, indanyl, tetrahydro-quinolinyl, each of which is optionally selected from the group consisting of N (C)_1-4Alkyl radical)₂、CONH-C_1-4Alkyl, ═ O, and one or two residue substitutions;

piperidinyl, optionally substituted with pyridinyl; or

4, 5-dihydro-naphtho [2,1-d ]]Thiazole, optionally substituted with NHCO-C_1-4Alkyl is substituted, wherein

R^1.2.1Is H or C_1-4An alkyl group;

R^1.2.2is H or C_1-4An alkyl group;

R^1.3selected from phenyl, pyrazolyl, isoxazolyl, pyrimidinyl, indolyl or oxadiazolyl, each of which is optionally substituted with one or two residues selected from the group consisting of: c_1-4Alkyl radical, C_3-6Cycloalkyl, O-C_1-4Alkyl, O-C_1-4A haloalkyl group;

R²is selected from CH₂-phenyl or CH₂-naphthyl, both optionally substituted by one or two residues selected from the group consisting of: c_1-4Alkyl radical, C_1-4Haloalkyl, O-C_1-4Haloalkyl, halogen; or CH₂-thienyl, optionally substituted with one or two residues selected from the group consisting of halogen;

R³is H;

R⁴is H;

or R³And R⁴Together form CH₂-CH₂A group.

5. The method of claim 1 or 2, wherein formula 1 is

A is CH₂O or NMe;

R¹is selected from

NHR^1.1、NMeR^1.1；

NHR^1.2、NMeR^1.2；

NHCH₂-R^1.3；

NH-piperidinyl, optionally substituted with pyridinyl;

NH-cyclohexyl optionally substituted with one or two residues selected from the group consisting of: t-Bu, NHSO₂-phenyl, NHCONH-phenyl, F;

NH-pyrrolidinyl, optionally selected from SO₂One or two residues of the group consisting of Me, COO-t-Bu;

piperidinyl, optionally selected from NHSO₂-n-Bu, m-methoxyphenyl, or two residues;

dihydro-indolyl, dihydro-isoindolyl, tetrahydro-quinolyl or tetrahydro-isoquinolyl, optionally selected from Me, COOMe, CF₃、OMe、NO₂F, Br;

selected from NHCH (pyridyl) CH₂COOMe、NHCH(CH₂OMe) -benzimidazolyl, optionally substituted with Cl;

or 1-aminocyclopentyl optionally substituted with methyl-oxadiazolyl; wherein

R^1.1Is phenyl, optionally substituted with one or two residues selected from the group consisting of: me, Et, t-Bu, CF₃、CH₂CONMe₂、CH₂NHCONH-cyclohexyl, CN, CONR^1.1.1R^1.1.2、COOMe、COOEt、OMe、SO₂Me、SO₂CH₂CH₂OH、SO₂Et、SO₂-cyclopropyl, SO₂Piperidinyl, SO₂NHEt、SO₂NMeEt, F, Cl, CO-morpholinyl, CH₂-pyridyl or imidazolidinyl, piperidinyl, oxazidohexanyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyridyl, pyrimidinyl, each of which is optionally substituted with one or two residues selected from the group consisting of Me, NHMe, ═ O;

R^1.1.1selected from H, Me, Et, t-Bu, i-Pr, cyclopropyl, CH₂-i-Pr、CH₂-t-Bu、CH(CH₃)CH₂CH₃、CH₂CHF₂、CH₂CONMe₂、CH₂CO-azetidinyl, CH₂-cyclopropyl, CH₂-cyclobutyl, CH₂-pyranyl, CH₂-tetrahydrofuranyl, CH₂-furyl, CH₂CH₂OH or thiadiazolyl optionally substituted by Me;

R^1.1.2selected from H, Me, Et, SO₂Me or SO₂Et，

Or R^1.1.1And R^1.1.2Together form a four-, five-or six-membered carbocyclic ring, optionally containing one O replacing a carbon atom of the ring, optionally selected from CH₂One or two residues of the group consisting of OH;

R^1.2is selected from

Pyridyl, pyrrolyl, pyrazolyl, isoxazolyl, thiazolyl, thiadiazolyl, optionally substituted with one or two residues selected from the group consisting of: me, Et, Pr, Bu, cyclopropyl, CH₂COOEt、CONR^1.2.1R^1.2.2、COOMe、COOEt、CONH₂OMe, Cl, Br, CO-pyrrolidinyl, CO-morpholinyl or pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, each of which is optionally substituted with Me;

benzothiazolyl, indazolyl, dihydro-indolyl, indanyl, tetrahydro-quinolinyl, each of which is optionally selected from the group consisting of NMe₂One or two residue substitutions of the group consisting of, CONHMe, ═ O;

4, 5-dihydro-naphtho [2,1-d ] thiazole, optionally substituted with NHCOMe, wherein

R^1.2.1Is H or Me;

R^1.2.2is H or Me;

R²Is selected from CH₂-phenyl or CH₂-naphthyl, both optionally substituted by one or two residues selected from the group consisting of: CH (CH)₃、CF₃、OCF₃F, Cl, Br, Et; or CH₂-thienyl, optionally substituted with one or two residues selected from the group consisting of Cl, Br;

R³is H;

R⁴is H;

or R³And R⁴Together form CH₂-CH₂A group.

6. The method of claim 1 or 2, wherein formula 1 is

A is CH₂O or NMe;

R¹is selected from

NHR^1.1

NHR^1.2，

R^1.1Is phenyl, optionally substituted with one or two residues selected from the group consisting of: me, Et, Bu, CF₃、CH₂CONMe₂、CH₂NHCONH-cyclohexyl, CN, CONR^1.1.1R^1.1.2、COOMe、COOEt、OMe、SO₂Me、SO₂CH₂CH₂OH、SO₂Et、SO₂-cyclopropyl, SO₂Piperidinyl, SO₂NHEt、SO₂NMeEt, F, Cl, CO-morpholinyl, CH₂Pyridyl or imidazolidinyl, piperidyl, oxazacyclohexanyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyridineOptionally substituted with one or two residues selected from the group consisting of Me, NHMe, ═ O; wherein

R^1.1.1Selected from H, Me, Et, t-Bu, i-Pr, cyclopropyl, CH₂-i-Pr、CH₂-t-Bu、CH(CH₃)CH₂CH₃、CH₂CHF₂、CH₂CONMe₂、CH₂CO-azetidinyl, CH₂-cyclopropyl, CH₂-cyclobutyl, CH₂-pyranyl, CH₂-tetrahydrofuranyl, CH₂-furyl, CH₂CH₂OH or thiadiazolyl optionally substituted by Me;

R^1.1.2selected from H, Me, Et, SO₂Me、SO₂Et；

R^1.2Is selected from

4, 5-dihydro-naphtho [2,1-d ] thiazole, optionally substituted with NHCOMe, wherein

R^1.2.1Is H or Me;

R^1.2.2is H or Me;

R²is selected from CH₂-phenyl or CH₂-naphthyl, both optionally selected from CH₃、CF₃、OCF₃F, Cl, Br, Et;

R³is H; and is

R⁴Is H.

7. The method of claim 1 or 2, wherein formula 1 is

A is CH₂O or NMe;

R¹is selected from

R²Is selected from

R³Is H;

R⁴is H;

or R³And R⁴Together form CH₂-CH₂A group.

8. The method of claim 1 or 2, wherein the compound of formula 1 administered is

9. The method of claim 1 or 2, wherein the compound of formula 1 administered is

10. The method of claim 1 or 2, wherein the compound of formula 1 administered is

11. The method of claim 1 or 2, wherein the compound of formula 1 administered is

12. The method of claim 1 or 2, wherein the compound of formula 1 administered is

13. The method of claim 1 or 2, wherein the compound of formula 1 administered is

14. The method of claim 1 or 2, wherein the compound of formula 1 administered is

15. The method of claim 1 or 2, wherein the compound of formula 1 administered is

16. The method of claim 1 or 2, wherein the compound of formula 1 administered is

17. The method of claim 1 or 2, wherein the compound of formula 1 administered is

18. The method of claim 1 or 2, wherein the compound of formula 1 administered is

19. The method of claim 1 or 2, wherein the compound of formula 1 administered is

20. The method of claim 1 or 2, wherein the compound of formula 1 administered is

21. The method of claim 1 or 2, wherein the compound of formula 1 administered is

22. The method of claim 1 or 2, wherein the compound of formula 1 administered is

23. The method of claim 1 or 2, wherein the compound of formula 1 administered is

24. The method of claim 1 or 2, wherein the compound of formula 1 administered is

25. The method of claim 1 or 2, wherein the compound is a co-crystal of the formula

Wherein

R¹Is C_1-6Alkyl radical, C_1-6Haloalkyl, O-C_1-6Haloalkyl, halogen;

m is 1,2 or 3;

R^2aand R^2bEach independently selected from H, C_1-6Alkyl radical, C_1-6Alkenyl radical, C_1-6Alkynyl, C_3-6Cycloalkyl, COO-C_1-6Alkyl, O-C_1-6Alkyl, CONR^2b.1R^2b.2Or halogen;

R^2b.1is H, C_1-6Alkyl radical, C_0-4alkyl-C_3-6Cycloalkyl radicals, or C_1-6A haloalkyl group;

R^2b.2is H or C_1-6An alkyl group;

or R^2b.1And R^2b.2Together are C_3-6Alkylene, forming a heterocyclic ring with the nitrogen atom, wherein optionally one carbon atom or the ring is replaced by an oxygen atom

R³Is H or C_1-6An alkyl group;

x is an anion selected from the group consisting of: chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, benzoate, citrate, salicylate, fumarate, tartrate, dibenzoyltartrate, oxalate, succinate, benzoate, and p-toluenesulfonate;

j is 0, 0.5, 1, 1.5 or 2;

wherein the co-crystal former is selected from the group consisting of; orotic acid, hippuric acid, L-pyroglutamic acid, D-pyroglutamic acid, nicotinic acid, L- (+) -ascorbic acid, saccharin, piperazine, 3-hydroxy-2-naphthoic acid, mucic acid (galactaric acid), pamoic acid (methylenepamoic acid), stearic acid, cholic acid, deoxycholic acid, nicotinamide, isonicotinamide, succinamide, uracil, L-lysine, L-proline, D-valine, L-arginine, glycine.

26. The method of claim 1 or 2, wherein the compound is a co-crystal of the formula

R^2aIs H, C_1-6Alkyl radical, C_1-6Alkenyl radical, C_1-6Alkynyl, C_3-6Cycloalkyl, O-C_1-6Alkyl or CONR^2a.1R^2a.2；

R^2a.1Is H, C_1-6Alkyl or C_1-6A haloalkyl group;

R^2a.2is H or C_1-6An alkyl group;

R^2bis H, C_1-6Alkyl radical, C_1-6Alkenyl radical, C_1-6Alkynyl, C_3-6Cycloalkyl, COO-C_1-6Alkyl, O-C_1-6Alkyl, CONR^2b.1R^2b.2Or halogen;

R^2b.1is H, C_1-6Alkyl radical, C_0-4alkyl-C_3-6Cycloalkyl or C_1-6A haloalkyl group;

R^2b.2is H or C_1-6An alkyl group;

or R^2b.1And R^2b.2Together are C_3-6Alkylene, which together with the nitrogen atom forms a heterocyclic ring, wherein optionally one carbon atom or the ring is replaced by an oxygen atom.

27. The method of claim 1 or 2, wherein the compound is a co-crystal of the formula

R¹Is C_1-6Alkyl radical, C_1-6Haloalkyl, O-C_1-6Haloalkyl or halogen;

m is 1 or 2;

R^2ais H or C_1-4An alkyl group;

R^2bis H or CONR^2b.1R^2b.2；

R^2b.1Is C_1-4Alkyl radical, C_0-4alkyl-C_3-6Cycloalkyl or C_1-4A haloalkyl group;

R^2b.2is H or C_1-4An alkyl group;

or R^2b.1And R^2b.2Together are C_3-6Alkylene, forming a heterocyclic ring with said nitrogen atom, wherein optionally one carbon atom or said ring is replaced by an oxygen atom

R³Is H or C_1-6An alkyl group;

x is an anion selected from the group consisting of chloride or dibenzoyl tartrate, and

j is 1 or 2.

28. The method of claim 1 or 2, wherein the compound is a co-crystal of the formula

R^2aIs H or C_1-4An alkyl group;

R^2bis H or CONR^2b.1R^2b.2；

R^2b.1Is C_1-4An alkyl group;

R^2b.2is C_1-4An alkyl group.

29. The method of claim 1 or 2, wherein the compound is a co-crystal of the formula

R^2aIs H or C_1-4An alkyl group;

R^2bis H or CONR^2b.1R^2b.2；

R^2b.1Is C_0-4alkyl-C_3-6A cycloalkyl group;

R^2b.2is H or C_1-4An alkyl group.

30. The method of claim 1 or 2, wherein the compound is a co-crystal of the formula

R^2aIs H or C_1-4An alkyl group;

R^2bis H or CONR^2b.1R^2b.2；

R^2b.1Is C_1-4A haloalkyl group;

R^2b.2is H, C_1-4An alkyl group.

31. The method of claim 1 or 2, wherein the compound is a co-crystal of formula (la) according to claim 25, wherein R is^2b.1And R^2b.2Together are C_3-6Alkylene, forming a heterocyclic ring with said nitrogen atom, wherein optionally one carbon atom or said ring is replaced by an oxygen atom.

32. The method of claim 1 or 2, wherein the compound is a co-crystal having the formula shown below,

wherein j is a number of 0 s,

and the co-crystal former is selected from the group consisting of: l- (+) -ascorbic acid, mucic acid, pamoic acid, nicotinic acid, succinamide, nicotinamide, isonicotinamide, L-lysine and L-proline.

33. The method of claim 1 or 2, wherein the compound is a crystalline salt of the formula,

34. the method of claim 1 or 2, wherein the compound is a crystalline salt of the formula,

35. the method of claim 33, wherein the crystalline salt is characterized by four highest X-ray powder diffraction peaks occurring at 3.72, 13.60, 16.89, and 19.34 degrees 2 Θ (± 0.05 degrees 2 Θ) when measured using cuka radiation.

36. The method of claim 34, wherein the crystalline salt is characterized by four highest X-ray powder diffraction peaks occurring at 16.02, 16.86, 19.45, and 19.71 degrees 2 Θ (± 0.05 degrees 2 Θ) when measured using cuka radiation.

37. The method of claim 1 or 2, wherein the compound comprises a co-crystal of at least one compound of formula (la) according to claim 25 and a pharmaceutically acceptable carrier.

38. The method according to claim 1 or 2, wherein the compound of formula 1 is administered in the form of individual optical isomers, mixtures of individual enantiomers, racemates or in the form of enantiomerically pure compounds.

39. The method of claim 1 or 2, wherein the compound is a pharmaceutical composition comprising one or more compounds of the formula as active ingredients,

wherein

R¹Is H, C_1-6Alkyl radical, C_0-4alkyl-C_3-6Cycloalkyl or C_1-6A haloalkyl group;

R²is H or C_1-6An alkyl group;

x is an anion selected from the group consisting of chloride or 1/2 dibenzoyl tartrate; and is

j is 1 or 2, and

a first diluent, a second diluent, a binder, a disintegrant, and a lubricant.

40. The method of claim 39, wherein the pharmaceutical composition is characterized by

R¹Is H or methyl;

R²is H or methyl;

x is an anion selected from the group consisting of chloride or 1/2 dibenzoyl tartrate; and is

j is 1 or 2

41. The method of claim 39, wherein the pharmaceutical composition is characterized by X being chloride and j being 2.

42. The method of claim 39, 40 or 41, wherein the pharmaceutical composition further comprises an additional disintegrant.

43. The method of claim 39, 40, or 41, wherein the pharmaceutical composition further comprises an additional glidant.

44. The method of claim 39, 40, or 41, wherein the diluent of the pharmaceutical composition further comprises cellulose powder, anhydrous dicalcium phosphate, dehydrated dicalcium phosphate, erythritol, low-substituted hydroxypropyl cellulose, mannitol, pregelatinized starch, or xylitol.

45. The method of claim 39, 40, or 41, wherein the lubricant of the pharmaceutical composition is talc, polyethylene glycol, calcium behenate, calcium stearate, hydrogenated castor oil, or magnesium stearate.

46. The method of claim 39, 40 or 41, wherein the binder of the pharmaceutical composition is copovidone (copolymer of vinylpyrrolidone with other vinyl derivatives), Hydroxypropylmethylcellulose (HPMC), Hydroxypropylcellulose (HPC) or polyvinylpyrrolidone (povidone).

47. The method of claim 39, 40, 41, 42, 43, 44, 45 or 46, wherein the disintegrant of the pharmaceutical composition of claim is corn starch.

48. The method of claim 39, 40, 41, 42, 43, 44, 45, 46 or 47, wherein the optional glidant of the pharmaceutical composition is colloidal silicon dioxide.

49. The method of claim 39, wherein the pharmaceutical composition further comprises

50. The method of claim 39, wherein the pharmaceutical composition further comprises

51. The method of claim 42, wherein the additional disintegrant of the pharmaceutical composition is crospovidone.

52. The method of claim 39, wherein the pharmaceutical composition is in a capsule, tablet or film-coated tablet dosage form.

53. The method of claim 52, wherein the pharmaceutical composition further comprises 2-4% film coating.

54. The method of claim 53, wherein the film coating comprises a film forming agent, a plasticizer, a glidant, and optionally one or more pigments.

55. The method of claim 54, wherein the film coating comprises polyvinyl alcohol (PVA) or Hydroxypropylmethylcellulose (HPMC), polyethylene glycol (PEG), talc, titanium dioxide, and iron oxide.

56. The method of any one of the preceding claims, further comprising administering a therapeutically effective amount of an anti-VEGF therapy.

Technical Field

The present invention relates to materials and methods for improving visual acuity in an individual in need thereof.

Background

Among the various retinal-related diseases, there are those that manifest themselves early in life and those that manifest themselves in association with aging. An example of the former class of diseases is retinopathy of prematurity (ROP). Examples of age-related retinal-related diseases include: age-related macular degeneration (AMD), which is the most common macular degenerative disease; central Retinal Vein Occlusion (CRVO), and diabetic retinopathy. Untreated retinal related diseases can lead to statutory blindness.

AMD is the leading cause of irreversible blindness in developed countries for people 50 years or older. (Jager, R. et al, New England Journal of Medicine 358(2606-17), 2008). AMD is a term used to describe a family of diseases all characterized by progressive loss of central visual acuity associated with abnormalities of bruch's membrane, choroid, neuroretina and/or retinal pigment epithelium. In the early stages of AMD, commonly referred to as age-related macular degeneration (ARM), the accumulation of drusen (biochemical by-products of photoreceptor cells that accumulate in bruch's membrane, classified by their appearance) and disorders of Retinal Pigment Epithelium (RPE) are often observed.

AMD that becomes clinically advanced is divided into two forms- "dry", non-exudative or atrophic AMD and exudative "wet" or neovascular AMD. Dry AMD occurs in about 15% of AMD patients, and wet AMD occurs in about 10% of AMD patients. Wet AMD is considered to be the more debilitating form of AMD, and is thought to be caused by the growth of abnormal choroidal neovascular membranes (CNVM). These new blood vessels grow from choroidal capillaries, under the RPE or subretinal space, and leak serum and blood. This fluid accumulates in the subretinal pigment epithelium (sub-RPE) and subretinal space as well as in the neurosensory retina, and in turn causes measurable thickening of the macula. If the fovea involves CNVM, the resulting edema and hemorrhage can severely impair Visual Acuity (VA), resulting in severe loss of visual acuity.

It is estimated that approximately 10% of people 65-74 years of age and 30% of people 75-85 years of age exhibit symptoms of AMD. The current standard of care for wet AMD is anti-angiogenic therapy, such as ranibizumab administered Intravitreally (IVT) (i.e., injected directly into the eye)

And Abbesypu

These therapies target vascular endothelial growth factors (VEGF, VEGF-a) and their angiogenesis promoting properties. Monthly IVT injections, however, are associated with adverse effects of geographic atrophy. (Desai, SJ et al, "Current ophthalmic report (Curr Opthalmol. Rep.) (2017, 2 months 01)). Currently, there is no effective less invasive treatment, underscoring the unmet need for orally administered non-anti-VEGF based therapies for the treatment of AMD. In addition to alleviating and reversing symptoms and the significant detrimental effects on visual acuity in patients, such treatments have the additional benefit of increasing compliance. IVT injections increase the risk to the patient and are a burden to both the patient and the caregiver.

The mechanistic basis for anti-VEGF therapy is also at risk. VEGF, and VEGF-A in particular, has a physiological cytoprotective effect in the retina. Modulation of VEGF expression and activity may be toxic to a variety of cell types. (Ambati, J., et al, Neuron 75(1):26-39,2012, 7 months). Evidence suggests that anti-VEGF-a therapy may also promote physiological changes in the retinal vasculature in the short term as well as long-term RPE toxicity. (Papadopoulou DN et al, Ophthalmology (Ophthalmology)116(9):1755-61 (2009); Sacu S et al, ophthalmologic research and visual acuity (invest. Ophthalmol. Vis. Sci.)52(6):3046-50(2011), and Rofagha S et al, J.Essel.Eseqeul (am. J.Ophthalmol.)159(5):915-24 (2015)).

In contrast, treatment with CC motif chemokine receptor 3(CCR3) antagonists did not alter VEGF-A levels or broadly affect the immune system. Additionally, the CCR3 antagonist may be in the form of a small organic molecule and may be prepared in an oral formulation. The compounds, co-crystals, salts and formulations of the present invention provide highly specific and potent small molecule modulators of human CC chemokine receptor type 3, which is the primary receptor for eotaxin-1. The CCR 3/eotaxin axis is a key chemokine for eosinophils, mast cells, and (in the retinal environment) endothelial cells of retinal vasculature, and studies in rodents have shown promise in alleviating neovascularization associated with retinal disease.

Despite this promise, the industry has failed to develop CCR3 antagonists for the treatment of retinal-related diseases. However, the compounds, co-crystals, salts and formulations disclosed herein that specifically modulate/antagonize CCR3 are effective in improving visual acuity in a large number of subjects, even though their effect on neovascularization is insignificant.

Disclosure of Invention

Methods of treating retinal-related diseases in a patient are provided, including dry and wet age-related macular degeneration, central retinal vein occlusion, retinopathy of prematurity, and diabetic retinopathy. A method of improving visual acuity in a subject (e.g., a subject diagnosed with a retinal-related disease) is provided. Aspects of the methods include modulating the principal receptor for CCR3, CCL 11/eotaxin-1 by administering an effective amount of a CCR3 antagonist of the invention. The methods comprise administering to a subject or patient a therapeutically effective dose of a CCR3 antagonist (e.g., a compound of formula 1 described herein) and monitoring a specific clinical endpoint.

Drawings

FIG. 1 is a table of the potency and species selectivity of the study products of the present invention.

Figure 2 depicts the overall clinical trial design and plan, including screening, treatment and follow-up periods, using the study products of the present invention.

Figure 3 depicts the mean central 1mm retinal thickness of a patient on the clinical trial time line depicted in figure 2.

Fig. 4 is a descriptive statistical table of neovascular leakage on the timeline of the clinical trial depicted in fig. 2.

Fig. 5 depicts the Best Corrected Visual Acuity (BCVA) for the number of letters read by the patient over the trial time depicted in fig. 2. The visual acuity of BCVA was tested using the ETDRS chart.

Detailed Description

Methods of treating symptoms of a retinal-related disease are provided, the methods comprising administering a compound of the formula discussed below. One embodiment of the invention comprises a method of improving visual acuity in a subject having a retinal related disease comprising administering a therapeutically effective amount of a compound from the formula discussed below. Additional embodiments include administering a therapeutically effective amount of a compound, wherein the compound is in the form of a co-crystal or salt of the formula discussed below. Other embodiments of the invention include administering a therapeutically effective amount of a compound, wherein the compound is in the form of an individual optical isomer, a mixture of individual enantiomers, a racemate or an enantiomerically pure compound. Additional embodiments of the invention further comprise administering a therapeutically effective amount of a compound, wherein the compound is in the form of pharmaceutical compositions and formulations discussed further below.

Another embodiment of the invention comprises a method of improving visual acuity in a subject having a retinal-related disease comprising administering a therapeutically effective amount of a compound from the formulae discussed below in combination with the current us standard of care for retinal-related diseases. Other embodiments of the invention include the administration of a therapeutically effective amount of a compound from the formulae discussed below with anti-VEGF-A therapyIn combination, the anti-VEGF-A therapy is, for example, an antibody to VEGF-A (e.g., ranibizumab

) (ii) a BevacizumabRecombinant fusion proteins that bind to one or more VEGF receptor types (e.g. aflibercept,) (ii) a Or a small organic molecule that binds to VEGF-A or one or more of its receptor types (e.g., VEGF receptor 1 or 2).

"treating" or "treatment" refers to at least ameliorating one or more symptoms associated with a retinal related disease afflicting a patient, wherein ameliorating is used in a broad sense to mean at least reducing the magnitude of a parameter, such as a symptom associated with the disease being treated. Thus, treatment further comprises that the pathological condition, or at least the symptoms associated therewith, are completely inhibited, e.g., prevented from occurring or from being stopped (e.g., terminated), such that the patient no longer suffers from the injury, or at least the symptoms that characterize the injury. In some instances, "treating" or the like means obtaining a desired pharmacological and/or physiological effect. The effect may be prophylactic in terms of completely or partially preventing a disease or a symptom thereof, and/or may be therapeutic in terms of a partial or complete cure for a disease and/or a side effect attributable to a disease. "treatment" can be any treatment of a disease in a subject, and includes: (a) preventing a disease from occurring in a subject that may be predisposed to the disease but has not yet been diagnosed with the disease; (b) inhibiting the disease, i.e., arresting its development; or (c) relieving the disease, i.e., causing regression of the disease. Treatment can result in a variety of different physical manifestations, e.g., modulation of gene expression, increased neurogenesis, regeneration of a tissue or organ, etc. Treatment of an ongoing disease occurs in some embodiments, wherein the treatment stabilizes or reduces adverse clinical symptoms in the patient. Such treatment may be performed prior to complete loss of function of the affected tissue. The present therapies can be administered during and in some cases after the symptomatic phase of the disease.

In certain instances, the subject is a mammal. Mammalian species that can be treated by the methods of the invention include canines and felines; a horse; cattle; sheep; and primates, including humans. The methods, compositions and reagents of the invention are also applicable to animal models, including small mammals, such as rodents, lagomorphs, etc., e.g., for experimental studies.

a.Compound (I)

The methods of the invention further comprise administering to the subject the following compounds. In the groups, radicals or moieties defined in the "compound" moiety, the number of carbon atoms is generally specified before the group, e.g. C_1-6Alkyl represents an alkyl group or a group having 1 to 6 carbon atoms. Typically, for groups comprising two or more subgroups as disclosed in the "compounds" section herein, the last named group is the point of attachment of the group, e.g., "thioalkyl" refers to a monovalent group of the formula HS-Alk-. Unless otherwise indicated below, the term control and the conventional definition of the valency of the conventional stabilizing atoms are presumed and carried out in all formulae and groups.

One embodiment of the invention further comprises administering to the subject a compound of formula 1, wherein

A is CH₂O or N-C_1-6An alkyl group;

R¹selected from NHR^1.1、NMeR^1.1；NHR^1.2、NMeR^1.2；NHCH₂-R^1.3；NH-C_3-6Cycloalkyl, and optionally one carbon atom is replaced by a nitrogen atom, and the ring is optionally substituted by one or two residues selected from the group consisting of: c_1-6Alkyl, O-C_1-6Alkyl, NHSO₂Phenyl, NHCONH-phenyl, halogen, CN, SO₂-C_1-6Alkyl, COO-C_1-6An alkyl group; c_{9 or 10}Bicyclic ring, and one or two carbon atomsSubstituted by a nitrogen atom and the ring system is bonded to the basic structure of formula 1 through a nitrogen atom, and the ring system is optionally substituted by one or two residues selected from the group consisting of: c_1-6Alkyl, COO-C_1-6Alkyl radical, C_1-6Haloalkyl, O-C_1-6Alkyl radical, NO₂Halogen, CN, NHSO₂-C_1-6Alkyl, methoxy-phenyl; selected from NHCH (pyridyl) CH₂COO-C_1-6Alkyl, NHCH (CH)₂O-C_1-6Alkyl) -benzimidazolyl, optionally substituted with halogen or CN; or 1-aminocyclopentyl optionally substituted with methyl-oxadiazole;

R^1.1.1selected from H, C_1-6Alkyl radical, C_3-6Cycloalkyl radical, C_1-6Haloalkyl, CH₂CON(C_1-6Alkyl radicals)₂、CH₂CO-azetidinyl, C_1-6alkylene-C_3-6Cycloalkyl radical, CH₂-pyranyl, CH₂-tetrahydrofuranyl、CH₂-furyl, C_1-6alkylene-OH or thiadiazolyl, optionally substituted by C_1-6Alkyl substitution;

R^1.1.2H、C_1-6alkyl, SO₂C_1-6An alkyl group; or

R^1.1.1And R^1.1.2Together form a four-, five-or six-membered carbocyclic ring, optionally containing one N or O replacing carbon atoms of the ring, optionally substituted by one or two groups selected from C_1-6Alkyl radical, C_1-4alkylene-OH, ═ O; or

R^1.2selected from heteroaryl, optionally substituted with one or two residues selected from the group consisting of: c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl radical, CH₂COO-C_1-6Alkyl, CONR^1.2.1R^1.2.2、COR^1.2.3、COO-C_1-6Alkyl, CONH₂、O-C_1-6Alkyl, halogen, CN, SO₂N(C_1-6Alkyl radical)₂Or optionally selected from C_1-6Heteroaryl substituted with one or two residues of the group consisting of alkyl; heteroaryl, optionally substituted by a five-or six-membered carbocyclic non-aromatic ring containing, independently of one another, two N, O, S or SO₂N, O, S or SO replacing a carbon atom of said ring₂(ii) a Aromatic or non-aromatic C_{9 or 10}Bicyclic, with one or two carbon atoms replaced by N, O or S, each optionally selected from N (C)_1-6Alkyl radical)₂、CONH-C_1-6Alkyl, ═ O, and one or two residue substitutions; a heterocyclic non-aromatic ring, optionally substituted with pyridyl; or 4, 5-dihydronaphtho [2,1-d ]]Thiazole, optionally substituted with NHCO-C_1-6Alkyl substitution;

R^1.2.2Selected from H, C_1-6An alkyl group;

R^1.2.3selected from five-or six-membered carbocyclic non-aromatic rings, optionally containing, independently of one another, one or two N, O, S or SO replacing carbon atoms of said rings₂；

R²selected from the group consisting of: c_1-6Alkylene-phenyl, C_1-6Alkylene-naphthyl, and C_1-6An alkylene-heteroaryl group; each of which is optionally substituted with one, two or three residues selected from the group consisting of: c_1-6Alkyl radical, C_1-6Haloalkyl, O-C_1-6Alkyl, O-C_1-6Haloalkyl, halogen;

R³selected from H, C_1-6An alkyl group;

R⁴selected from H, C_1-6An alkyl group; or

R³And R⁴Together form CH₂-CH₂A group.

Another embodiment of the invention further comprises administering to the subject a compound of formula 1 (above), wherein

A is CH₂O or N-C_1-4An alkyl group;

R¹selected from NHR^1.1、NMeR^1.1；NHR^1.2、NMeR^1.2；NHCH₂-R^1.3(ii) a Wherein

R^1.1Is phenyl, optionally substituted with one or two residues selected from the group consisting of: c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Haloalkyl, C_1-6alkylene-OH, C_2-6alkenylene-OH, C_2-6alkynylene-OH, CH₂CON(C_1-6Alkyl radical)₂、CH₂NHCONH-C_3-6Cycloalkyl, CN, CO-pyridyl, CONR^1.1.1R^1.1.2、COO-C_1-6Alkyl, N (SO)₂-C_1-6Alkyl) (CH₂CON(C_1-4Alkyl radical)₂)O-C_1-6Alkyl, O-pyridyl, SO₂-C_1-6Alkyl, SO₂-C_1-6alkylene-OH, SO₂-C_3-6Cycloalkyl, SO₂Piperidinyl, SO₂NH-C_1-6Alkyl, SO₂N(C_1-6Alkyl radical)₂Halogen, CN, CO-morpholinyl, CH₂-a pyridyl or heterocyclic ring, said heterocyclic ring being optionally substituted by one or two groups selected from C_1-6Alkyl, NHC_1-6Alkyl, ═ O;

R^1.1.2selected from H, C_1-6Alkyl, SO₂C_1-6An alkyl group;

or R^1.1.1And R^1.1.2Together form a four-, five-or six-membered carbocyclic ring, optionally containing one N or O replacing carbon atoms of the ring, optionally substituted by one or two groups selected from C_1-6Alkyl radical, C_1-4alkylene-OH, ═ O; or

R^1.1Selected from phenyl, wherein two adjacent residues together form a five-or six-membered carbocyclic aromatic or non-aromatic ring, optionally containing, independently of each other, one or two N, S or SO replacing carbon atoms of said ring₂Wherein said ring is optionally substituted with C_1-4Alkyl or ═ O substitution;

R^1.2.1Selected from H, C_1-6Alkyl radical, C_1-6alkylene-C_3-6Cycloalkyl radical, C_1-4Alkylene-phenyl, C_1-4Alkylene-furyl group, C_3-6Cycloalkyl radical, C_1-4alkylene-O-C_1-4Alkyl radical, C_1-6Haloalkyl or a five-or six-membered carbocyclic non-aromatic ring, optionally containing, independently of one another, one or two N, O, S or SO replacing carbon atoms of the ring₂Optionally substituted by 4-cyclopropylmethyl-piperazinyl

R^1.2.2Selected from H, C_1-6An alkyl group;

R^1.2.3selected from five-or six-membered carbocyclic non-aromatic rings, optionally containing, independently of one another, one or two N, O, S or SO replacing carbon atoms of said rings₂；

R^1.3Selected from phenyl, heteroAryl or indolyl, each of which is optionally substituted by one or two residues selected from the group consisting of: c_1-6Alkyl radical, C_3-6Cycloalkyl, O-C_1-6Alkyl, O-C_1-6Haloalkyl, phenyl, heteroaryl; wherein in some instances, R^1.3Selected from phenyl, pyrazolyl, isoxazolyl, pyridinyl, pyrimidinyl, indolyl or oxadiazolyl, each of which is optionally substituted with one or two residues selected from the group consisting of: c_1-6Alkyl radical, C_3-6Cycloalkyl, O-C_1-6Alkyl, O-C_1-6Haloalkyl, phenyl, pyrrolidinyl;

R²selected from the group consisting of: c_1-6Alkylene-phenyl, C_1-6Alkylene-naphthyl, and C_1-6Alkylene-thienyl; each of which is optionally substituted with one, two or three residues selected from the group consisting of: c_1-6Alkyl radical, C_1-6Haloalkyl, O-C_1-6Alkyl, O-C_1-6Haloalkyl, halogen;

R³selected from H, C_1-4An alkyl group;

R⁴selected from H, C_1-4An alkyl group; or

R³And R⁴Together form CH₂-CH₂A group.

Another embodiment of the invention further comprises administering to the subject a compound of formula 1 (above), wherein

A is CH₂O or N-C_1-4An alkyl group;

R¹selected from NHR^1.1、NMeR^1.1；

R^1.1.2selected from H, C_1-6Alkyl, SO₂C_1-6An alkyl group;

R²selected from the group consisting of: c_1-6Alkylene-phenyl, C_1-6Alkylene-naphthyl, and C_1-6Alkylene-thienyl; each of which isOptionally substituted with one, two or three residues selected from the group consisting of: c_1-6Alkyl radical, C_1-6Haloalkyl, O-C_1-6Alkyl, O-C_1-6Haloalkyl, halogen;

R³selected from H, C_1-4An alkyl group;

R⁴selected from H, C_1-4An alkyl group; or

R³And R⁴Together form CH₂-CH₂A group.

Another embodiment of the invention further comprises administering to the subject a compound of formula 1, wherein

A is CH₂O or N-C_1-4An alkyl group;

R¹selected from NHR^1.2、NMeR^1.2(ii) a Wherein

R^1.2Selected from heteroaryl, optionally substituted with one or two residues selected from the group consisting of: c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl radical, CH₂COO-C_1-6Alkyl, CONR^1.2.1R^1.2.2、COR^1.2.3、COO-C_1-6Alkyl, CONH₂、O-C_1-6Alkyl, halogen, CN, SO₂N(C_1-4Alkyl radical)₂Or optionally selected from C_1-6Heteroaryl substituted with one or two residues of the group consisting of alkyl; heteroaryl, optionally substituted by a five-or six-membered carbocyclic non-aromatic ring containing, independently of one another, two N, O, S or SO₂N, O, S or SO replacing a carbon atom of said ring₂(ii) a Benzothiazolyl, indazolyl, dihydro-indolyl, indanyl, tetrahydro-quinolinyl, each of which is optionally substituted with one or two residues selected from the group consisting of: n (C)_1-6Alkyl radical)₂、CONH-C_1-6Alkyl, ═ O; piperidinyl, optionally substituted with pyridinyl; or 4, 5-dihydro-naphtho [2,1-d ]]Thiazole, optionally substituted with NHCO-C_1-6The substitution of the alkyl group is carried out,

R^1.2.2Selected from H, C_1-6An alkyl group;

R^1.2.3selected from five-or six-membered carbocyclic non-aromatic rings, optionally containing, independently of one another, one or two N, O, S or SO replacing carbon atoms of said rings₂；

R²Selected from the group consisting of: c_1-6Alkylene-phenyl, C_1-6Alkylene-naphthyl, and C_1-6Alkylene-thienyl; each of which is optionally substituted with one, two or three residues selected from the group consisting of: c_1-6Alkyl radical, C_1-6Haloalkyl, O-C_1-6Alkyl, O-C_1-6Haloalkyl, halogen;

R³selected from H, C_1-4An alkyl group;

R⁴selected from H, C_1-4An alkyl group; or

R³And R⁴Together form CH₂-CH₂A group.

Another embodiment of the invention further comprises administering to the subject a compound of formula 1 (above), wherein

A is CH₂O or N-C_1-4An alkyl group;

R¹selected from NHR^1.2、NMeR^1.2(ii) a Wherein

R^1.2.2Selected from H, C_1-6An alkyl group;

R^1.2.3selected from five-or six-membered carbocyclic non-aromatic rings, optionally containing, independently of one another, one or two N, O, S or SO replacing carbon atoms of said rings₂；

R³selected from H, C_1-4An alkyl group;

R⁴selected from H, C_1-4An alkyl group; or

R³And R⁴Together form CH₂-CH₂A group.

Another embodiment of the invention further comprises administering to the subject a compound of formula 1, wherein

A is CH₂O or N-C_1-4An alkyl group;

R¹is NHCH₂-R^1.3(ii) a Wherein the content of the first and second substances,

R^1.3selected from phenyl, pyrazolyl, isoxazolyl, pyridinyl, pyrimidinyl, indolyl or oxadiazolyl, each of which is optionally substituted with one or two residues selected from the group consisting of: c_1-6Alkyl radical, C_3-6Cycloalkyl, O-C_1-6Alkyl, O-C_1-6Haloalkyl, phenyl, pyrrolidinyl;

R³selected from H, C_1-4An alkyl group;

R⁴selected from H, C_1-4An alkyl group; or

R³And R⁴Together form CH₂-CH₂A group.

Another embodiment of the invention further comprises administering to the subject a compound of formula 1, wherein

A is selected from CH₂O or N-C_1-4An alkyl group;

R¹selected from NHR^1.1、NMeR^1.1；NHR^1.2、NMeR^1.2；NHCH₂-R^1.3；NH-C_3-6Cycloalkyl, and optionally one carbon atom is replaced by a nitrogen atom, and the ring is optionally substituted by one or two residues selected from the group consisting of: c_1-6Alkyl, O-C_1-6Alkyl, NHSO₂Phenyl, NHCONH-phenyl, halogen, CN, SO₂-C_1-6Alkyl, COO-C_1-6An alkyl group; c_{9 or 10}Bicyclic ring, with one or two carbon atoms replaced by nitrogen atoms and the ring system being bound to the ring via the nitrogen atomThe basic structure of formula 1, and said ring system is optionally substituted with one or two residues selected from the group consisting of: c_1-6Alkyl, COO-C_1-6Alkyl radical, C_1-6Haloalkyl, O-C_1-6Alkyl radical, NO₂Halogen, CN, NHSO₂-C_1-6Alkyl, methoxy-phenyl; selected from NHCH (pyridyl) CH₂COO-C_1-6Alkyl, NHCH (CH)₂O-C_1-6Alkyl) -benzimidazolyl, optionally substituted with halogen or CN; or 1-aminocyclopentyl optionally substituted with methyl-oxadiazole; wherein

R^1.1Is phenyl, optionally substituted with one or two residues selected from the group consisting of: c_1-6Alkyl radical, C_1-6Haloalkyl, CH₂CON(C_1-6Alkyl radical)₂、CH₂NHCONH-C_3-6Cycloalkyl, CN, CONR^1.1.1R^1.1.2、COO-C_1-6Alkyl, O-C_1-6Alkyl, SO₂-C_1-6Alkyl, SO₂-C_1-6alkylene-OH, SO₂-C_3-6Cycloalkyl, SO₂Piperidinyl, SO₂NH-C_1-6Alkyl, SO₂N(C_1-6Alkyl radical)₂Halogen, CN, CO-morpholinyl, CH₂-pyridyl or optionally selected from the group consisting of C_1-6Alkyl, NHC_1-6Alkyl and one or two residue substituted heterocycle of the group consisting of ═ O;

R^1.1.2selected from H, C_1-6Alkyl, or SO₂C_1-6An alkyl group; or

R^1.1.1And R^1.1.2Together form a four-, five-or six-membered carbocyclic ring, optionally containing one O replacing a carbon atom of the ring, optionally substituted with one or two groups selected from the group consisting of CH₂A residue substitution of the group consisting of OH;

R^1.2selected from heteroaryl, optionally substituted with one or two residues selected from the group consisting of: c_1-6Alkyl radical, C_3-6Cycloalkyl radical, CH₂COO-C_1-6Alkyl, CONR^1.2.1R^1.2.2、COO-C_1-6Alkyl, CONH₂、O-C_1-6Alkyl, halogen, CN, CO-pyrrolidinyl, CO-morpholinyl, or heteroaryl optionally substituted with one or two residues selected from the group consisting of: c_1-6An alkyl group; benzothiazolyl, indazolyl, dihydro-indolyl, indanyl, tetrahydro-quinolinyl, each of which is optionally substituted with one or two residues selected from the group consisting of: n (C)_1-6Alkyl radical)₂、CONH-C_1-6Alkyl, ═ O; piperidinyl, optionally substituted with pyridinyl; and 4, 5-dihydro-naphtho [2,1-d ]]Thiazole, optionally substituted with NHCO-C_1-6The substitution of the alkyl group is carried out,

R^1.2.1selected from H, C_1-6An alkyl group;

R^1.2.2selected from H, C_1-6An alkyl group;

R²is selected from C_1-6Alkylene-phenyl or C_1-6Alkylene-naphthyl, both optionally substituted with one or two residues selected from the group consisting of: c_1-6Alkyl radical, C_1-6Haloalkyl, O-C_1-6Alkyl, O-C_1-6Haloalkyl, halogen; or CH₂-thienyl, optionally substituted with one or two residues selected from the group consisting of halogen;

R³is selected fromH、C_1-4An alkyl group;

R⁴selected from H, C_1-4An alkyl group; or

R³And R⁴Together form CH₂-CH₂A group.

Another embodiment of the invention further comprises administering to the subject a compound of formula 1, wherein

A is CH₂O or NMe;

R¹selected from NHR^1.1、NMeR^1.1；NHR^1.2、NMeR^1.2；NHCH₂-R^1.3(ii) a NH-cyclohexyl optionally substituted with one or two residues selected from the group consisting of: c_1-4Alkyl, NHSO₂-phenyl, NHCONH-phenyl, halogen; NH-pyrrolidinyl, optionally substituted with one or two residues selected from the group consisting of: SO (SO)₂-C_1-4Alkyl, COO-C_1-4An alkyl group; piperidinyl optionally substituted with one or two residues selected from the group consisting of: NHSO₂-C_1-4Alkyl, m-methoxyphenyl; an dihydro-indolyl, dihydro-isoindolyl, tetrahydro-quinolinyl, or tetrahydro-isoquinolinyl group, optionally substituted with one or two residues selected from the group consisting of: c_1-4Alkyl, COO-C_1-4Alkyl radical, C_1-4Haloalkyl, O-C_1-4Alkyl radical, NO₂A halogen; selected from NHCH (pyridyl) CH₂COO-C_1-4Alkyl, NHCH (CH)₂O-C_1-4Alkyl) -benzimidazolyl, optionally substituted with Cl; or 1-aminocyclopentyl optionally substituted with methyl-oxadiazolyl; wherein

R^1.1.1Selected from H, C_1-6Alkyl radical, C_3-6Cycloalkyl radical, C_1-4Haloalkyl, CH₂CON(C_1-4Alkyl radicals)₂、CH₂CO-azetidinyl, C_1-4alkylene-C_3-6Cycloalkyl radical, CH₂-pyranyl, CH₂-tetrahydrofuranyl, CH₂-furyl, C_1-4alkylene-OH or thiadiazolyl, optionally substituted by C_1-4Alkyl substitution;

R^1.1.2selected from H, C_1-4Alkyl, or SO₂C_1-4An alkyl group; or

R^1.2Selected from pyridyl, pyridazinyl, pyrrolyl, pyrazolyl, isoxazolyl, thiazolyl, thiadiazolyl, optionally substituted with one or two residues selected from the group consisting of: c_1-4Alkyl radical, C_3-6Cycloalkyl radical, CH₂COO-C_1-4Alkyl, CONR^1.2.1R^1.2.2、COO-C_1-4Alkyl, CONH₂、O-C_1-4Alkyl, halo, CO-pyrrolidinyl, CO-morpholinyl or pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, each of which is optionally substituted with one or two residues selected from the group consisting of: c_1-4An alkyl group; benzothiazolyl, indazolylDihydro-indolyl, indanyl, tetrahydro-quinolinyl, each of which is optionally substituted with one or two residues selected from the group consisting of: n (C)_1-4Alkyl radical)₂、CONH-C_1-4Alkyl, ═ O; piperidinyl, optionally substituted with pyridinyl; 4, 5-dihydro-naphtho [2,1-d ]]Thiazole, optionally substituted with NHCO-C_1-4Alkyl substitution;

R^1.2.1selected from H, C_1-4An alkyl group;

R^1.2.2selected from H, C_1-4An alkyl group;

R^1.3selected from phenyl, pyrazolyl, isoxazolyl, pyrimidinyl, indolyl or oxadiazolyl, each of which is optionally substituted with one or two residues selected from the group consisting of: c_1-4Alkyl radical, C_3-6Cycloalkyl, O-C_1-4Alkyl, O-C_1-4A haloalkyl group;

R²is selected from C_1-6Alkylene-phenyl or C_1-6Alkylene-naphthyl, both optionally substituted with one or two residues selected from the group consisting of: c_1-4Alkyl radical, C_1-4Haloalkyl, O-C_1-4Haloalkyl, halogen; or CH₂-thienyl, optionally substituted with one or two residues selected from the group consisting of halogen;

R³is H;

R⁴is H; or

R³And R⁴Together form CH₂-CH₂A group.

Another embodiment of the invention further comprises administering to the subject a compound of formula 1, wherein

A is CH₂O or NMe;

R¹selected from NHR^1.1、NMeR^1.1；NHR^1.2、NMeR^1.2；NHCH₂-R^1.3(ii) a NH-piperidinyl, optionally substituted with pyridinyl; NH-cyclohexyl optionally substituted with one or two residues selected from the group consisting of: t-Bu, NHSO₂-phenyl, NHCONH-phenyl, F; NH-pyrrolidinyl, which is optionalOne or two residues selected from the group consisting of: SO (SO)₂Me, COO-t-Bu; piperidinyl optionally substituted with one or two residues selected from the group consisting of: NHSO₂-n-Bu, m-methoxyphenyl; an dihydro-indolyl, dihydro-isoindolyl, tetrahydro-quinolinyl, or tetrahydro-isoquinolinyl group, optionally substituted with one or two residues selected from the group consisting of: me, COOMe, CF₃、OMe、NO₂F, Br; selected from NHCH (pyridyl) CH₂COOMe、NHCH(CH₂OMe) -benzimidazolyl, optionally substituted with Cl; or 1-aminocyclopentyl optionally substituted with methyl-oxadiazolyl;

R^1.1is phenyl, optionally substituted with one or two residues selected from the group consisting of: me, Et, t-Bu, CF₃、CH₂CONMe₂、CH₂NHCONH-cyclohexyl, CN, CONR^1.1.1R^1.1.2、COOMe、COOEt、OMe、SO₂Me、SO₂CH₂CH₂OH、SO₂Et、SO₂-cyclopropyl, SO₂Piperidinyl, SO₂NHEt、SO₂NMeEt, F, Cl, CO-morpholinyl, CH₂-pyridyl or imidazolidinyl, piperidinyl, oxazidohexanyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyridyl, pyrimidinyl, each of which is optionally substituted with one or two residues selected from the group consisting of Me, NHMe, ═ O;

R^1.1.2selected from H, Me, Et, SO₂Me、SO₂Et; or

R^1.2Selected from pyridyl, pyrrolyl, pyrazolyl, isoxazolyl, thiazolyl, thiadiazolyl, optionally substituted with one or two residues selected from the group consisting of: me, Et, Pr, Bu, cyclopropyl, CH₂COOEt、CONR^1.2.1R^1.2.2、COOMe、COOEt、CONH₂OMe, Cl, Br CO-pyrrolidinyl, CO-morpholinyl or pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, each of which is optionally substituted with Me; benzothiazolyl, indazolyl, dihydro-indolyl, indanyl, tetrahydro-quinolinyl, each of which is optionally substituted with one or two residues selected from the group consisting of: NMe₂CONHMe, ═ O; 4, 5-dihydro-naphtho [2,1-d ]]Thiazole, optionally substituted with NHCOMe, wherein

R^1.2.1Selected from H, Me;

R^1.2.2selected from H, Me;

R³is H;

R⁴is H; or

R³And R⁴Together form CH₂-CH₂A group.

Another embodiment of the invention further comprises administering to the subject a compound of formula 1, wherein

A is CH₂O or NMe;

R¹selected from NHR^1.1Or NHR^1.2Wherein

R^1.1Is phenyl, optionally substituted with one or two residues selected from the group consisting of: me, Et, Bu, CF₃、CH₂CONMe₂、CH₂NHCONH-cyclohexyl, CN, CONR^1.1.1R^1.1.2、COOMe、COOEt、OMe、SO₂Me、SO₂CH₂CH₂OH、SO₂Et、SO₂-cyclopropyl, SO₂Piperidinyl, SO₂NHEt、SO₂NMeEt, F, Cl, CO-morpholinyl, CH₂-pyridyl or imidazolidinyl, piperidinyl, oxazidohexanyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyridyl, pyrimidinyl, each optionally substituted with one or two residues selected from the group consisting of Me, NHMe, ═ O;

R^1.1.2selected from H, Me, Et, SO₂Me、SO₂Et

Or R^1.1.1And R^1.1.2Together form a four-, five-or six-membered carbocyclic ring, optionally containing one O replacing a carbon atom of the ring, optionally substituted with one or two groups selected from the group consisting of CH₂A residue substitution of the group consisting of OH;

R^1.2selected from pyridyl, pyrrolyl, pyrazolyl, isoxazolyl, thiazolyl, thiadiazolylOptionally substituted with one or two residues selected from the group consisting of: me, Et, Pr, Bu, cyclopropyl, CH₂COOEt、CONR^1.2.1R^1.2.2、COOMe、COOEt、CONH₂OMe, Cl, Br CO-pyrrolidinyl, CO-morpholinyl or pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, each of which is optionally substituted with Me; benzothiazolyl, indazolyl, dihydro-indolyl, indanyl, tetrahydro-quinolinyl, each of which is optionally substituted with one or two residues selected from the group consisting of: NMe₂CONHMe, ═ O; 4, 5-dihydro-naphtho [2,1-d ]]Thiazole, optionally substituted with NHCOMe, wherein

R^1.2.1Selected from H, Me;

R^1.2.2selected from H, Me;

R²is selected from CH₂-phenyl or CH₂-naphthyl, both optionally substituted with one or two residues selected from the group consisting of: CH (CH)₃、CF₃、OCF₃、F、Cl、Br、Et

R³Is H;

R⁴is H.

Another embodiment of the invention further comprises administering to the subject a compound of formula 1, wherein

A is CH₂O or NMe;

R¹selected from NHR^1.1、NMeR^1.1；NHR^1.2、NMeR^1.2(ii) a Or NHCH₂-R^1.3；

R^1.1Is phenyl, optionally substituted with one or two residues selected from the group consisting of: me, Et, Bu, CF₃、CH₂CONMe₂、CH₂NHCONH-cyclohexyl, CN, CONR^1.1.1R^1.1.2、COOMe、COOEt、OMe、SO₂Me、SO₂CH₂CH₂OH、SO₂Et、SO₂-cyclopropyl, SO₂Piperidinyl, SO₂NHEt、SO₂NMeEt, F, Cl, CO-morpholinyl, CH₂-pyridyl or imidazolidinyl, piperidineA group, oxazidohexanyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyridinyl, pyrimidinyl, each optionally substituted with one or two residues selected from the group consisting of Me, NHMe, ═ O;

R^1.1.1selected from H, Me, Et, Pr, Bu, cyclopropyl, CH₂-i-Pr、CH₂-Bu、CH(CH₃)CH₂CH₃、CH₂CHF₂、CH₂CONMe₂、CH₂CO-azetidinyl, CH₂-cyclopropyl, CH₂-cyclobutyl, CH₂-pyranyl, CH₂-tetrahydrofuranyl, CH₂-furyl, CH₂CH₂OH or thiadiazolyl optionally substituted by Me;

R^1.1.2selected from H, Me, Et, SO₂Me、SO₂Et；

R^1.2.1Selected from H, Me;

R^1.2.2selected from H, Me;

R^1.3selected from benzeneA radical, pyrazolyl, isoxazolyl, pyrimidinyl, indolyl or oxadiazolyl, each of which is optionally substituted with one or two residues selected from the group consisting of: me, Et, Pr, cyclopentyl, OMe, OCHF₂；

R³is H;

R⁴is H;

or R³And R⁴Together form CH₂-CH₂A group.

Another embodiment of the invention further comprises administering to the subject a compound of formula 1, wherein

A is CH₂O or NMe;

R¹selected from NHR^1.1、NMeR^1.1；

R^1.1.1Selected from H, Me, Et, Bu, Pr, cyclopropyl, CH₂-Pr、CH₂-Bu、CH(CH₃)CH₂CH₃、CH₂CHF₂、CH₂CONMe₂、CH₂CO-azetidinyl, CH₂-cyclopropyl, CH₂-cyclobutyl, CH₂-pyranyl, CH₂-tetrahydrofuranyl, CH₂-furyl, CH₂CH₂OH or thiadiazolyl optionally substituted by Me;

R^1.1.2selected from H, Me, Et, SO₂Me、SO₂Et

R²is selected from CH₂-phenyl or CH₂-naphthyl, both optionally substituted by one or two residues selected from the group consisting of: CH (CH)₃、CF₃、OCF₃F, Cl, Br, Et; or CH₂-thienyl, optionally substituted with one or two residues selected from the group consisting of Cl, Br;

R³is H;

R⁴is H;

or R³And R⁴Together form CH₂-CH₂A group.

Another embodiment of the invention further comprises administering to the subject a compound of formula 1, wherein

A is CH₂O or NMe

R¹Selected from NHR^1.1、NMeR^1.1(ii) a Wherein

R^1.1.2selected from H, Me, Et, SO₂Me、SO₂Et

R²as defined in table 1 below;

R³is H;

R⁴is H.

Another embodiment of the invention further comprises administering to the subject a compound of formula 1, wherein

A is CH₂O or NMe;

R¹selected from NHR^1.1、NMeR^1.1(ii) a Wherein

and R is^1.1.1And R^1.1.2Together form a four-, five-or six-membered carbocyclic ring, optionally containing one O replacing a carbon atom of the ring, optionally substituted with one or two groups selected from the group consisting of CH₂A residue substitution of the group consisting of OH;

R²as defined in table 1 below;

R³is H;

R⁴is H.

Another embodiment of the invention further comprises administering to the subject a compound of formula 1, wherein

A is CH₂O or NMe;

R¹selected from NHR^1.1、NMeR^1.1(ii) a Wherein

R^1.1.2is selected fromH、Me、Et、SO₂Me、SO₂Et；

R²As defined in table 1 below;

R³is H;

R⁴is H.

Another embodiment of the invention further comprises administering to the subject a compound of formula 1, wherein

A is CH₂O or NMe;

R¹selected from NHR^1.1、NMeR^1.1(ii) a Wherein the content of the first and second substances,

R^1.1is phenyl, optionally substituted with one or two residues selected from the group consisting of: SO (SO)₂Me、SO₂CH₂CH₂OH、SO₂Et、SO₂-cyclopropyl, SO₂Piperidinyl, SO₂NHEt、SO₂NMeEt; wherein

R^1.1.2selected from H, Me, Et, SO₂Me、SO₂Et；

R²As defined in table 1 below;

R³is H;

R⁴is H.

Another embodiment of the invention further comprises administering to the subject a compound of formula 1, wherein

A is CH₂O or NMe;

R¹selected from NHR^1.1、NMeR^1.1(ii) a Wherein the content of the first and second substances,

R^1.1is phenyl, optionally selected from the group consisting ofA residue substitution of the group: me, Et, t-Bu, CF₃、CH₂CONMe₂、CH₂NHCONH-cyclohexyl, CN, CONR^1.1.1R^1.1.2、COOMe、COOEt、OMe、SO₂Me、SO₂CH₂CH₂OH、SO₂Et、SO₂-cyclopropyl, SO₂Piperidinyl, SO₂NHEt、SO₂NMeEt, F, Cl and further substituted by a residue of a group selected from: CO-morpholinyl, CH₂-pyridyl or imidazolidinyl, piperidinyl, oxazidohexanyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyridyl, pyrimidinyl, each of which is optionally substituted with one or two residues selected from the group consisting of Me, NHMe, ═ O; wherein

R^1.1.2selected from H, Me, Et, SO₂Me、SO₂Et；

R²As defined in table 1 below;

R³is H;

R⁴is H.

Another embodiment of the invention further comprises administering to the subject a compound of formula 1, wherein

A is CH₂O or NMe;

R¹selected from NHR^1.2、NMeR^1.2(ii) a Wherein the content of the first and second substances,

R^1.2selected from pyridyl, pyrrolyl, pyrazolyl, isoxazolyl, thiazolyl, thiadiazolyl, optionally substituted with one or two residues selected from the group consisting of:me, Et, Pr, Bu, cyclopropyl, CH₂COOEt、CONR^1.2.1R^1.2.2、COOMe、COOEt、CONH₂OMe, Cl, Br CO-pyrrolidinyl, CO-morpholinyl or pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, each of which is optionally substituted with Me; benzothiazolyl, indazolyl, dihydro-indolyl, indanyl, tetrahydro-quinolinyl, each of which is optionally substituted with one or two residues selected from the group consisting of: NMe₂CONHMe, ═ O; 4, 5-dihydro-naphtho [2,1-d ]]Thiazole, optionally substituted with NHCOMe, wherein

R^1.2.1Selected from H, Me;

R^1.2.2selected from H, Me;

R³is H;

R⁴is H;

or R³And R⁴Together form CH₂-CH₂A group.

Another embodiment of the invention further comprises administering to the subject a compound of formula 1, wherein

A is CH₂O or NMe;

R¹selected from NHR^1.2、NMeR^1.2(ii) a Wherein the content of the first and second substances,

R^1.2selected from pyridyl, pyridazinyl, pyrrolyl, pyrazolyl, isoxazolyl, thiazolyl, thiadiazolyl, optionally substituted with one or two residues selected from the group consisting of: me, Et, n-Pr, i-Pr, Bu, cyclopropyl, CH₂COOEt、CONR^1.2.1R^1.2.2、COOMe、COOEt、CONH₂OMe, Cl, Br CO-pyrrolidinyl, CO-morpholinyl or pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, each of whichOptionally substituted by Me; wherein

R^1.2.1Selected from H, Me;

R^1.2.2selected from H, Me;

R³is H;

R⁴is H;

or R³And R⁴Together form CH₂-CH₂A group.

Another embodiment of the invention further comprises administering to the subject a compound of formula 1, wherein

A is CH₂O or NMe;

R¹selected from NHCH₂-R^1.3(ii) a Wherein

R^1.3Selected from phenyl, pyrazolyl, isoxazolyl, pyrimidinyl, indolyl or oxadiazolyl, each of which is optionally substituted with one or two residues selected from the group consisting of: me, Et, Pr, cyclopentyl, OMe, OCHF₂；

R³is H;

R⁴is H;

or R³And R⁴Together form CH₂-CH₂A group.

Another embodiment of the invention further comprises administering to the subject a compound of formula 1, wherein

A is CH₂O or NMe;

R¹selected from NH-piperidinyl, optionally substituted with pyridinyl; NH-cyclohexyl optionally substituted with one or two residues selected from the group consisting of: t-Bu, NHSO₂-phenyl, NHCONH-phenyl, F; NH-pyrrolidinyl, optionally substituted with one or two residues selected from the group consisting of: SO (SO)₂Me, COO-t-Bu; piperidinyl optionally substituted with one or two residues selected from the group consisting of: NHSO₂-n-Bu, m-methoxyphenyl; an dihydro-indolyl, dihydro-isoindolyl, tetrahydro-quinolinyl, or tetrahydro-isoquinolinyl group, optionally substituted with one or two residues selected from the group consisting of: me, COOMe, CF₃、OMe、NO₂F, Br; selected from NHCH (pyridyl) CH₂COOMe、NHCH(CH₂OMe) -benzimidazolyl, optionally substituted with Cl; or 1-aminocyclopentyl optionally substituted with methyl-oxadiazolyl;

R³is H;

R⁴is H;

or R³And R⁴Together form CH₂-CH₂A group.

Another embodiment of the invention further comprises administering to the subject a compound of formula 1, wherein A is CH₂O or NMe, R¹Selected from NHR^1.2、NMeR^1.2；R²As defined in table 1 shown below; r³Is H; r⁴Is and R^1.2Selected from pyridyl, optionally substituted with one or two residues selected from the group consisting of: me, Et, i-Pr, n-Bu, cyclopropyl, CONR^1.2.1R^1.2.2、COOMe、COOEt、CONH₂OMe, Cl, BrCO-pyrrolidinyl, CO-morpholinyl or pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, each of which is optionally substituted with Me; an azole group optionally substituted with one or two residues selected from the group consisting of Me, Et, COOMe, COOEt; pyrazolyl optionally substituted with one or two residues selected from the group consisting of: me, Et, cyclopropyl, COOEt, CO-pyrrolidinyl; isoxazolyl optionally substituted with one or two residues selected from the group consisting of t-Bu, COOEt; thiazolyl optionally substituted with one or two residues selected from the group consisting of: me, n-Pr, i-Pr, Bu, COOMe, COOEt, CH₂COOEt、CONR^1.2.1R^1.2.2(ii) a Thiadiazolyl optionally substituted with one or two residues selected from the group consisting of COOEt; benzothiazolyl, indazolyl, dihydro-indolyl, indanyl, tetrahydro-quinolinyl, each of which is optionally substituted with one or two residues selected from the group consisting of: NMe₂CONHMe, ═ O; or 4, 5-dihydro-naphtho [2,1-d ]]A thiazole, which is optionally substituted with NHCOMe, and

R^1.2.1selected from H or Me;

R^1.2.2selected from H or Me.

Another embodiment of the invention further comprises administering to the subject a compound of formula 1, wherein A is CH₂O or NMe, R¹Selected from NHR^1.2、NMeR^1.2；R²As defined in table 1 shown below; r³Is H; r⁴Is and R^1.2Selected from pyridyl, optionally substituted with one or two residues selected from the group consisting of: me, Et, i-Pr, n-Bu, CONR^1.2.1R^1.2.2、COOMe、COOEt、CONH₂OMe, Cl, Br; an azole group optionally substituted with one or two residues selected from the group consisting of Me, Et, COOMe, COOEt; pyrazolyl optionally substituted with one or two residues selected from the group consisting of: me, Et, cyclopropyl, COOEt, CO-pyrrolidinyl; isoxazolyl, optionally substituted by one or two groups selected from the group consisting of t-Bu, COOEtResidue substitutions of the group; thiazolyl optionally substituted with one or two residues selected from the group consisting of: me, n-Pr, i-Pr, Bu, COOMe, COOEt, CONR^1.2.1R^1.2.2(ii) a Thiadiazolyl optionally substituted with one or two residues selected from the group consisting of COOEt; benzothiazolyl, indazolyl, dihydro-indolyl, indanyl, tetrahydro-quinolinyl, each of which is optionally substituted with one or two residues selected from the group consisting of: NMe₂CONHMe, ═ O; and is

R^1.2.1Is H or Me;

R^1.2.2is H or Me.

a is CH₂O or NMe, R¹Selected from NHR^1.2、NMeR^1.2；R²As defined in table 1 shown below; r³Is H; r⁴Is H; r^1.2Is a pyridyl group, optionally substituted with one or two residues selected from the group consisting of: me, Et, COOMe, COOEt; r^1.2.1Is H or Me and R^1.2.2Is H or Me;

a is CH₂O or NMe, R¹Selected from NHR^1.2、NMeR^1.2；R²As defined in table 1 shown below; r³Is H; r⁴Is H; r^1.2Is a pyridyl group, optionally substituted with one or two residues selected from the group consisting of: me, Et, cyclopropyl, COOEt, CO-pyrrolidinyl; r^1.2.1Is H or Me and R^1.2.2Is H or Me；

A is CH₂O or NMe, R¹Selected from NHR^1.2、NMeR^1.2；R²As defined in table 1 shown below; r³Is H; r⁴Is H; r^1.2Is isoxazolyl, optionally substituted with one or two residues selected from the group consisting of: t-Bu, COOE; r^1.2.1Is H or Me and R^1.2.2Is H or Me;

a is CH₂O or NMe, R¹Selected from NHR^1.2、NMeR^1.2；R²As defined in table 1 shown below; r³Is H; r⁴Is H; r^1.2Is thiazolyl, optionally substituted with one or two residues selected from the group consisting of: me, n-Pr, i-Pr, Bu, COOMe, COOEt, CONR^1.2.1R^1.2.2；R^1.2.1Is H or Me and R^1.2.2Is H or Me;

a is CH₂O or NMe, R¹Selected from NHR^1.2、NMeR^1.2；R²As defined in table 1 shown below; r³Is H; r⁴Is H; r^1.2Is a thiadiazolyl group optionally substituted with one or two residues selected from the group consisting of: COOEt; r^1.2.1Is H or Me and R^1.2.2Is H or Me; or

A is CH₂O or NMe, R¹Selected from NHR^1.2、NMeR^1.2；R²As defined in table 1 shown below; r³Is H; r⁴Is H; r^1.2Is benzothiazolyl, indazolyl, dihydro-indolyl, indanyl, tetrahydro-quinolinyl, each of which is optionally substituted with one or two residues selected from the group consisting of: NMe₂、CONHMe、＝O；R^1.2.1Is H or Me and R^1.2.2Is H or Me.

Another embodiment of the invention further comprises administering to the subject a compound of formula 1, wherein all radicals are as defined above, except that R^1.3Selected from phenyl, optionally substituted by OCHF₂Substitution; pyrazolyl optionally substituted by Me or Et; isoxazolyl, which optionallyIs substituted by Pr; pyrimidinyl optionally substituted with two OMe; an indolyl group; or oxadiazolyl optionally substituted with cyclopentyl.

Another embodiment of the invention further comprises administering to the subject a compound of formula 1, wherein all groups are as defined above, except A is CH₂。

Another embodiment of the invention further comprises administering to the subject a compound of formula 1, wherein all groups are as defined above, except a is O.

Another embodiment of the invention further comprises administering to the subject a compound of formula 1, wherein all groups are as defined above, except that a is NMe.

Another embodiment of the invention are compounds of formula 1, wherein

A is CH₂O or NMe;

R¹is selected from

R²Is selected from

R³Is H;

R⁴is H;

or R³And R⁴Together form CH₂-CH₂A group.

Another embodiment of the invention are compounds of formula 1, wherein a is as defined above; r³Is H; r⁴Is H; and R is²As defined in table 1 shown below; and R is¹Is selected from

Another embodiment of the invention further comprises administering to the subject a compound of formula 1, wherein a is as defined above; r³Is H; r⁴Is H; and R is²As defined in table 1 shown below; and R is¹Is selected from

Table 1: r²As defined for one of the groups shown in definitions 1 to 4:

another embodiment of the invention further comprises administering to the subject a compound of formula 1, wherein the compound of formula 1 is in the form of an individual optical isomer, a mixture of individual enantiomers or a racemate, such as an enantiomerically pure compound.

Another embodiment of the present invention further comprises administering to the subject a compound of formula 1, wherein the compound of formula 1 is present in the form of its acid addition salt with a pharmacologically acceptable acid and optionally in the form of a solvate and/or hydrate.

b.Co-crystals and salts

Additional embodiments of the invention further comprise administering to the subject a co-crystal of the compound of formula 2 (below). Typically, for groups comprising two or more subgroups in this "cocrystal and salt" moiety, the first named subgroup is the point of attachment of the group, e.g., substituent "C_1-3Alkyl-aryl "denotes a group with C_1-3An alkyl-bonded aryl group bonded to the core or to a group to which the substituent is attached.

Wherein

R¹Is selected from C_1-6Alkyl radical, C_1-6Haloalkyl, O-C_1-6Haloalkyl, halogen;

m is 1,2 or 3, in some examples 1 or 2;

R^2aand R^2bEach independently selected from H, C_1-6Alkyl radical, C_1-6Alkenyl radical, C_1-6Alkynyl, C_3-6Cycloalkyl, COO-C_1-6Alkyl, O-C_1-6Alkyl, CONR^2b.1R^2b.2A halogen;

R^2b.1selected from H, C_1-6Alkyl radical, C_0-4alkyl-C_3-6Cycloalkyl radical, C_1-6A haloalkyl group;

R^2b.2selected from H, C_1-6An alkyl group;

or R^2b.1And R^2b.2Together are C_3-6Alkylene, forming a heterocyclic ring with the nitrogen atom, wherein optionally one carbon atom or the ring is replaced by an oxygen atom;

R³selected from H, C_1-6An alkyl group;

j is 0, 0.5, 1, 1.5 or 2; in some instances 1 or 2;

Another aspect of the invention further comprises administering to the subject a co-crystal of a compound of formula 2, wherein

R^2aSelected from H, C_1-6Alkyl radical, C_1-6Alkenyl radical, C_1-6Alkynyl, C_3-6Cycloalkyl, O-C_1-6Alkyl, CONR^2a.1R^2a.2；

R^2a.1Selected from H, C_1-6Alkyl radical, C_1-6A haloalkyl group;

R^2a.2selected from H, C_1-6An alkyl group;

R^2bselected from H, C_1-6Alkyl radical, C_1-6Alkenyl radical, C_1-6Alkynyl, C_3-6Cycloalkyl, COO-C_1-6Alkyl, O-C_1-6Alkyl, CONR^2b.1R^2b.2A halogen;

R^2b.1selected from H, C_1-6Alkyl radical, C_0-4alkyl-C_3-6Cycloalkyl radical, C_1-6A haloalkyl group;

R^2b.2selected from H, C_1-6An alkyl group;

or R^2b.1And R^2b.2Together are C_3-6Alkylene, forming a heterocyclic ring with the nitrogen atom, wherein optionally one carbon atom or the ring is replaced by an oxygen atom and the remaining residue is as defined above.

Another aspect of the invention further comprises administering to the subject a co-crystal of a compound of formula 2, wherein

R^2aSelected from H, C_1-6Alkyl radical, C_1-6Alkynyl, C_3-6Cycloalkyl, O-C_1-6Alkyl, CONR^2a.1R^2a.2；

R^2a.1Is C_1-6An alkyl group;

R^2a.2is H;

R^2bselected from H, C_1-6Alkyl, O-C_1-6Alkyl, CONR^2b.1R^2b.2；

R^2b.1Is selected from C_1-6Alkyl radical, C_0-4alkyl-C_3-6Cycloalkyl radical, C_1-6A haloalkyl group;

R^2b.2selected from H, C_1-6An alkyl group;

Another aspect of the invention further comprises administering to the subject a co-crystal of a compound of formula 2, wherein

R^2aSelected from H, C_1-4Alkyl radical, C_1-4Alkynyl, C_3-6Cycloalkyl, O-C_1-4Alkyl, CONR^2a.1R^2a.2；

R^2a.1Is C_1-4An alkyl group;

R^2a.2is H;

R^2bselected from H, C_1-4Alkyl, O-C_1-4Alkyl, CONR^2b.1R^2b.2；

R^2b.1Is selected from C_1-4Alkyl radical, C_0-4alkyl-C_3-6Cycloalkyl radical, C_1-4A haloalkyl group;

R^2b.2selected from H, C_1-4An alkyl group;

Another aspect of the invention further comprises administering to the subject a co-crystal of a compound of formula 2, wherein

R^2aSelected from H, C_1-4An alkyl group;

R^2bselected from H, CONR^2b.1R^2b.2；

R^2b.1Is selected from C_1-4Alkyl radical, C_0-4alkyl-C_3-6Cycloalkyl radical, C_1-4A haloalkyl group;

R^2b.2selected from H, C_1-4An alkyl group;

Another aspect of the invention further comprises administering to the subject a co-crystal of a compound of formula 2, wherein

R¹Is selected from C_1-6Alkyl radical, C_1-6Haloalkyl, O-C_1-6Haloalkyl, halogen;

m is 1 or 2;

R^2aselected from H, C_1-4An alkyl group;

R^2bselected from H, CONR^2b.1R^2b.2；

R^2b.1Is selected from C_1-4Alkyl radical, C_0-4alkyl-C_3-6Cycloalkyl radical, C_1-4A haloalkyl group;

R^2b.2selected from H, C_1-4An alkyl group;

or R^2b.1And R^2b.2Together are C_3-6Alkylene, forming a heterocyclic ring with the nitrogen atom, wherein optionally one carbon atom or the ring is replaced by an oxygen atom

R³Selected from H, C_1-6An alkyl group;

x is an anion selected from the group consisting of chloride or dibenzoyl tartrate,

j is 1 or 2.

Another aspect of the invention further comprises administering to the subject a co-crystal of a compound of formula 2, wherein

R^2aSelected from H, C_1-4An alkyl group; methyl, ethyl, propyl in some examples;

R^2bselected from H, CONR^2b.1R^2b.2；

R^2b.1Is C_1-4An alkyl group; methyl, ethyl, propyl in some examples;

R^2b.2is C_1-4An alkyl group; methyl, ethyl, propyl in some examples;

and the remaining residues are as defined above.

Another aspect of the invention further comprises administering to the subject a co-crystal of a compound of formula 2, wherein

R^2aSelected from H, C_1-4An alkyl group; methyl, ethyl, propyl in some examples;

R^2bselected from H, CONR^2b.1R^2b.2；

R^2b.1Is C_0-4alkyl-C_3-6A cycloalkyl group;

R^2b.2is H, C_1-4An alkyl group; h, methyl, ethyl, propyl in some examples;

and the remaining residues are as defined above.

Another aspect of the invention further comprises administering to the subject a co-crystal of a compound of formula 2, wherein

R^2aSelected from H, C_1-4An alkyl group; methyl, ethyl, propyl in some examples;

R^2bselected from H, CONR^2b.1R^2b.2；

R^2b.1Is C_1-4A haloalkyl group;

R^2b.2selected from H, C_1-4An alkyl group; h, methyl, ethyl, propyl in some examples;

and the remaining residues are as defined above.

Another aspect of the invention further comprises administering to the subject a co-crystal of a compound of formula 2, wherein

R^2b.1And R^2b.2Together are C_3-6Alkylene, forming a heterocyclic ring with the nitrogen atom, wherein optionally one carbon atom or the ring is replaced by an oxygen atom and the remaining residue is as defined above.

Another aspect of the invention further comprises administering to the subject a co-crystal of a compound of formula 2, wherein R¹、m、R^2a、R^2b、R³X and j are as defined above and the co-crystal former is selected from the group consisting of: ascorbic acid, mucic acid, pamoic acid, succinamide, nicotinic acid, nicotinamide, isonicotinamide, l-lysine, l-proline or hydrates or hydrochlorides thereof.

Another aspect of the invention further comprises administering to the subject a co-crystal of a compound of formula 2a, wherein R^2a、R^2b、R³X and j are as defined above.

Another aspect of the invention further comprises administering to the subject a co-crystal of a compound of formula 2a, wherein

R^2aSelected from H, C_1-4An alkyl group; methyl, ethyl, propyl in some examples;

R^2bselected from H, CONR^2b.1R^2b.2；

R^2b.1Is C_1-4An alkyl group; methyl, ethyl, propyl in some examples;

R^2b.2is C_1-4An alkyl group; methyl, ethyl, propyl in some examples;

and the remaining residues are as defined above.

Another aspect of the invention further comprises administering to the subject a co-crystal of a compound of formula 2a, wherein

R^2aSelected from H, C_1-4An alkyl group; methyl, ethyl, propyl in some examples;

R^2bselected from H, CONR^2b.1R^2b.2；

R^2b.1Is C_0-4alkyl-C_3-6A cycloalkyl group;

R^2b.2is H, C_1-4An alkyl group; h, methyl, ethyl, propyl in some examples;

and the remaining residues are as defined above.

Another aspect of the invention further comprises administering to the subject a co-crystal of a compound of formula 2a, wherein

R^2aSelected from H, C_1-4An alkyl group; methyl, ethyl, propyl in some examples;

R^2bselected from H, CONR^2b.1R^2b.2；

R^2b.1Is C_1-4A haloalkyl group;

R^2b.2selected from H, C_1-4An alkyl group; h, methyl, ethyl, propyl in some examples;

and the remaining residues are as defined above.

Another aspect of the invention further comprises administering to the subject a co-crystal of a compound of formula 2a, wherein

The free base of the compound of formula 2 (j ═ 0) is typically amorphous and is used in a method for making co-crystals, and a method for making co-crystals can be used as desired using a salt of the compound of formula 2. Thus, another aspect of the present invention is a salt of a compound of formula 2, wherein R is¹、m、R^2a、R^2b、R³As defined above for the co-crystals and

j is 0, 0.5, 1, 1.5 or 2; such as 1 or 2.

Another aspect of the invention further comprises administering to the subject a co-crystal of a compound of formula 2, wherein R¹、m、R^2a、R^2b、R³As defined above for the co-crystals and

x is an anion selected from chlorine particles or dibenzoyl tartrate;

j is 1 or 2.

Another aspect of the invention further comprises administering to the subject a salt of a compound of formula 2, wherein R¹、m、R^2a、R^2b、R³As defined above for the co-crystal and X is chloride and j is 2.

Another aspect of the invention further comprises administering to the subject a salt of a compound of formula 2a, wherein R^2a、R^2b、R³X and j are as defined above.

Another aspect of the invention further comprises administering to the subject a salt of a compound of formula 2a, wherein

R^2aSelected from H, C_1-4An alkyl group; methyl, ethyl, propyl in some examples;

R^2bselected from H, CONR^2b.1R^2b.2；

R^2b.1Is C_1-4An alkyl group; methyl, ethyl, propyl in some examples;

R^2b.2is C_1-4An alkyl group; methyl, ethyl, propyl in some examples;

and the remaining residues are as defined above.

Another aspect of the invention further comprises administering to the subject a salt of a compound of formula 2a, wherein

R^2aSelected from H, C_1-4An alkyl group; methyl, ethyl, propyl in some examples;

R^2bselected from H, CONR^2b.1R^2b.2；

R^2b.1Is C_0-4alkyl-C_3-6A cycloalkyl group;

R^2b.2is H, C_1-4An alkyl group; h, methyl, ethyl, propyl in some examples;

and the remaining residues are as defined above.

Another aspect of the invention further comprises administering to the subject a salt of a compound of formula 2a, wherein

R^2aSelected from H, C_1-4An alkyl group; methyl, ethyl, propyl in some examples;

R^2bselected from H, CONR^2b.1R^2b.2；

R^2b.1Is C_1-4A haloalkyl group;

R^2b.2is H, C_1-4An alkyl group; in some examples, H, methyl, ethyl, propyl;

and the remaining residues are as defined above.

Another aspect of the invention further comprises administering to the subject a salt of a compound of formula 2a, wherein

Another aspect of the invention further comprises administering to the subject a salt of a compound of formula 2a, wherein R¹、m、R^2a、R^2b、R³As defined above for the salt and X is dibenzoyltartrate and j is 1. Another aspect of the invention further comprises administering to the subject a salt of a compound of formula 2a, wherein R¹、m、R^2a、R^2b、R³As defined above for the salts and X is (S) - (+) -2, 3-dibenzoyl-tartrate and j is 1.

c.Preparation

Additional embodiments of the invention further comprise administering to the subject a pharmaceutical composition comprising a compound of formula 3

Wherein

R¹Selected from H, C_1-6Alkyl radical, C_0-4alkyl-C_3-6Cycloalkyl radical, C_1-6A haloalkyl group;

R²selected from H, C_1-6An alkyl group;

x is an anion selected from the group consisting of chloride or 1/2 dibenzoyl tartrate

j is 1 or 2.

One embodiment of the invention further comprises administering to the subject a pharmaceutical composition comprising a compound of formula 3, wherein

R¹Selected from H, C_1-6An alkyl group;

R²selected from H, C_1-6An alkyl group;

x is an anion selected from the group consisting of chloride or 1/2 dibenzoyl tartrate

j is 1 or 2.

One embodiment of the invention further comprises administering to the subject a pharmaceutical composition comprising a compound of formula 3, wherein

R¹Selected from H, methyl, ethyl, propyl, butyl;

R²selected from H, methyl, ethyl, propyl, butyl;

x is an anion selected from the group consisting of chloride or 1/2 dibenzoyl tartrate, such as chloride;

j is 1 or 2, and in some cases 2.

One embodiment of the invention further comprises administering to the subject a pharmaceutical composition comprising a compound of formula 3, wherein

R¹Selected from H, methyl, ethyl, propyl, butyl;

R²selected from H, methyl;

x is an anion selected from the group consisting of chloride or 1/2 dibenzoyl tartrate, such as chloride;

j is 1 or 2, and in some cases 2.

One embodiment of the invention further comprises administering to the subject a pharmaceutical composition comprising a compound of formula 3, wherein

R¹Selected from H, methyl;

R²selected from H, methyl;

x is an anion selected from the group consisting of chloride or 1/2 dibenzoyl tartrate, such as chloride;

j is 1 or 2, and in some cases 2.

One embodiment of the invention further comprises administering to the subject a pharmaceutical composition containing a compound described in table 2 as the hydrochloride salt. One embodiment of the invention further comprises administering to the subject a pharmaceutical composition containing a compound described in table 2 as the dihydrochloride salt.

TABLE 2

Another aspect of the invention is a pharmaceutical dosage form for administering the above compound to a subject, wherein the dosage is an orally deliverable dosage form.

Another aspect of the invention is a pharmaceutical dosage form for administering the above compound to a subject in the form of a tablet, capsule, pill, powder, or granule.

Another aspect of the invention is the administration to a subject of a pharmaceutical dosage form as described above for use as a medicament.

Another aspect of the invention is the use of the above pharmaceutical dosage form for the manufacture of a medicament for the treatment of a retinal related disease or condition selected from the group consisting of dry age-related macular degeneration, wet age-related macular degeneration, central retinal vein occlusion, retinopathy of prematurity, and diabetic retinopathy.

Another aspect of the present invention is a method for the treatment and/or prevention of a disease or condition selected from the group consisting of retinal related diseases such as dry age-related macular degeneration, wet age-related macular degeneration, central retinal vein occlusion, retinopathy of prematurity and diabetic retinopathy, characterized in that an effective amount of the above pharmaceutical dosage form is orally administered to a subject or patient once, twice, three times or several times daily.

The present invention further provides a method of improving visual acuity in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound described herein. Optionally, the subject has a retinal-related disease, such as a retinal-related disease described herein. Also contemplated is the use of a compound described herein in the manufacture of a medicament, and the use of the compound for improving visual acuity.

d.Dosage forms/compositions

Solid pharmaceutical compositions made from the compound of formula 3 that are easy to use/ingest include, for example, powders, granules, pellets, tablets, capsules, chewable tablets, dispersible tablets, dragees, and buccal tablets.

The capsule formulation according to the present invention comprises a powder intermediate of the compound of formula 3; an intermediate blend comprising powdered intermediate, granules or granules obtained by conventional wet, dry or hot melt granulation or hot melt extrusion or spray drying of a suitable intermediate blend, filled in conventional capsules (e.g. hard gelatin or HPMC capsules).

The above capsule formulation may further comprise a powder intermediate of the compound of formula 3 in a compacted form.

The capsule formulation according to the present invention may further comprise a compound of formula 3 suspended or diluted in a liquid or liquid mixture.

The tablet formulation according to the invention comprises a tablet obtained, for example, by direct compression of a suitable final blend or by tabletting granules or granules obtained by conventional wet, dry or hot melt granulation or hot melt extrusion or spray drying of a suitable intermediate mixture.

Another aspect of the invention is a dosage form wherein a pH adjusting agent or buffer is added to improve the stability of the active ingredient. The pH adjusting/buffering agent may be a basic amino acid having amino and basic characteristics (isoelectric point, pI: 7.59-10.76), such as L-arginine, L-lysine or L-histidine. A buffer within the meaning of the present invention is L-arginine. L-arginine has a particularly suitable stabilizing effect on the compositions of the invention, for example, by inhibiting chemical degradation of the compound of formula 3.

Accordingly, in one embodiment, the present invention relates to a pharmaceutical composition (e.g., an oral solid dosage form, particularly a tablet) comprising a compound of formula 3 and L-arginine for stabilizing the composition, particularly against chemical degradation; and one or more pharmaceutical excipients.

Suitably, the pharmaceutical excipients used in the present invention are conventional materials such as cellulose and its derivatives, D-mannitol, corn starch, pregelatinized starch as filler, copovidone as binder, crospovidone as disintegrant, magnesium stearate as lubricant, anhydrous colloidal silicon dioxide as glidant, hypromellose as film coating agent, polyethylene glycol as plasticizer, titanium dioxide, iron oxide red/yellow as pigment, talc, etc.

The pharmaceutical excipients may be first and second diluents, binders, disintegrants and lubricants; additional disintegrants and additional glidants are another option.

Diluents suitable for the pharmaceutical composition according to the invention are, for example, cellulose powder, microcrystalline cellulose, lactose of various crystalline modifications, anhydrous dibasic calcium phosphate, dibasic calcium phosphate dihydrate, erythritol, low-substituted hydroxypropylcellulose, mannitol, starch or modified (e.g. pregelatinized or partially hydrolyzed) starch or xylitol. Among these diluents, mannitol and microcrystalline cellulose are used in some cases.

Diluents which may be used as secondary diluents in some cases are the diluents mannitol and microcrystalline cellulose mentioned above.

Lubricants suitable for the pharmaceutical compositions according to the invention are, for example, talc, polyethylene glycol, calcium behenate, calcium stearate, sodium stearyl fumarate, hydrogenated castor oil or magnesium stearate, magnesium stearate being used in some cases.

Binders suitable for use in pharmaceutical compositions according to the present invention include, but are not limited to, copovidone (copolymer of vinylpyrrolidone and other vinyl derivative), Hydroxypropylmethylcellulose (HPMC), Hydroxypropylcellulose (HPC), polyvinylpyrrolidone (povidone), pregelatinized starch, stearic-palmitic acid, low-substituted hydroxypropylcellulose (L-HPC), in some cases copovidone and pregelatinized starch are used. The above binders pregelatinized starch and L-HPC exhibit additional diluent and disintegrant properties, and may also act as a secondary diluent or disintegrant.

Disintegrants suitable for the pharmaceutical compositions according to the invention are, for example, corn starch, crospovidone, polacrilin potassium, croscarmellose sodium, low-substituted hydroxypropylcellulose (L-HPC) or pregelatinized starches, such as croscarmellose sodium.

As an optional glidant, colloidal silicon dioxide may be used.

Exemplary compositions according to the present invention comprise mannitol as a diluent, microcrystalline cellulose as a diluent with additional disintegration properties, a binder copovidone, sodium croscarmellose as a disintegrant, and magnesium stearate as a lubricant.

Typical pharmaceutical compositions comprise (in weight%):

a pharmaceutical composition according to some embodiments comprises (in weight%):

in some cases pharmaceutical compositions containing 10-90% active ingredient, preferably 30-70% active ingredient (wt.%) are used.

The tablet formulation according to the invention may be uncoated or coated, e.g. film coated, using a suitable coating known not to negatively affect the dissolution properties of the final formulation. For example, tablets may provide a seal coat for protection of the patient environment and clinical personnel, as well as for moisture protection purposes, by dissolving a high molecular weight polymer (such as polyvinylpyrrolidone or hydroxypropyl-methylcellulose) together with a plasticizer, a lubricant, and optionally pigments and surfactants in water or an organic solvent (such as acetone), and spraying this mixture onto the tablet core in a coating apparatus (such as a pan coater or a fluid bed coater with a wurster insert).

In addition, agents such as beeswax, shellac, cellulose acetate phthalate, polyvinyl acetate phthalate, zein, film forming polymers (such as hydroxypropyl cellulose, ethyl cellulose and polymeric methacrylates) may be applied to the tablets, provided that the coating does not significantly affect the disintegration/dissolution of the dosage form and the stability of the coated dosage form is not affected.

After film coating of the dosage form, a sugar coating may be applied to the sealed pharmaceutical dosage form. The glaze may comprise sucrose, dextrose, sorbitol, and the like, or mixtures thereof. If desired, a coloring or opacifying agent may be added to the sugar solution.

The solid formulations of the present invention tend to be hygroscopic. They may be packaged using PVC blisters, PVDC blisters or moisture-proof packaging materials, such as aluminium foil blister packs, aluminium/aluminium blisters, transparent or opaque polymer blisters, as well as sachets, polypropylene tubes, glass bottles and HDPE bottles, optionally containing child-proofing functions or possibly being tamper-proof. The primary packaging material may include a desiccant, such as a molecular sieve or silica gel, to improve the chemical stability of the API. Opaque packaging such as colored blister materials, tubes, brown glass bottles, and the like can be used to extend the shelf life of an API by reducing photodegradation.

e.Dosage form

The dosage range of the compound of formula 3 is typically between 100 and 1000mg, in particular between 200 and 900mg, 300 and 900mg, or 350 and 850mg, or 390 and 810 mg. One or two tablets may be provided, and in some cases, two tablets are used, with a daily oral dose of 100, 200, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, or 900mg, for example 350, 400, 450, 750, 800, or 850 mg.

Dosage ranges may be achieved by one or two tablets; for example, in the case of administering two tablets, each tablet contains half the dose.

Administration of the active ingredient may be carried out up to three times a day, such as once or twice a day. The specific dose strength is 400mg or 800 mg.

f.Terms and definitions of use

Terms not specifically defined herein should be given the meanings that would be given by a person of ordinary skill in the art in light of this disclosure and the context. However, as used in the specification, unless specified to the contrary, the following terms have the meanings indicated and comply with the following conventions.

The term "about" means more or less than 5% of the specified value. Thus, approximately 100 minutes may also be read as 95 to 105 minutes.

When the compounds of the present invention are described in the form of chemical names and chemical formulas, the chemical formulas prevail if there is any difference. Asterisks may be used in the sub-formulae to indicate the bond to the defined core molecule.

Unless specifically indicated otherwise throughout the specification and the appended claims, a given chemical formula or name shall include tautomers and all stereoisomers, optical and geometric isomers (e.g., enantiomers, diastereomers, E/Z isomers, etc.) and racemates thereof, as well as mixtures of individual enantiomers in varying proportions, mixtures of diastereomers, or mixtures of any of the foregoing forms in which such isomers and enantiomers exist, as well as salts, including pharmaceutically acceptable salts thereof and solvates thereof, such as hydrates including solvates of the free compounds or solvates of salts of the compounds.

The term "substitution" as used herein refers to the selective substitution of any one or more hydrogens on the designated atom with a designated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.

The term "optionally substituted" in the context of the present invention means that the above-mentioned groups are optionally substituted by low molecular weight groups. Examples of low molecular groups which are considered to have chemical significance are groups consisting of 1 to 200 atoms. Of interest are groups that do not negatively impact the pharmacological efficacy of the compound. For example, the group may comprise:

a linear or branched carbon chain, optionally interrupted with heteroatoms, optionally substituted with rings, heteroatoms or other common functional groups;

an aromatic or non-aromatic ring system consisting of carbon atoms and optionally heteroatoms, which in turn may be substituted by functional groups; or

Many aromatic or non-aromatic ring systems, consisting of carbon atoms and optionally heteroatoms, which may be linked by one or more carbon chains, optionally interrupted with heteroatoms, optionally substituted with heteroatoms or other common functional groups.

The compounds disclosed herein may be present in the form of a therapeutically acceptable salt. The present invention includes the compounds listed above in the form of salts (including acid addition salts). Suitable salts include those formed with organic and inorganic acids. Such acid addition salts are generally pharmaceutically acceptable. However, salts of non-pharmaceutically acceptable salts may be used for the preparation and purification of the compounds in question. Basic addition salts may also be formed and are pharmaceutically acceptable. For a more complete discussion of the preparation and selection of salts, see "pharmaceutically acceptable salts: properties, selection and uses (Stahl, P.Heinrich.Wiley-VCHA, Zurich, Switzerland, 2002).

The term "therapeutically acceptable salt" as used herein represents a salt or zwitterionic form of a compound disclosed herein, which is water or oil soluble or dispersible and is therapeutically acceptable as defined herein. Salts may be prepared during the final isolation and purification of the compound or separately by reacting the appropriate compound in free base form with a suitable acid. Representative acid addition salts include acetate, adipate, alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate (benzanesulfonate/besylate), bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isethionate), lactate, maleate, malonate, DL-mandelate, mesitylenesulfonate, methanesulfonate, naphthalenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectate, persulfate, 3-phenylpropionate, phosphonate, picrate, etc, Pivalate, propionate, pyroglutamate, succinate, sulfonate, tartrate, L-tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, p-toluenesulfonate (para-tolenesulfonate/p-tosylate), and undecanoate. Additionally, the basic groups in the compounds disclosed herein can be substituted with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl and dimethyl sulfates; decyl, lauryl, myristyl and sterol chlorides, bromides and iodides; and benzyl and phenethyl bromides. Examples of acids that can be used to form therapeutically acceptable addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid; and organic acids such as oxalic acid, maleic acid, succinic acid, and citric acid. Salts may also be formed by coordination of the compound with an alkali or alkaline earth metal ion. Accordingly, the present invention encompasses sodium, potassium, magnesium, and calcium salts, and the like, of the compounds disclosed herein.

Basic addition salts can be prepared during the final isolation and purification of the compounds by reacting the carboxyl group with a suitable base, such as the hydroxide, carbonate or bicarbonate of a metal cation, or with ammonia or an organic primary, secondary or tertiary amine. Cations of therapeutically acceptable salts include lithium, sodium, potassium, calcium, magnesium and aluminum, as well as non-toxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, benzhydrylamine, N-benzhydrylphenylethylamine, 1-benzhydrylamine and N, P-benzhydrylethylenediamine. Other representative organic amines useful for forming base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.

Although the compounds of the present invention may be administered as the starting chemicals, they may also be administered as pharmaceutical formulations. Accordingly, provided herein are pharmaceutical formulations comprising one or more of certain compounds disclosed herein, or one or more pharmaceutically acceptable salts, esters, prodrugs, amides, or solvates thereof, and one or more pharmaceutically acceptable carriers thereof and optionally one or more other therapeutic ingredients. A carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The appropriate formulation depends on the route of administration chosen. Any of the well known techniques, carriers and excipients may be suitably employed and as is understood in the art; for example, Remington's Pharmaceutical Sciences. The pharmaceutical compositions disclosed herein may be prepared in any manner known in the art, for example, by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compressing methods.

The term heterocycle ("het") refers to a five-, six-or seven-membered saturated or unsaturated heterocycle or a 5-to 10-membered bicyclic heterocycle which may contain one, two or three heteroatoms selected from oxygen, sulfur and nitrogen; the ring may be attached to the molecule through a carbon atom or through a nitrogen atom if present. The following are examples of five-, six-or seven-membered saturated or unsaturated heterocycles:

unless otherwise specified, the heterocycle may have a keto group. Examples include:

examples of 5-to 10-membered bicyclic heterocycles are pyrrolizine, indole, indolizine, isoindole, indazole, purine, quinoline, isoquinoline, benzimidazole, benzofuran, benzopyran, benzothiazole, benzisothiazole, pyridopyrimidine, pteridine, pyrimidopyrimidine, pyridinopyrimidine,

Although the term heterocycle includes heterocyclic aromatic groups, the term heterocyclic aromatic group ("heteroaryl") denotes a five or six membered heterocyclic aromatic group or a 5 to 10 membered bicyclic heteroaryl ring, which may contain one, two or three heteroatoms (selected from oxygen, sulfur and nitrogen), said ring containing sufficient conjugated double bonds to form an aromatic system. The ring may be attached to the molecule through a carbon atom, or through a nitrogen atom if present. The following are examples of five-or six-membered heterocyclic aromatic groups:

examples of 5-10 membered bicyclic heteroaryl rings include pyrrolizine, indole, indolizine, isoindole, indazole, purine, quinoline, isoquinoline, benzimidazole, benzofuran, benzopyran, benzothiazole, benzisothiazole, pyridopyrimidine, pteridine, pyrimidopyrimidine.

The term "halogen" as used herein refers to a halogen substituent selected from fluorine, chlorine, bromine or iodine.

The term "C_1-6Alkyl groups "(including those that are part of other groups) refer to branched and unbranched alkyl groups having 1 to 6 carbon atoms, and the term" C_1-4Alkyl "refers to branched and unbranched alkyl groups having 1 to 4 carbon atoms. In some cases alkyl groups having 1 to 4 carbon atoms are present. Examples of these include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or hexyl. The abbreviations Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, etc. may also be optionally used for the above groups. Unless otherwise indicated, the definitions of propyl, butyl, pentyl and hexyl include all possible isomeric forms of the groups in question. Thus, for example, propyl includes n-propyl and isopropyl, and butyl includes isobutyl, sec-butyl, tert-butyl, and the like.

The term "C_1-6Alkylene "(including those that are part of other groups) refers to branched and unbranched alkylene groups having 1 to 6 carbon atoms and the term" C_1-4Alkylene "refers to both branched and unbranched alkylene groups having 1 to 4 carbon atoms. In some cases alkylene groups having 1 to 4 carbon atoms are present. Examples include: methylene, ethylene, propylene, 1-methylethylene, butylene, 1-methylpropylene, 1-dimethylethylene, 1, 2-dimethylethylene, pentylene, 1-dimethylpropylene, 2-dimethylpropylene, 1, 3-dimethylpropylene or hexylene. Unless otherwise indicated, the definition of propylene, butylene, pentylene, and hexylene further includes all possible isomeric forms of the relevant groups having the same carbon number. Thus, for example, propyl further includes 1-methylethylene and butylene includes 1-methylpropylene, 1-dimethylethylene, 1, 2-dimethylethylene.

The term "C_2-6Alkenyl "(including those as part of other groups) denotes branched and unbranched alkenyl having 2 to 6 carbon atoms, and the term"C_2-4Alkenyl "denotes branched and unbranched alkenyl groups having 2 to 4 carbon atoms, provided that they have at least one double bond. In some embodiments, of interest are alkenyl groups having 2 to 4 carbon atoms. Examples include: ethenyl (ethenyl) or vinyl (vinyl), propenyl, butenyl, pentenyl or hexenyl. Unless otherwise indicated, the definitions propenyl, butenyl, pentenyl and hexenyl include all possible isomeric forms of the group in question. Thus, for example, propenyl includes 1-propenyl and 2-propenyl, and butenyl includes 1-, 2-and 3-butenyl, 1-methyl-1-propenyl, 1-methyl-2-propenyl, and the like.

The term "C_2-6Alkenylene "(including those that are part of other groups) refers to branched and unbranched alkenylene groups having 2 to 6 carbon atoms and the term" C_2-4Alkenylene "refers to branched and unbranched alkylene groups having 2 to 4 carbon atoms. Alkenylene groups having 2 to 4 carbon atoms are present in some cases. Examples include: vinylidene, propenylene, 1-methylvinylene, butenylene, 1-methylpropylene, 1-dimethylvinylene, 1, 2-dimethylvinylene, pentenylene, 1-dimethylpropenyl, 2-dimethylpropenyl, 1, 3-dimethylpropenyl or hexenylene. Unless otherwise indicated, the definitions of propenylene, butenylene, pentenylene and hexenylene include all possible isomeric forms of the respective groups having the same number of carbon atoms. Thus, for example, propenyl further includes 1-methylphenylene, and butenylene includes 1-methylpropenylene, 1-dimethylvinylene, 1, 2-dimethylvinylene.

The term "C_2-6Alkynyl groups "(including those as part of other groups) refer to branched and unbranched alkynyl groups having 2 to 6 carbon atoms and the term" C_2-4Alkynyl "refers to branched and unbranched alkynyl groups having 2 to 4 carbon atoms, provided that they have at least one triple bond. Alkynyl groups having 2 to 4 carbon atoms are present in some cases. Examples include: ethynyl, propynyl, butynyl, pentynyl or hexynyl. Propynyl, butynyl and the like unless otherwise statedThe definitions of alkyl, pentynyl and hexynyl include all possible isomeric forms of the radicals. Thus, for example, propynyl includes 1-propynyl and 2-propynyl, butynyl includes 1-, 2-, and 3-butynyl, 1-methyl-1-propynyl, 1-methyl-2-propynyl, and the like.

The term "C_2-6Alkynylene "(including those as part of other groups) refers to branched and unbranched alkynylene groups having 2 to 6 carbon atoms and the term" C_2-4Alkynylene "refers to branched and unbranched alkylene groups having 2 to 4 carbon atoms. In some cases alkynylene groups having 2 to 4 carbon atoms are present. Examples include: ethynylene, propynyl, 1-methylacetylene, butynyl, 1-methylpropylene, 1-dimethylethynylene, 1, 2-dimethylethynylene, pentynyl, 1-dimethylpropylene, 2-dimethylpropylene, 1, 3-dimethylpropylene or hexenyl. Unless otherwise indicated, the definitions propynyl, butynyl, pentynyl and hexynyl include all possible isomeric forms of the respective radicals having the same carbon number. Thus, for example, propynyl further includes 1-methylacetylene and butynyl includes 1-methylpropynyl, 1-dimethylethyleneene, 1, 2-dimethylethyleneene.

The term "C" as used herein_3-6Cycloalkyl "(including those as part of other groups) means cyclic alkyl groups having 3 to 8 carbon atoms, with cyclic alkyl groups having 5 to 6 carbon atoms being contemplated in certain embodiments. Examples include: cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

The term "C_1-6Haloalkyl "(including those as part of other groups) refers to branched and unbranched alkyl groups having 1 to 6 carbon atoms in which one or more hydrogen atoms are substituted by a halogen atom selected from fluorine, chlorine or bromine, such as fluorine and chlorine, wherein in some cases the halogen atom is fluorine. The term "C_1-4Haloalkyl "refers to branched and unbranched alkyl groups having 1 to 4 carbon atoms respectively in which one or more hydrogen atoms are substituted similarly to as described above. In some cases C is present_1-4A haloalkyl group. Examples include: CH (CH)₂F、CHF₂、CF₃。

The term "C_1-nAlkyl ", wherein n is an integer from 2 to n, alone or in combination with another group, represents an acyclic, saturated, branched or linear hydrocarbon radical having from 1 to n C atoms. For example, the term C_1-5Alkyl includes the group H₃C-、H₃C-CH₂-、H₃C-CH₂-CH₂-、H₃C-CH(CH₃)-、H₃C-CH₂-CH₂-CH₂-、H₃C-CH₂-CH(CH₃)-、H₃C-CH(CH₃)-CH₂-、H₃C-C(CH₃)₂-、H₃C-CH₂-CH₂-CH₂-CH₂-、H₃C-CH₂-CH₂-CH(CH₃)-、H₃C-CH₂-CH(CH₃)-CH₂-、H₃C-CH(CH₃)-CH₂-CH₂-、H₃C-CH₂-C(CH₃)₂-、H₃C-C(CH₃)₂-CH₂-、H₃C-CH(CH₃)-CH(CH₃) -and H₃C-CH₂-CH(CH₂CH₃)-。

The term "C_1-nHaloalkyl "wherein n is an integer from 2 to n, represents, alone or in combination with another group, an acyclic, saturated, branched, or linear hydrocarbon radical having 1 to n C atoms, wherein one or more hydrogen atoms are substituted with a halogen atom selected from fluorine, chlorine, or bromine (e.g., fluorine and chlorine), wherein in some cases halogen is fluorine. Examples include: CH (CH)₂F、CHF₂、CF₃。

The term "C_1-nAlkylene ", wherein n is an integer from 2 to n, alone or in combination with another group, represents an acyclic, linear or branched divalent alkyl radical containing from 1 to n carbon atoms. For example, the term C_1-4Alkylene groups including-CH₂-、-CH₂-CH₂-、-CH(CH₃)-、-CH₂-CH₂-CH₂-、-C(CH₃)₂-、-CH(CH₂CH₃)-、-CH(CH₃)-CH₂-、-CH₂-CH(CH₃)-、-CH₂-CH₂-CH₂-CH₂-、-CH₂-CH₂-CH(CH₃)-、-CH(CH₃)-CH₂-CH₂-、-CH₂-CH(CH₃)-CH₂-、-CH₂-C(CH₃)₂-、-C(CH₃)₂-CH₂-、-CH(CH₃)-CH(CH₃)-、-CH₂-CH(CH₂CH₃)-、-CH(CH₂CH₃)-CH₂-、-CH(CH₂CH₂CH₃)-、-CH(CH(CH₃))₂-and-C (CH)₃)(CH₂CH₃)-。

The term "C_2-nAlkenyl radicals "for example in" C_1-nAlkyl "is a group as defined in the definition which has at least two carbon atoms, two of those carbon atoms of the group being bonded to each other by a double bond.

The term "C_3-nCycloalkyl ", wherein n is an integer from 4 to n, alone or in combination with another group, represents a cyclic, saturated, unbranched hydrocarbon group having 3 to n C atoms. For example, the term C_3-7Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

g.Combination of

The compounds of formula 1 can be used alone or in combination with other active substances of formula 1 according to the invention. The compounds of formula 1 may optionally also be combined with other pharmacologically active substances. These include beta 2-adrenoceptor agonists (short and long acting), anticholinergics (short and long acting), anti-inflammatory steroids (oral and topical corticosteroids), cromoglycates, methylxanthines, dissociated glucocorticoids, PDE3 inhibitors, PDE4 inhibitors, PDE7 inhibitors, LTD4 antagonists, EGFR inhibitors, dopamine agonists, PAF antagonistsAgents, lipoxin A4 derivatives, FPRL1 modulators, LTB4 receptor (BLT1, BLT2) antagonists, histamine H1 receptor antagonists, histamine H4 receptor antagonists, dual histamine H1/H3 receptor antagonists, PI3 kinase inhibitors, inhibitors of non-receptor tyrosine kinases (e.g., LYN, LCK, SYK, ZAP-70, FYN, BTK, or ITK), inhibitors of MAP kinases (e.g., p38, ERK1, ERK2, JNK1, JNK2, JNK3, or SAP), inhibitors of the NF- κ B signaling pathway (e.g., IKK2 kinase inhibitors, iNOS inhibitors, MRP4 inhibitors), leukotriene biosynthesis inhibitors (e.g., 5-lipoxygenase (5-LO) inhibitors), cPLA2 inhibitors, leukotriene A4 hydrolase inhibitors or FLAP inhibitors, non-steroidal anti-inflammatory agents (NSAIDs), CRTH2 antagonists, DP1 receptor modulators, thromboxane receptor antagonists, CCR3 antagonists, CCR.⁴Antagonists, CCR¹Antagonists, CCR5 antagonists, CCR6 antagonists, CCR7 antagonists, CCR8 antagonists, CCR9 antagonists, CCR30 antagonists, CXCR³Antagonists, CXCR⁴Antagonists, CXCR²Antagonists, CXCR¹Antagonists, CXCR5 antagonists, CXCR6 antagonists, CX3CR³Antagonists, neurokinin (NK1, NK2) antagonists, sphingosine 1-phosphate receptor modulators, sphingosine 1 phosphate lyase inhibitors, adenosine receptor modulators (e.g., A2a agonists), purinergic receptor modulators (e.g., P2X7 inhibitors), Histone Deacetylase (HDAC) activators, bradykinin (BK1, BK2) antagonists, TACE inhibitors, PPAR γ modulators, Rho kinase inhibitors, interleukin 1-beta converting enzyme (ICE) inhibitors, Toll-like receptor (TLR) modulators, HMG-CoA reductase inhibitors, VLA-4 antagonists, ICA M-1 inhibitors, SHIP agonists, GABAa receptor antagonists, ENaC inhibitors, melanocortin receptor (MC1R, MC2R, MC3R, MC4R, MC5R) modulators, CGCGantagonist, endothelin antagonist, TNF α antagonist, anti-TNF antibody, anti-GM-antibody, anti-CD 46 antibodies, anti-IL-1 antibodies, anti-IL-2 antibodies, anti-IL-4 antibodies, anti-IL-5 antibodies, anti-IL-13 antibodies, anti-IL-4/IL-13 antibodies, anti-TSLP antibodies, anti-OX 40 antibodies, mucus regulators, immunotherapeutics, anti-airway tumescence compounds, anti-cough compounds, VEGF inhibitors, and combinations of two or three active agents.

Also contemplated are betamimetics, anticholinergics, corticosteroids, PDE4 inhibitors, LTD 4-antagonists, EGFR inhibitors, CRTH2 inhibitors, 5-LO inhibitors, histamine receptor antagonists, and SYK inhibitors, as well as combinations of two or three active agents, e.g., betamimetics with corticosteroids, PDE4 inhibitors, CRTH2 inhibitors, or LTD 4-antagonists; an anticholinergic agent with a betamimetic, corticosteroid, PDE4 inhibitor, CRTH2 inhibitor or LTD4 antagonist, a corticosteroid with a PDE4 inhibitor, CRTH2 inhibitor or LTD4 antagonist; PDE4 inhibitors with CRTH2 inhibitors or LTD 4-antagonists; and CRTH2 inhibitors and LTD 4-antagonists.

The invention also contemplates the use of compounds of general formula 1 in combination with anti-VEGF therapy (e.g., one or more VEGF modulators and inhibitors) for the treatment of the indications disclosed herein. In various aspects, the methods comprise improving visual acuity by administering a compound of formula 1 and further administering an anti-VEGF therapy that reduces the biological effect of VEGF at the target site. VEGF modulators/inhibitors include, but are not limited to, antibodies and small molecule VEGF-a inhibitors, such as ranibizumab, bevacizumab, and aflibercept, which are listed by way of example and not limitation. anti-VEGF antibody-like constructs, such as the single chain antibody fragment VEGF inhibitor brolucizumab (also known as RTH258), are also contemplated. Furthermore, the compounds of formula 1 may be used in combination with VEGF receptor modulators or inhibitors (such as antibodies) and small molecule inhibitors of VEGF receptors or downstream signaling mechanisms. Examples include, by way of example and not limitation, sunitinib (sunitnib), sorafenib (sorafenib), cabozantinib (cabozantinib), ponatinib (ponatinib), and axitinib (axitinib). The present disclosure contemplates a treatment regimen comprising administering a compound of formula 1 and administering any one or more of: aptamers that inhibit VEGF expression or function, such as pegaptanib sodium (Macugen, Eyetech Pharmaceuticals, Cedarnols (NJ), N.J.); tyrosine kinase inhibitors (e.g., PAN-90806, a topical anti-VEGF eye drop, PanOptica, Bernardsville, NJ); siRNA (e.g. bevacizinib); soluble VEGF or gene therapy vectors encoding soluble VEGF, such as RGX-314(Regenxbio corporation); or soluble VEGF receptor proteins such as Conbecept (fusion of domain 2 of VEGFR-1, domains 3 and 4 of VEGFR-2, and the IgG1Fc region).

In these embodiments, the compounds comprising the combination are co-administered to the subject. The terms "co-administration" and "in combination with … …" include the simultaneous, concurrent or sequential administration of two or more therapeutic agents over a non-specific time frame. In one embodiment, the agents are present in the cell or subject at the same time or exert their biological or therapeutic effects at the same time. In one embodiment, the therapeutic agents are present in the same composition or unit dosage form. In other embodiments, the therapeutic agent is present in a separate composition or unit dosage form. In certain embodiments, the first agent can be administered prior to (e.g., minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concurrently with, or after (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of the second therapeutic agent. "concomitant administration" of a known therapeutic agent with a pharmaceutical composition of the present disclosure refers to administration of the compound and the second agent at a time when both the known agent and the composition of the present invention have a therapeutic effect. Such concomitant administration may involve administration of the drug simultaneously (i.e., simultaneously), prior to, or subsequent to administration of the compound of the invention. The route of administration of the two agents may vary, with representative routes of administration described in more detail below. The appropriate timing, sequence and dosage of administration of a particular drug and a compound of the invention can be readily determined by one of ordinary skill in the art. In some embodiments, the compounds (e.g., the subject compound and at least one additional compound) are administered to the subject within 24 hours of each other, such as within 12 hours of each other, within 6 hours of each other, within 3 hours of each other, or within 1 hour of each other. In certain embodiments, the compounds are administered within 1 hour of each other. In certain embodiments, the compounds are administered substantially simultaneously. By substantially simultaneously administering is meant that the compounds are administered to the subject within about 10 minutes or less of each other, e.g., 5 minutes or less, or 1 minute or less of each other.

h.Pharmaceutical forms

Suitable formulations for administration of the compound of formula 1 and the co-crystals or salt forms of formulae 2 and 2a include, for example, tablets, capsules, suppositories, solutions, powders and the like. The amount of pharmaceutically active compound should be in the range of 0.05 to 90 wt%, for example 0.1 to 50 wt% of the total composition. Suitable tablets may be obtained, for example, by mixing the active substance with known excipients, for example inert diluents, such as calcium carbonate, calcium phosphate or lactose; disintegrating agents, such as corn starch or alginic acid; binders, such as starch or gelatin; lubricants, such as magnesium stearate or talc and/or agents for delaying release, for example carboxymethylcellulose, cellulose acetate phthalate or polyvinyl acetate. The tablet may also comprise several layers.

Coated tablets may accordingly be prepared by coating cores prepared analogously to tablets with substances conventionally used for tablet coatings, such as collidone or shellac, gum arabic, talc, titanium dioxide or sugar. The core may also be composed of a number of layers in order to achieve delayed release or to prevent incompatibilities. Similarly, the tablet coating may consist of some or more layers to achieve delayed release, possibly using excipients as described above for the tablets.

A syrup or elixir containing an active substance or a combination thereof according to the invention may additionally contain a sweetening agent such as saccharin, cyclamate, glycerol or sugar and a flavour enhancer, for example a flavouring agent such as vanillin or orange extract. They may also contain suspending aids or thickeners, such as sodium carboxymethylcellulose; wetting agents, such as condensation products of fatty alcohols with ethylene oxide; or preservatives, such as parabens.

Solutions are prepared in a conventional manner, e.g., by addition of isotonic agents; preservatives, such as parabens; or stabilizers, such as alkali metal salts of ethylenediaminetetraacetic acid; optionally emulsifiers and/or dispersants are used, while if water is used as diluent, for example, organic solvents can optionally be used as solubilizers or dissolution aids, and the solution can be transferred into injection vials or ampoules or infusion bottles.

Capsules containing one or more active substances or combinations of active substances can be prepared, for example, by mixing the active substances with inert carriers, such as lactose or sorbitol, and packaging them in gelatin capsules.

Suitable suppositories may be prepared, for example, by mixing with carriers provided for this purpose, such as neutral fats or polyethylene glycols or derivatives thereof.

Excipients that may be used include, for example, water; pharmaceutically acceptable organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. peanut or sesame oil), mono-or polyfunctional alcohols (e.g. ethanol or glycerol); carriers such as natural mineral powders (e.g., kaolin, clay, talc, chalk), synthetic mineral powders (e.g., highly dispersed silicic acid and silicates), sugars (e.g., sucrose, lactose, and glucose); emulsifiers (such as lignin, spent sulfite, methylcellulose, starch, and polyvinylpyrrolidone) and lubricants (such as magnesium stearate, talc, stearic acid, and sodium lauryl sulfate).

For oral use, the tablets may obviously contain, in addition to the indicated carrier, additives such as sodium citrate, calcium carbonate and dicalcium phosphate, as well as various other substances, for example starches, such as potato starch, gelatin and the like. Lubricants such as magnesium stearate, sodium lauryl sulfate and talc may also be used to prepare tablets. In the case of aqueous suspensions, the active substance may be combined with various taste-enhancing agents or colorants in addition to the excipients mentioned above.

In some cases, for administration of the compound of formula 1 or the co-crystal or salt form of formulae 2 and 2a, a formulation suitable for inhalation or a pharmaceutical formulation is used. Inhalable formulations include inhalable powders, metered dose aerosols with propellant or inhalable solutions without propellant. Within the scope of the present invention, the term propellant-free inhalable solutions further comprises ready-to-use concentrates or sterile inhalable solutions. The formulations that can be used within the scope of the invention are described in more detail in the next part of the description.

The inhalable powders which can be used according to the invention may contain the compound of formula 1 or the co-crystals or salt forms of formulae 2 and 2a alone or in a mixture with suitable physiologically acceptable excipients.

If the active substance of the compound of formula 1 or the cocrystals or salt forms of formulae 2 and 2a are present in admixture with a physiologically acceptable excipient, the following physiologically acceptable excipients may be used for the preparation of the inhalable powders according to the invention: monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, sucrose, maltose), oligo-and polysaccharides (e.g. dextran), polyols (e.g. sorbitol, mannitol, xylitol), salts (e.g. sodium chloride, calcium carbonate) or mixtures of these excipients in some cases mono-or disaccharides are used, e.g. lactose or glucose, e.g. in the form of their hydrates. In some cases, lactose, e.g. in the form of lactose hydrate, is used as excipient.

Within the scope of the inhalable powder according to the invention, the maximum average particle size of the excipient is at most 250 μm, for example between 10 and 150 μm, and comprised between 15 and 80 μm. It sometimes seems appropriate to add a finer excipient fraction having an average particle size of 1 to 9 μm to the above excipient. These finer excipients are also selected from the group of possible excipients listed above. Finally, to prepare the inhalable powders according to the invention, the micronized active substance of the compound of formula 1 or the co-crystals or salt forms of formulae 2 and 2a (e.g. average particle size of 0.5 to 10 μm, including 1 to 5 μm) is added to the excipient mixture. Methods for producing the inhalable powders according to the invention by grinding and micronization and finally mixing the ingredients together are known from the prior art.

The inhalable powders according to the invention can be administered using inhalers known in the art.

The inhalation aerosols containing propellant gas according to the invention may contain the compound of formula 1 or the cocrystals or salt forms of formulae 2 and 2a dissolved in the propellant gas or in dispersed form. The compound of formula 1 or the co-crystals or salt forms of formulae 2 and 2a may be contained in separate formulations or in a common formulation, in which they are either soluble or dispersible or in each case only one component is dissolved and the other component is dispersed. Propellant gases which can be used for producing inhalation aerosols are known from the prior art. Suitable propellant gases are selected from hydrocarbons such as n-propane, n-butane or isobutane; and halogenated hydrocarbons such as fluorinated derivatives of methane, ethane, propane, butane, cyclopropane, or cyclobutane. The propellant gases mentioned above may be used alone or mixed together. Specific propellant gases which may be used are haloalkane derivatives selected from TG134a and TG227 and mixtures thereof.

The propellant driven inhalation aerosol may also contain other ingredients such as cosolvents, stabilizers, surfactants, antioxidants, lubricants, and pH adjusters. All of these ingredients are known in the art.

The propellant-driven inhalation aerosols according to the invention described above can be administered using inhalers known in the art (MDI ═ metered dose inhalers).

Furthermore, the active substance of the compound of formula 1 or the cocrystals or salt forms of formulae 2 and 2a according to the invention can be administered in the form of propellant-free inhalable solutions and suspensions. The solvent used may be an aqueous solution or an alcohol, for example an ethanol solution. The solvent may be water itself or a mixture of water and ethanol. The relative proportion of ethanol compared to water is not limited, but in some cases can be up to 70% by volume, for example up to 60% by volume, including up to 30% by volume. The remainder of the volume may consist of water. The solution or suspension containing the compound of formula 1 or the co-crystals or salt forms of formulae 2 and 2a is adjusted to a pH of 2 to 7, for example 2 to 5, using a suitable acid. The pH can be adjusted using an acid selected from inorganic or organic acids. Examples of particularly suitable inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and/or phosphoric acid. Examples of particularly suitable organic acids include ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid, and/or propionic acid, and the like. The mineral acids used in some cases are hydrochloric acid and sulfuric acid. It is also possible to use acids which have formed acid addition salts with one of the active substances. Among the organic acids, ascorbic acid, fumaric acid and citric acid are used in some cases. Mixtures of the above acids can be used if desired, in particular in the case of acids which have other properties in addition to the acidifying properties, for example as flavoring agents, antioxidants or complexing agents, such as citric acid or ascorbic acid. Hydrochloric acid, which in some cases adjusts the pH, is used according to the invention.

If desired, the addition of ethylenediaminetetraacetic acid (EDTA) or one of its known salts, sodium ethylenediaminetetraacetate, as a stabilizer or complexing agent, can be omitted from these formulations. Other embodiments may contain the compound or compounds. In one embodiment, the amount is less than 100mg/100ml, such as less than 50mg/100ml, including less than 20mg/100ml, based on sodium edetate. In some cases inhalable solutions are used in which the sodium edetate is present in an amount of 0 to 10mg/100 ml. Co-solvents and/or other excipients may be added to the propellant-free inhalable solution. Cosolvents which may be used are those containing hydroxyl groups or other polar groups, such as alcohols, in particular isopropanol, glycols, in particular propylene glycol, polyethylene glycol, polypropylene glycol, glycol ethers, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters. The terms excipient and additive in this context mean any pharmacologically acceptable substance which is not an active substance but which can be formulated with the active substance in a physiologically suitable solvent in order to improve the qualitative properties of the active substance preparation. In some cases, these substances have no pharmacological effect, or, in combination with the desired therapy, no significant or at least no undesired pharmacological effect. Excipients and additives include, for example, surfactants such as soy lecithin, oleic acid, sorbitan esters (e.g., polysorbates), polyvinylpyrrolidone, other stabilizers, complexing agents, antioxidants and/or preservatives (to ensure or extend the shelf life of the finished pharmaceutical formulation), flavoring agents, vitamins, and/or other additives known in the art. The additive further comprises a pharmacologically acceptable salt, such as sodium chloride, as an isotonic agent.

Excipients used in some embodiments include antioxidants, such as ascorbic acid, provided that it has not been used to adjust pH, vitamin a, vitamin E, tocopherol, and similar vitamins and provitamins present in the human body.

Preservatives can be used to protect the formulation from contamination by pathogens. Suitable preservatives are those known in the art, in particular cetylpyridinium chloride, benzalkonium chloride or benzoic acid or benzoates, for example sodium benzoate, in concentrations known in the art. In some cases, the concentration of the above-mentioned preservatives is up to 50mg/100ml, more preferably 5-20mg/100 ml. In addition to the solvent water and the compound of formula 1 or the co-crystal or salt form of formulae 2 and 2a, the formulations of some embodiments contain only benzalkonium chloride and sodium edetate. In one embodiment, sodium edetate is absent.

The dosage of the compounds according to the invention is naturally highly dependent on the method of administration and the disease being treated. When administered by inhalation, the compound of formula 1 or the co-crystal or salt form of formulae 2 and 2a is characterized by high potency even at doses in the microgram range. The compound of formula 1 or the co-crystal or salt form of formulae 2 and 2a may also be used effectively in the range above micrograms. For example, the dosage may be in the gram range.

In another aspect, the present invention relates to the above pharmaceutical preparations, characterized in that they contain the compound of formula 1 or the co-crystals or salt forms of formulae 2 and 2a, in particular the above pharmaceutical preparations. Administration may be by inhalation.

The following formulation examples illustrate the invention without limiting its scope.

Examples of pharmaceutical preparations

The finely ground active substance, lactose and some corn starch are mixed together. The mixture is sieved and then moistened with an aqueous solution of polyvinylpyrrolidone, kneaded, wet-granulated and dried. The granules, the remaining corn starch and magnesium stearate are sieved and mixed together. The mixture is compressed into tablets of suitable shape and size.

The finely powdered active substance, some corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is sieved and processed with the remaining corn starch and water to form granules, which are dried and sieved. Sodium carboxymethyl starch and magnesium stearate are added and mixed, and the mixture is compressed to form tablets of appropriate size.

The active substance is dissolved in water at its own pH or optionally at a pH of 5.5 to 6.5, and the solution is made isotonic by the addition of sodium chloride. The resulting solution is filtered to remove pyrogens and the filtrate is transferred aseptically to ampoules, which are then sterilized and heat sealed. Ampoules contain 5mg, 25 mg and 50mg of active substance.

The suspension was transferred to a conventional aerosol container with a metering valve. Preferably 50 μ l of suspension is released at each actuation. The active substance can also be released in higher doses (e.g. 0.02 wt.%), if desired.

This solution can be prepared in a conventional manner.

Inhalable powders are prepared in a conventional manner by mixing the ingredients.

i.Indications of

Methods of improving visual acuity are provided, including methods of improving visual acuity by treating a subject/patient for a retinal related disease. In some aspects, the subject has (or is diagnosed with) a retinal-related disease, resulting in a loss of visual acuity. The retinal-related disease may be associated with neovascularization, or the retinal-related disease may not include vascular components (i.e., may not originate from or be associated with neovascularization). For example, in various embodiments, the patient may suffer from a loss of visual acuity that is not caused by ocular neovascularization. Aspects of the methods include modulating CCR3 with a modulator of CCR3, for example, in a manner sufficient to improve visual acuity and, in various aspects, treat a retinal related disease in a patient. The methods comprise improving visual acuity (e.g., by treating a retinal-related disease) with an orally administrable and bioavailable composition comprising a compound of formula 1, a salt or co-crystal of formula 2 or 2a, or a composition of a formulation of formula 3, as described above. Compositions that modulate CCR3 may be administered to patients/subjects in need of improved visual acuity, including subjects diagnosed with retinal-related diseases such as age-related macular degeneration (dry or wet form), central retinal vein occlusion, central retinal artery occlusion, macular edema (e.g., diabetic macular edema), glaucoma, Stargardt disease, retinopathy of prematurity, or diabetic retinopathy, as described further below. The methods of the invention may further comprise monitoring the improvement in progression of the retinal-related disease by visual acuity or other tests. Various exemplary retinal-related disease indications are described in further detail below.

j. Indications for retinal related diseases

i. Macular degeneration

Macular degeneration is a term used to describe a family of diseases all characterized by a progressive loss of central visual acuity associated with abnormalities of bruch's membrane, choroid, neural retina and/or retinal pigment epithelium. These disorders include very common conditions affecting elderly subjects-such as age-related macular degeneration (AMD) and in some cases rare early-onset dystrophies that can be detected in the first decade of life. Other macular pathologies include macular dystrophy, Best disease, and Malattia leventinese, in northern carolina.

AMD is the leading cause of permanent loss of visual acuity in individuals over 65 years of age, currently affecting about 1500 million americans. AMD affects light-sensitive photoreceptor cells and pigment epithelial cells in the macula, the center of the retina of the eye. While it may not lead to complete blindness, this disease can undermine central visual acuity, making reading, viewing electronic display screens, and driving impossible. It has no record of cure, never exhibits spontaneous remission, and effective treatment is limited, with considerable burden on patients and caregivers, and side effects.

The neural part of the retina or eye is a complex network of nerve cells that turn light into nerve impulses that are transmitted to the brain where they are interpreted as visual images. There are five types of neurons in the retina. These include photoreceptors, bipolar cells, ganglion cells, horizontal cells, and amacrine cells. The central portion of the retina, known as the macula, is responsible for the visual acuity needed for reading and other detailed tasks. Damage to the macula results in poor visual acuity. The most common disease process affecting the macula is AMD. In patients with AMD, retinal photoreceptors and pigment epithelial cells in the macula die within a few years. Cell death and progressive loss of visual acuity generally do not begin until the age of 60 or above 60 years, and are therefore referred to as age-related macular degeneration.

There are two types of AMD: dry macular degeneration and wet macular degeneration. Dry macular degeneration, while more common, often results in a less severe, more progressive loss of visual acuity. Patients affected by dry AMD experience a progressive loss of central visual acuity due to death of photoreceptor cells and their closely related Retinal Pigment Epithelium (RPE) cells, where a complex mixture of waxy amyloid proteins, known as "drusen," is deposited. Photoreceptors, which are the cells in the retina that actually "see" the light, are critical to visual acuity. Macrophage RPE cells are essential for photoreceptor survival, function and renewal. Patients with wet macular degeneration form new blood vessels under the retina. As photoreceptor and RPE cells slowly degenerate, blood vessels tend to grow from normal locations in the choroid to abnormal locations beneath the retina. This abnormal new blood vessel growth is called Choroidal Neovascularization (CNV). Abnormal vascular leakage and hemorrhage, resulting in bleeding, swelling, scar tissue, and severe loss of central visual acuity. Only 10% of AMD patients have the wet form, but it causes 90% of all blindness due to AMD.

Central Retinal Vein Occlusion (CRVO)

Central retinal vein occlusion, also known as CRVO, occurs when venous occlusion prevents oxygen-depleted blood from flowing out of the vasculature of the eye. Due to the reduced flow of oxygen-depleted blood in the eye, the oxygen-enriched blood is inhibited from reaching the surface layers of the retina, resulting in an anoxic state. In response, the surface layer of the retina produces pro-angiogenic factors that contribute to the development of abnormal macular edema and neovascularization. One use of the compounds of formula 1 is in the treatment of macular edema and neovascularization caused by CRVO.

Retinopathy of prematurity

Affecting premature infants, retinopathy of prematurity (ROP) is an ocular disease associated with oxygen toxicity and local hypoxia. These conditions are thought to contribute to the development of ROP. The underlying pathophysiology of the disease is that hypoxic conditions lead to stimulation of pro-angiogenic factors, leading to disordered growth of blood vessels, resulting in scarring and retinal detachment. Some patients with ROP may leave them in a mild state and recover completely without therapeutic intervention, but in other patients it may lead to permanent blindness. The exact cause of the disease is not known, but the main hypothesis is that supplemental oxygen causes local retinal hypoxia through vasoconstriction, triggering neovascularization, or that normal vascular processes are attenuated by supplemental oxygen, but when abruptly ablated, result in rapid vascular proliferation and fibrovascular disease. Surgery and therapeutic intervention are current therapies to treat the severe forms of the disease. The surgical therapy may include a scleral buckle and/or a vitrectomy for retinal detachment. However, laser-induced photocoagulation is currently the predominant method of treatment for ROP. The compounds of formula 1 are useful for preventing neovascularization associated with ROP. The compounds described herein are useful for improving visual acuity associated with ROP.

Diabetic retinopathy

Diabetic retinopathy is a complication of diabetes mellitus and can lead to blindness. The mechanism that causes it is the damage to the blood vessels of the retinal tissue. Diabetic retinopathy may occur in subjects with type 1 or type 2 diabetes mellitus, which is associated with a loss of control over blood glucose levels. Symptoms include macular or muscae volitantes in the visual acuity, blurred visual acuity, fluctuations in visual acuity, impaired color vision, dark/blank areas of the visual field, and loss of visual acuity in the subject, typically affecting both eyes. The cause of this disease is excessive sugar in the blood of the subject, leading to obstruction of blood vessels that nourish the retina, and to obstruction of retinal blood supply. In response, the retina attempts to grow new blood vessels, thereby producing a pro-angiogenic factor. The subsequent inappropriate regulation of the growth of these vessels leads to vessels that are prone to leakage.

There are two types of diabetic retinopathy: early stage diabetic retinopathy, or nonproliferative diabetic Neuropathy (NPDR) and late stage diabetic retinopathy. When new blood vessels do not grow, NPDR results in weakening of the retinal vessel wall and development of microaneurysms. These microaneurysms can herniate and leak fluid and blood into the retina. NPDR becomes more severe as more and more blood vessels become occluded. Retinal nerve fibers and the macula (the central portion of the retina) swell, a condition known as macular edema. In advanced diabetic retinopathy (or proliferative diabetic retinopathy), blood vessels that have been damaged close, leading to new abnormal blood vessel growth, and to infiltration into the vitreous of the eye. Scar tissue resulting from the growth of new blood vessels can lead to retinal detachment and elevated intraocular pressure-ultimately leading to damage to the optic nerve and glaucoma.

k. Diagnostic and monitoring methods for improving retinal related diseases and visual acuity

i. Introduction to

The methods of the invention further comprise methods of diagnosing a retinal-related disease. Such methods may include, for example, but are not limited to, Visual Acuity (VA) testing, macular degeneration or Amsler grid, retinal examination with dilated pupils, fundus photography, fluorescence angiography, or Optical Coherence Tomography (OCT), which may determine such endpoint as Central Retinal Thickness (CRT).

Visual Acuity (VA)

One way in which disease progression/improvement can be diagnosed or determined is by testing visual acuity. Methods for testing visual acuity are well known to those of ordinary skill in the art. Visual acuity tests the clarity of visual acuity in a subject, typically using a "visual acuity chart" in which the most common is the Snellen visual acuity chart (Snellen eye chart). Other visual acuity testing methods include the use of Early Treatment Diabetic Retinopathy Study (ETDRS) charts, as with other VA tests, can be used to diagnose and measure the progression/improvement of visual acuity in subjects with retinal related diseases such as, but not limited to, macular degeneration, central retinal vein occlusion, retinopathy of prematurity, and diabetic retinopathy. (see Bokinni, Y et al, Eye 29:1085-91 (2015)).

One way to determine an improvement in a patient's visual acuity is to determine whether the subject is able to recognize more letters on the snellen, ETDRS, or other similar chart after treatment before treatment. Since such visual acuity tests require communication between the subject and a medical professional (e.g., reading a letter aloud), it is difficult to obtain similar readings of visual acuity when testing animal models in preclinical studies.

The advantage of visual acuity as a clinical endpoint may be independent of other visual tests that rely on the observation of retinal vascularization or neovascularization (e.g., fundus photography/observation, fluorescein angiography, or even optical coherence tomography). That is, if the improvement in visual acuity is not due to a mechanism affecting the retinal vasculature, the test may still reveal the efficacy of the treatment. While the magnitude of the improvement may vary for a given patient, in some cases the magnitude of the improvement determined using a visual acuity test (e.g., as described above) is 5% or more, such as 10% or more, including 20% or more.

Macular degeneration/amsler grid

One method commonly used to diagnose macular degeneration and determine disease progression is the use of an amsler (macular degeneration) grid table, methods of which are well known to those of ordinary skill in the art. The grid comprises squares similar in appearance to a paper square, with dark lines forming a square grid and dark spots in the middle of the squares. Covering each eye in succession, the subject focused each eye on a dark spot and noted whether any lines of the grid were broken, distorted, wavy, or blurred.

Comprehensive retinal examination with pupil dilation

Comprehensive retinal examination utilizing pupil dilation is a method by which the retina can be directly viewed by a practitioner, such as an optometrist or ophthalmologist, and is well known to those of ordinary skill in the art. The practitioner administers an expansion eye drop to the subject. The eye drops may have both types of mydriatic drugs and may be administered together or separately. One to stimulate the contraction of the muscle that dilates the pupil (e.g., phenylephrine), and the other to relax the muscle that contracts the pupil (e.g., cyclamate). Pupil dilation allows practitioners to better view the larger field of vision of the retina during eye examination.

Comprehensive retinal examinations using pupil dilation allow ophthalmologists to diagnose and determine disease progression for various eye and retina-related diseases such as, by way of example and not limitation, glaucoma, diabetic retinopathy, retinopathy of prematurity, central retinal vein occlusion, and age-related macular degeneration. The signs of these diseases, which can be determined by fundus photography, include dilation or leakage of blood vessels in the retina, abnormal growth of blood vessels in or under the retina, and degeneration of the macula of the retina.

v. fundus photography

Similar to retinal examinations with pupil dilation, fundus photography is a method by which the retina can be directly photographed and is well known to those of ordinary skill in the art. (Saine, PJ et al, "review of fundus Photography," ophthalmography: retinography, Angiography, and Electronic Imaging (opthalmic Photography: RetinalPhotography, Angiography, and Electronic Imaging), Butterworth-Heinemann Medical (2 nd edition)). The procedure includes pupil dilation with the patient sitting in front of the fundus camera. The flash emits light to the patient's eye, producing a fundus picture or retinal image. Various color filters may be used to take the picture or a dose of, for example, fluorescein, may be administered to the patient to aid in imaging.

The fundus camera is a dedicated low power microscope connected to the camera. The acceptance angle of the lens may produce different outputs. One of ordinary skill in the art recognizes a 30 degree angle as the normal viewing angle of the retina. The wide angle fundus camera is capable of taking images between 45 and 140 degrees, while the narrow angle fundus camera has an angle of view of 20 degrees or less.

As with comprehensive retinal examinations utilizing pupil dilation, fundus photography allows ophthalmologists to diagnose and determine disease progression for various eye and retina-related diseases such as, by way of example and not limitation, glaucoma, retinopathy of prematurity, diabetic retinopathy, central retinal vein occlusion, and age-related macular degeneration. The signs of these diseases, which can be determined by fundus photography, include dilation or leakage of blood vessels in the retina, abnormal growth of blood vessels in or under the retina, and degeneration of the macula of the retina.

Fluorescein angiography

Fluorescein angiography is a method by which retinal blood vessels can be assessed and is well known to those of ordinary skill in the art. It is most commonly used to diagnose or measure the progression of wet macular degeneration/choroidal neovascularization.

The fluorescein dye is injected into a vein of a subject (whose eye has been previously dilated) to allow the dye to travel to the vasculature of the eye and retina. Prior to dye injection, a baseline photograph of the retina was taken. Additional pictures of the retina are taken at intervals of one to several minutes when it is determined that the dye has entered the retinal vasculature. Looking at the photograph, the ophthalmologist can determine if any dye has leaked from the blood vessel, which helps them understand where new and fragile blood vessels are located.

Optical Coherence Tomography (OCT)

OCT is a non-invasive test that provides high resolution cross-sectional images of the retina and uses light waves to generate the images. (Fujimoto, JG et al, Neoplasia (Neoplasia),2(1-2):9-25 (1/2000)). OCT allows imaging of every distinct layer of the retina. Thus, the ophthalmologist is provided with a method by which the retina can be mapped and its thickness determined. By way of example and not limitation, the Central Retinal Thickness (CRT) of a subject's retina can be accurately measured. Methods of performing OCT testing and determining CRT are well known to those skilled in the art.

OCT can be performed using eye drops that dilate the pupil and allow for better inspection of the subject's retina. Once the pupil is fully dilated, the OCT scanner can scan the subject's eye in a non-invasive manner. OCT can help diagnose a number of retinal related conditions/diseases including macular edema, age-related macular degeneration, glaucoma, diabetic retinopathy, and retinopathy of prematurity.

Reagents, devices and kits

Also provided are reagents, devices and kits for carrying out one or more of the above methods. The subject reagents, devices, and kits can vary widely. Agents and devices of interest include those described above with respect to the methods of administering a compound described herein (e.g., a compound of formula 1) to a subject.

In addition to the above components, the subject kits further comprise instructions for practicing the subject methods. These instructions may be present in the subject kits in various forms, one or more of which may be present in the kit. One form in which these instructions may be present is printed information on a suitable medium or substrate, e.g., one or more sheets of paper on which the information is printed, in the packaging of the kit, in package instructions, etc. Another approach is a computer readable medium, such as a diskette, CD, portable flash drive, etc., having information recorded thereon. Another way that may exist is a website address that may be used over the internet to access information at a remote site. Any convenient means may be present in the kit.

The following examples are provided for illustration and not for limitation.

Examples of the invention

a. Pharmaceutical preparation

Pharmaceutical compositions for administration to subjects having retinal-related diseases can be synthesized, prepared, and formulated using the examples disclosed in U.S. patent application publication nos. 2013/0266646, 2016/0081998, 8,278,302, 8,653,075, RE45323, 8,742,115, 9,233,950, and 8,680,280, which are incorporated herein by reference in their entirety. In addition, pharmaceutical compositions may be prepared as described in the examples below:

1. tablet formulation-Wet granulation

Copovidone was dissolved in ethanol at ambient temperature to produce a granulation liquid. The active CCR3 antagonist ingredient, lactose, and a portion of crospovidone were mixed in a suitable mixer to create a pre-blend. The premix is wetted with a granulating liquid and subsequently granulated. The wet granules are optionally sieved through a sieve having a mesh size of 1.6-3.0 mm. The granules were dried at 45 ℃ in a suitable dryer to a residual moisture content corresponding to a loss on drying of 1-3%. The dried granules were sieved through a sieve having a mesh size of 1.0 mm. The granules are mixed with a portion of crospovidone and microcrystalline cellulose in a suitable mixer. After being deblocked through a 1.0mm sieve, magnesium stearate was added to the mixture. The final blend is then prepared by final blending in a suitable mixer and compressed into tablets. The following tablet compositions can be obtained:

components	Milligram/tablet	%/tablet
			Active ingredient	28.500	30.0
Crospovidone	1.500	1.6
			Lactose	28.000	29.5
Co-polyvidone	3.000	3.2
			Total amount (granule)	61.000	64.3
Microcrystalline cellulose	31.000	32.6
			Crospovidone	2.500	2.6
Magnesium stearate	0.500	0.5
			Total of	95.000	100.000

2. Tablet formulation-melt granulation

The active CCR3 antagonist ingredient, lactose, part mcc, polyethylene glycol, lactose, and part crospovidone were mixed in a suitable mixer to create a premix. The premix is heated in a high shear mixer and then granulated. The hot granules were cooled to room temperature and sieved through a sieve having a mesh size of 1.0 mm. The granules are mixed with a portion of crospovidone and microcrystalline cellulose in a suitable mixer. After being deblocked through a 1.0mm sieve, magnesium stearate was added to the mixture. The final blend is then prepared by final blending in a suitable mixer and compressed into tablets. The following tablet compositions can be obtained:

components	Milligram/tablet	%/tablet
			Active ingredient	28.500	30.0
Crospovidone	1.500	1.6
			Lactose	11.000	11.6
Polyethylene glycol	14.300	15.1
			MCC	5.700	6.0
Total amount (granule)	61.000	64.3
			Microcrystalline cellulose	31.000	32.6
Crospovidone	2.500	2.6
			Magnesium stearate	0.500	0.5
Total of	95.000	100.000

3. Tablet formulation-Hot melt granulation

The active CCR3 antagonist ingredient, mannitol, polyethylene glycol, and partially crospovidone were mixed in a suitable mixer to create a pre-mix. The premix is heated in a high shear mixer and then granulated. The hot granules were cooled to room temperature and sieved through a sieve having a mesh size of 1.0 mm. The granules were mixed with a portion of crospovidone and mannitol in a suitable mixer. After being deblocked through a 1.0mm sieve, magnesium stearate was added to the mixture. The final blend is then prepared by final blending in a suitable mixer and compressed into tablets. The following tablet compositions can be obtained:

components	Milligram/tablet	%/tablet
			Active ingredient	28.500	30.0
Crospovidone	1.500	1.6
			Mannitol	16.700	17.6
Polyethylene glycol	14.300	15.1
			Total amount (granule)	61.000	64.3
Mannitol	31.000	32.6
			Crospovidone	2.500	2.6
Magnesium stearate	0.500	0.5
			Total of	95.000	100.000

4. Tablet formulation-Hot melt extrusion

The active CCR3 antagonist ingredient and stearic-palmitic acid were mixed in a suitable mixer to create a pre-mix. The premix is extruded in a twin-screw extruder and subsequently granulated. The granules were sieved through a sieve having a mesh size of 1.0 mm. The granules were mixed with mannitol and crospovidone in a suitable mixer. After being deblocked through a 1.0mm sieve, magnesium stearate was added to the mixture. The final blend is then prepared by final blending in a suitable mixer and compressed into tablets. The following tablet compositions can be obtained:

components	Milligram/tablet	%/tablet
			Active ingredient	28.500	30.0
Stearic acid-palmitic acid	27.500	28.9
			Total amount (granule)	56.000	58.9
Mannitol	32.600	34.3
			Crospovidone	5.600	5.9
Magnesium stearate	0.800	0.9
			Total of	95.000	100.000

5. Tablet formulation-Hot melt extrusion

components	Milligram/tablet	%/tablet
			Active ingredient	70.000	70.0
Stearic acid-palmitic acid	30.000	30.0
			Total amount (granule)	100.000	100.0
Capsule	90.000	-
			Total of	190.000	100.000

6. Tablet formulation-roller compaction

The active CCR3 antagonist ingredients, mannitol and crospovidone, and a portion of magnesium stearate are mixed in a suitable mixer to create a pre-mix. The premix is compacted with a roller press and subsequently granulated. Optionally, the granules are sieved through a sieve with a mesh size of 0.8 mm. The granules were mixed with a portion of mannitol and crospovidone in a suitable mixer. After being deblocked through a 1.0mm sieve, magnesium stearate was added to the mixture. The final blend is then prepared by final blending in a suitable mixer and compressed into tablets. The following tablet compositions can be obtained:

components	Milligram/tablet	%/tablet
			Active ingredient	28.500	30.0
Crospovidone	1.400	1.5
			Mannitol	34.600	36.4
Magnesium stearate	0.500	0.5
			Total amount (granule)	65.000	68.4
Mannitol	27.000	28.4
			Co-polyvidone	1.600	1.7
Crospovidone	0.950	1.0
			Magnesium stearate	0.450	0.5
Total of	95.000	100.000

7. Tablet formulation-roller compaction

The active CCR3 antagonist ingredient and magnesium stearate are mixed in a suitable mixer to create a pre-mix. The premix is compacted with a roller press and subsequently granulated. Optionally, the granules are sieved through a sieve with a mesh size of 0.8 mm. The granules were mixed with mannitol and croscarmellose sodium in a suitable mixer. After being deblocked through a 1.0mm sieve, magnesium stearate was added to the mixture. The final blend is then prepared by final blending in a suitable mixer and compressed into tablets. The following tablet compositions can be obtained:

components	Milligram/tablet	%/tablet
			Active ingredient	114.200	66.0
Magnesium stearate	1.800	1.0
			Total amount (granule)	116.000	67.0
Mannitol	51.000	29.5
			Croscarmellose sodium	3.500	2.0
Magnesium stearate	2.500	1.5
			Total of	173.000	100.000

8. Tablet formulation-roller compaction

The active CCR3 antagonist ingredient and magnesium stearate are mixed in a suitable mixer to create a pre-mix. The premix is compacted with a roller press and subsequently granulated. Optionally, the granules are sieved through a sieve with a mesh size of 0.8 mm. The granules are mixed with microcrystalline cellulose and crospovidone in a suitable mixer. After being deblocked through a 1.0mm sieve, magnesium stearate was added to the mixture. The final blend is then prepared by final blending in a suitable mixer and compressed into tablets. The following tablet compositions can be obtained:

components	Milligram/tablet	%/tablet
			Active ingredient	114.200	66.0
Magnesium stearate	1.800	1.0
			Total amount (granule)	116.000	67.0
MCC	51.000	29.5
			Crospovidone	3.500	2.0
Magnesium stearate	2.500	1.5
			Total of	173.000	100.000

9. Coated tablet formulation

Tablet cores according to the above formulation can be used to produce film coated tablets. Hydroxypropyl methylcellulose, polyethylene glycol, talc, titanium dioxide and iron oxide are suspended in purified water at ambient temperature in a suitable mixer to produce a coating suspension. The tablet cores were coated with the coating suspension to about 3% weight gain to prepare film coated tablets. The following thin film coating compositions can be obtained:

b. pharmaceutical formulations and administration

The study product of the invention conforms to the following chemical structure:

one of ordinary skill in the relevant art will recognize that the compounds, co-crystals, salts, and formulations previously described in the above section may also be used in these examples.

The study products of the present invention are provided in 100mg, 200mg and 400mg film-coated tablets having a biconvex, circular or oval shape and a dark red color. Tablets are prepared by dry granulation and contain microcrystalline cellulose, hydrogen phosphate, croscarmellose sodium, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, red iron oxide and yellow iron oxide as inactive ingredients. Placebo tablets matching the study product were produced by direct compression and contained the same inactive ingredients.

c. Preclinical examples

The antagonistic potency of the investigational products of the invention was determined in several human CCR 3-dependent assays (figure 1). Determination of the efficacy, IC, of the study products of the invention by receptor binding assays₅₀The measurement was 4.0. + -. 1.8nM and the Ki was 3.2. + -. 0.6 nM. IC of calcium influx assay using human CCR 3-transfected CHEM 1-G.alpha.15 cells₅₀The assay was 0.9. + -. 0.2 nM. With IC₅₀Antagonism of the study products of the present invention against human eotaxin-1 induced eosinophil shape change in human whole blood at 42.5 ± 43.5 nM.

The efficacy of several other mammalian species was also determined in different assays. Species include cynomolgus monkey (macaque), mouse, rat, and canine. With respect to receptor binding assays, the study drug of the present invention was shown to have K for mouse CCR3_i124.3. + -. 0.9nM and IC₅₀The concentration was 87.3. + -. 5.6 nM. For rat CCR3, K for the study drug of the invention_i1488.6 + -127.6 nM, and IC₅₀It was 1719.0. + -. 129.9 nM.

d. Design of clinical trial (treatment-untreated, 4 week protocol)

Patients newly diagnosed (e.g., treatment-naive) with CNF in the fovea are secondary to wAMD and enter the single-arm open label study. Patients orally took 400mg of study drug of the invention, b.o.d. (twice daily) for 4 weeks and scheduled one visit per week for the physician. The regimen calls for two 200mg tablets in the morning and two 200mg tablets in the evening. Eligible patients may receive standard therapy (anti-VEGF therapy) at the end of treatment (EoT) or after withdrawal from study drug therapy. Patients were followed twice within 4 weeks after EoT. FIG. 2 is a depiction of a clinical trial design. Boxes V1, V2, V3, V4, and V5 represent patient visits 1 through 5, respectively. The gaps between boxes represent the number of days between visits. The box labeled EoT indicates visit 6 or the end of treatment. Visits 7 and 8 occurred during the follow-up (FU) visit.

1. Primary endpoint-Central Retina Thickness (CRT)

The primary endpoint was the change in Central Retinal Thickness (CRT) from baseline as determined by spectral domain optical coherence tomography (SD-OCT) on day 29 (visit 6). For all primary and secondary endpoints, the last assessment before the first study drug intake was used as baseline on day 1 (visit 2).

Fig. 3 shows the CRT variation over time. CRT is reported as mean (SEM) in microns and time is reported in number of visits. The retinal layers and thickness are observed and measured by SD-OCT, and for a person having ordinary skill in the art and trained using OCT equipment, visualization and measurement of the retinal layers involve well-known techniques. (see, e.g., Fujimoto, JG et al, neoplasia 2(1-2)9-25 (2000); and Keane, PA et al, ophthalmologic research and Visual acuity 50(7):3378-85 (2009)). Overall, median or mean CRT did not change significantly from baseline during the treatment period.

2. Secondary endpoint

(a) Neovascular leakage as assessed by fluorescence angiography and fundus photography

The retinal vasculature of the eye was studied by Fluorescein Angiography (FA) evaluation. Changes in neovascular leakage of FA compared to baseline were determined on day 29 (visit 6). Figure 4 reports the absolute values as well as the mean and median changes over time relative to baseline. N is the number of patients evaluated. Overall, there was no significant change in median or mean from baseline during the treatment period.

(b) Visual acuity

Visual acuity was determined using ETDRS charts over the treatment time. Patients were evaluated for absolute change in the number of letters read from their baseline level during the visit. Fig. 5 depicts the absolute change (x-axis) over time (y-axis) during treatment with the study drug of the present invention (inv. cmpd.). Of the 14 patients in total, a subset of 8 patients showed a significant improvement in Best Corrected Visual Acuity (BCVA) compared to the mock control and the overall larger patient group. The improvement in visual acuity is surprising, at least in part, in view of the therapy not significantly affecting central retinal thickness. For a subgroup of 8 patients, the best corrected visual acuity compares favorably to the anti-VEGF treatment (ranibizumab intravitreal injection) previously reported in the MARINA and VIEW studies. (Rosenfeld PJ et al, N.Engl. J.Med.)355(14) 1419-31(2006) and Heier JS et al, Ophthalmology (Ophthalology) 119(12) 2537-48(2012)) thus it is apparent that the methods described herein improve visual acuity to levels observed relative to anti-VEGF therapy, but employ a different mechanism of action than the current standard of care.

This significant improvement in visual acuity in over half of patients was both surprising and unexpected in view of the observation that the study compounds of the present invention failed to significantly alter central retinal thickness or neovascular leakage. This indicates that the study compounds have neuroprotective effects on neurons associated with retinal and retinal diseases.

d. Design of clinical trial (treatment-untreated, 6 week protocol)

Newly diagnosed (e.g., untreated) patients with depressed central retinal CNF were secondary to wAMD and entered the one-armed open label study. During each visit, the patients were assessed for safety and tolerability. At the designated visit, BCVA was determined by ETDRS and morphological evaluation was performed using SD-OCT and fundus photography/FA. Patients self-orally take 800mg (400mg bid) of study drug of the present invention per day. The trial lasted 10 weeks, including 6 weeks of treatment plus 4 weeks of follow-up.

1. Main endpoint (BCVA)

The primary endpoint was the mean change in BCVA letter score determined by the ETDRS (early treatment diabetic retinopathy study) test method. BCVA was measured during visit 1 (screening visit), 2-7 (treatment visit), 9-10 (follow-up).

2. Exploratory endpoint (morphism)

Exploratory endpoint studies the ocular morphological effects associated with twice daily administration of study drugs of the present invention. Measurements of Central Retinal Thickness (CRT), intraretinal fluid (IRF), subretinal fluid (SRF) and Pigment Epithelium Detachment (PED) were all performed using SD-OCT and fundus photography/FA (fluorescein angiography).

e. Design of clinical trial (refractory wAMD, 6 week protocol)

Patients with refractory CNV secondary to wAMD after monthly treatment (for at least 3 months) with Intravitreal (IVT) anti-vascular endothelial growth factor (anti-VEGR) therapy entered the one-arm open label study. During each visit, the patients were assessed for safety and tolerability. At the designated visit, BCVA was determined by ETDRS and morphological evaluation was performed using SD-OCT and fundus photography/FA. Patients self-orally take 800mg (400mg bid) of study drug of the present invention per day. The trial lasted 10 weeks, including 6 weeks of treatment plus 4 weeks of follow-up.

1. Main endpoint (BCVA)

2. Exploratory endpoint (morphism)

f. Combination therapy trial (refractory wAMD, 1.5 years protocol)

Newly diagnosed (e.g., untreated) patients with CNV enter the two-arm randomized study secondary to wAMD. The first group contained an anti-VEGF agent delivered as an intravitreal injection (e.g., current standard of care, such as ranibizumab) plus an orally administered study drug of the invention. The second group contained anti-VEGF injections plus oral placebo (i.e., active standard of care).

During each visit, the patients were assessed for safety and tolerability. At the designated visit, BCVA was determined by ETDRS and morphological evaluation was performed using SD-OCT and fundus photography/FA. The first group of patients self-orally took 800mg (400mg bid) of study drug of the present invention per day and received 0.5mg of an anti-VEGF agent, such as ranibizumab, per visit injection at a dose of 10mg/ml in pre-filled syringes. The second group of patients self-administered placebo capsules twice daily and injected 0.5mg of an anti-VEGF agent such as ranibizumab monthly at a dose of 10mg/ml in a pre-filled syringe.

1. Main endpoint (BCVA)

The primary endpoint was the mean change in BCVA letter score determined by the ETDRS (early treatment diabetic retinopathy study) test method. BCVA was measured during screening visits, treatment visits and follow-up visits with anti-VEGF agents. Mean changes in BCVA between the two treatment groups were determined at 18 months and 24 months.

2. Secondary endpoint (number of injections)

The number of intravitreal injections administered per year in the patients in the first treatment group was determined. These two treatment groups were compared to these results to determine how many injections per year resulted in equal BCVA results.

Other endpoints studied the ocular morphological effects of each treatment group. Measurements of Central Retinal Thickness (CRT), intraretinal fluid (IRF), subretinal fluid (SRF) and Pigment Epithelium Detachment (PED) were all performed using SD-OCT and fundus photography/FA (fluorescein angiography). These results help to determine the degree of synergy between anti-VEGF standard of care and study drug administration of the invention, further elucidating the comparison of the mechanism of action between the two therapies.

Is incorporated by reference

All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

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Methods and compositions for treating retinal-related diseases using CCR3 inhibitors

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