Inhibitors of short chain dehydrogenase activity for promoting neurogenesis and inhibiting neuronal cell death
阅读说明：本技术 用于促进神经发生并抑制神经细胞死亡的短链脱氢酶活性的抑制剂 (Inhibitors of short chain dehydrogenase activity for promoting neurogenesis and inhibiting neuronal cell death ) 是由 S·马科维茨 J·雷迪 A·皮珀 于 2017-07-18 设计创作，主要内容包括：本发明提供了促进受试对象的神经保护而免于损伤后轴索变性、神经元细胞死亡和/或胶质细胞损伤；增强学习和记忆的潜在的神经元信号传递；刺激损伤后神经元再生；和/或治疗有需要的受试对象的疾病、紊乱和/或状况的方法,其包括向所述的受试对象给予治疗有效量的15-PGDH抑制剂。(The present invention provides methods of promoting neuroprotection from post-injury axonal degeneration, neuronal cell death, and/or glial cell injury in a subject; potential neuronal signaling to enhance learning and memory; stimulating neuronal regeneration after injury; and/or a method of treating a disease, disorder and/or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a 15-PGDH inhibitor.)
1. A method of promoting neuroprotection in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of a 15-PGDH inhibitor.
2. The method of claim 1, wherein the subject has or is at risk of post-injury axonal degeneration, neuronal cell death, and/or glial cell injury.
3. The method of claim 1, wherein said 15-PGDH inhibitor is capable of being administered in an amount effective to stimulate hippocampal neurogenesis, thereby being useful for treating neuropsychiatric and neurodegenerative diseases.
4. The method of claim 3, wherein the neuropsychiatric and neurodegenerative diseases are schizophrenia, major depression, bipolar disorder, normal aging, epilepsy, traumatic brain injury, post-traumatic psychotic disorder, Parkinson's disease, Alzheimer's disease, Down's syndrome, spinocerebellar ataxia, lateral sclerosis, Huntington's disease, stroke, radiation therapy, chronic stress, and abuse of neuroactive drugs.
5. A method of treating a disease, disorder and/or condition of the nervous system in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of a 15-PGDH inhibitor.
6. The method of claim 5, wherein the disease, disorder and/or condition of the nervous system comprises at least one of a neurological disorder, neuropsychiatric disorder, neurological injury, neurotoxic disorder, neuropathic pain and neurodegenerative disorder.
7. The method of claim 6, wherein the neurological disorder comprises at least one of trauma or toxic injury to peripheral or cranial nerves, spinal cord, brain or cranial nerves, traumatic brain injury, stroke, cerebral aneurysm, and spinal cord injury.
8. The method of claim 6, wherein the neurological disorder comprises at least one of Alzheimer's disease, dementia associated with Alzheimer's disease, Parkinson's disease, diffuse Lewy body disease, senile dementia, Huntington's disease, Gilles de Ia Tourette's syndrome, multiple sclerosis, lateral sclerosis, hereditary motor and sensory neuropathy, diabetic neuropathy, progressive supranuclear palsy, epilepsy, or Jakob-Creutzfeldt disease.
9. The method of claim 6, wherein the nerve damage is caused by or associated with at least one of: epilepsy, cerebrovascular disorders, autoimmune disorders, sleep disorders, autonomic disorders, bladder disorders, abnormal metabolic states, disorders of the muscular system, infectious and parasitic diseases, neoplasms, endocrine disorders, nutritional and metabolic disorders, immune disorders, diseases of the blood and hematopoietic organs, psychiatric disorders, diseases of the nervous system, diseases of the sensory organs, diseases of the circulatory system, diseases of the respiratory system, diseases of the digestive system, diseases of the genitourinary system, diseases of the skin and subcutaneous tissue, diseases of the musculoskeletal and connective tissue, congenital disorders or conditions of perinatal origin.
10. A method of enhancing underlying neuronal signaling of learning and memory in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of a 15-PGDH inhibitor.
11. A method of stimulating neuronal regeneration following injury in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of a 15-PGDH inhibitor.
12. A method of treating alzheimer's disease in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of a 15-PGDH inhibitor.
13. A method of treating traumatic brain injury in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of a 15-PGDH inhibitor.
14. The method of any one of claims 1 to 13, wherein the 15-PGDH inhibitor has the following formula (I):
Wherein n is 0-2;
Y1,Y2And R1Are identical or different and are each selected from hydrogen, substituted or unsubstituted C1-C24Alkyl radical, C2-C24Alkenyl radical, C2-C24Alkynyl, C3-C20Aryl, heteroaryl, heterocycloalkenyl containing 5 to 6 ring atoms (wherein 1 to 3 ring atoms are independently selected from N, NH, N (C)1-C6Alkyl radical, NC (O) (C)1-C6Alkyl), O and S), C6-C24Alkylaryl group, C6-C24Aralkyl, halogen, -Si (C)1-C3Alkyl radical)3Hydroxy, sulfhydryl, C1-C24Alkoxy radical, C2-C24alkenyloxy radical, C2-C24Alkynyloxy, C5-C20Aryloxy, acyl (including C)2-C24Alkylcarbonyl (- -CO-alkyl) and C6-C20arylcarbonyl (-CO-aryl)), acyloxy (-O-acyl), C2-C24Alkoxycarbonyl (- (CO) -O-alkyl), C6-C20Aryloxycarbonyl (- (CO) -O-aryl), C2-C24Alkyl carbonic acids (-O- (CO) -O-alkyl), C6-C20Aryl carbonic acid (-O- (CO) -O-aryl), carboxyl (-COOH), carboxylic acid (-COO)-) Carbamoyl (- (CO) -NH)2),C1-C24Alkyl-carbamoyl (- (CO) -NH (C)1-C24Alkyl)), arylcarbamoyl (- (CO) -NH-aryl), thiocarbamoyl (- (CS) -NH2) Ureido (-NH- (CO) -NH)2) Cyano (-CN), isocyano (-N)+C-) Cyanoacyl (-O-CN), isocyanato (-O-N)+＝C-) Thio-isocyanoyl (-S-CN), azide (-N ═ N)+＝N-) A formate (- - (CO) - - -H), a thiocarbamate (- - (CS) - - - -H), an amino (- -NH)2),C1-C24Alkylamino radical, C5-C20arylamino, C2-C24Alkylamides (-NH- (CO) -alkyl), C6-C20Arylamides (-NH- (CO) -aryl), imino (-CR ═ NH, where R is hydrogen, C1-C24Alkyl radical, C5-C20Aryl radical, C6-C24Alkylaryl group, C6-C24Aralkyl, etc.), alkylimino (-CR ═ N (alkyl), where R ═ hydrogen, alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (-CR ═ N (aryl), where R ═ hydrogen, alkyl, aryl, alkaryl, etc.), nitro (-NO), and the like2) Nitroso group (-NO), sulfo group (-SO)2-OH), sulfonic acid (-SO)2-O-),C1-C24Alkylsulfanyl (-S-alkyl; also known as "alkylthio"), arylsulfanyl (-S-aryl; also known as "arylthio"), C1-C24Alkylsulfinyl (- (SO) -alkyl), C5-C20Arylsulfinyl (- (SO) -aryl), C1-C24Alkylsulfonyl (-SO)2-alkyl), C5-C20Arylsulfonyl (-SO)2Aryl), sulfanilamide (-SO)2-NH2,-SO2NY2(wherein Y is independently H, aryl or alkyl), phosphono (-P (O) (OH)2) Phosphonic acid (-P (O) (O))-)2) Phosphinic acid (-P (O)) (O)-) Phosphoric acid (-PO)2) Phosphino (- -PH)2) Polyalkyl ethers, phosphoric acids, phosphoric acid esters, groups incorporating amino acids or other moieties (predicted to carry a positive or negative charge at physiological pH) and combinations thereof, and wherein Y1And Y2Can be linked to form a ring or a polycyclic ring, wherein the ring is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclyl;
U1Is N, C-R2Or C-NR3R4Wherein R is2Selected from H, lower alkyl groups, O, (CH)2)n1OR' (where n1 is 1,2 OR 3), CF3,CH2-CH2X,O-CH2-CH2X,CH2-CH2-CH2X,O-CH2-CH2X, (wherein X ═ H, F, Cl, Br or I), CN, (C ═ O) -R ', (C ═ O) N (R')2O (CO) R ', COOR ' (wherein R ' is H)Or a lower alkyl group), and wherein R is1And R2Can be linked to form a cyclic or polycyclic ring, wherein R3And R4Are identical or different and are each selected from the group consisting of H, lower alkyl radicals, O, (CH)2)n1OR' (where n1 is 1,2 OR 3), CF3,CH2-CH2X,CH2-CH2-CH2X, (wherein X ═ H, F, Cl, Br or I), CN, (C ═ O) -R ', (C ═ O) N (R')2COOR '(wherein R' is H or a lower alkyl group), and R3Or R4Can be default;
X1And X2Independently is N or C, and wherein when X is1And/or X2When is N, Y1And/or Y2Are respectively default;
Z1Is O, S, CRaRbOr NRaWherein R isaAnd RbIndependently is H or C1-8An alkyl group which is linear, branched or cyclic, and which is unsubstituted or substituted.
15. The method of any one of claims 1 to 13, wherein the 15-PGDH inhibitor has the following formula (II):
Wherein n is 0-2;
X4,X5,X6And X7Independently is N or CRc；
R1,R6,R7And RcIndependently selected from hydrogen, substituted or unsubstituted C1-C24Alkyl radical, C2-C24Alkenyl radical, C2-C24Alkynyl, C3-C20Aryl, heteroaryl, heterocycloalkenyl containing 5 to 6 ring atoms (wherein 1 to 3 ring atoms are independently selected from N, NH, N (C)1-C6Alkyl radical, NC (O) (C)1-C6Alkyl), O and S), C6-C24Alkylaryl group, C6-C24Aralkyl, halogen, -Si (C)1-C3Alkyl radical)3Hydroxy, sulfhydryl, C1-C24Alkoxy radical, C2-C24Alkenyloxy radical, C2-C24Alkynyloxy, C5-C20Aryloxy, acyl (including C)2-C24Alkylcarbonyl (- -CO-alkyl) and C6-C20Arylcarbonyl (-CO-aryl)), acyloxy (-O-acyl), C2-C24Alkoxycarbonyl (- (CO) -O-alkyl), C6-C20Aryloxycarbonyl (- (CO) -O-aryl), C2-C24Alkyl carbonic acids (-O- (CO) -O-alkyl), C6-C20Aryl carbonic acid (-O- (CO) -O-aryl), carboxyl (-COOH), carboxylic acid (-COO)-) Carbamoyl (- (CO) -NH)2),C1-C24Alkyl-carbamoyl (- (CO) -NH (C)1-C24Alkyl)), arylcarbamoyl (- (CO) -NH-aryl), thiocarbamoyl (- (CS) -NH2) Ureido (-NH- (CO) -NH)2) Cyano (-CN), isocyano (-N)+C-) Cyanoacyl (-O-CN), isocyanato (-O-N)+＝C-) Thio-isocyanoyl (-S-CN), azide (-N ═ N)+＝N-) A formate (- - (CO) - - -H), a thiocarbamate (- - (CS) - - - -H), an amino (- -NH)2),C1-C24Alkylamino radical, C5-C20Arylamino, C2-C24Alkylamides (-NH- (CO) -alkyl), C6-C20Arylamides (-NH- (CO) -aryl), imino (-CR ═ NH, where R is hydrogen, C1-C24Alkyl radical, C5-C20Aryl radical, C6-C24Alkylaryl group, C6-C24Aralkyl, etc.), alkylimino (-CR ═ N (alkyl), where R ═ hydrogen, alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (-CR ═ N (aryl), where R ═ hydrogen, alkyl, aryl, alkaryl, etc.), nitro (-NO), and the like2) Nitroso group (-NO), sulfo group (-SO)2-OH), sulfonic acid (-SO)2-O-),C1-C24Alkylsulfanyl (-S-alkyl; also known as "alkylthio"), arylsulfanyl (-S-aryl; also known as "arylthio"), C1-C24Alkylsulfinyl (- (SO) -alkyl), C5-C20Arylsulfinyl (- (SO)) -aryl), C1-C24Alkylsulfonyl (-SO)2-alkyl), C5-C20Arylsulfonyl (-SO)2Aryl), sulfanilamide (-SO)2-NH2,-SO2NY2(wherein Y is independently H, aryl or alkyl), phosphono (-P (O) (OH)2) Phosphonic acid (-P (O) (O))-)2) Phosphinic acid (-P (O)) (O)-) Phosphoric acid (-PO)2) Phosphino (- -PH)2) Polyalkyl ethers, phosphoric acids, phosphoric acid esters, groups incorporating amino acids or other moieties (predicted to carry a positive or negative charge at physiological pH) and combinations thereof, and wherein R6And R7can be linked to form a ring or a polycyclic ring, wherein the ring is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclyl;
U1Is N, C-R2Or C-NR3R4Wherein R is2Selected from H, lower alkyl groups, O, (CH)2)n1OR' (where n1 is 1,2 OR 3), CF3,CH2-CH2X,O-CH2-CH2X,CH2-CH2-CH2X,O-CH2-CH2X, (wherein X ═ H, F, Cl, Br or I), CN, (C ═ O) -R ', (C ═ O) N (R')2O (CO) R ', COOR ' (wherein R ' is H or a lower alkyl group), and wherein R1And R2Can be linked to form a cyclic or polycyclic ring, wherein R3And R4Are identical or different and are each selected from the group consisting of H, lower alkyl radicals, O, (CH)2)n1OR' (where n1 is 1,2 OR 3), CF3,CH2-CH2X,CH2-CH2-CH2X, (wherein X ═ H, F, Cl, Br or I), CN, (C ═ O) -R ', (C ═ O) N (R')2COOR '(wherein R' is H or a lower alkyl group), and R3Or R4Can be default;
X1And X2Independently is N or C, and wherein when X is1And/or X2When is N, Y1And/or Y2Are respectively default;
Z1Is O, S, CRaRbOr NRaWherein R isaAnd RbIndependently is H or C1-8An alkyl group which is linear, branched or cyclic, and which is unsubstituted or substituted.
16. The method of any one of claims 1 to 13, wherein the 15-PGDH inhibitor has the following formula (III) or (IV):or
wherein n is 0-2;
X6Independently is N or CRc；
R1,R6,R7And RcIndependently selected from hydrogen, substituted or unsubstituted C1-C24Alkyl radical, C2-C24Alkenyl radical, C2-C24Alkynyl, C3-C20Aryl, heteroaryl, heterocycloalkenyl containing 5 to 6 ring atoms (wherein 1 to 3 ring atoms are independently selected from N, NH, N (C)1-C6Alkyl radical, NC (O) (C)1-C6Alkyl), O and S), C6-C24Alkylaryl group, C6-C24Aralkyl, halogen, -Si (C)1-C3Alkyl radical)3Hydroxy, sulfhydryl, C1-C24Alkoxy radical, C2-C24Alkenyloxy radical, C2-C24Alkynyloxy, C5-C20Aryloxy, acyl (including C)2-C24Alkylcarbonyl (- -CO-alkyl) and C6-C20Arylcarbonyl (-CO-aryl)), acyloxy (-O-acyl), C2-C24Alkoxycarbonyl (- (CO) -O-alkyl), C6-C20Aryloxycarbonyl (- (CO) -O-aryl), C2-C24Alkyl carbonic acids (-O- (CO) -O-alkyl), C6-C20Aryl carbonic acid (-O- (CO) -O-aryl), carboxyl (-COOH), carboxylic acid (-COO)-) Carbamoyl (- (CO) -NH)2),C1-C24Alkyl-carbamoyl (- (CO) -NH (C)1-C24Alkyl)), arylcarbamoyl (- (CO) -NH-aryl), thiocarbamoyl (- (CS) -NH2) Ureido (-NH- (CO) -NH)2) Cyano (-CN), isocyano (-N)+C-) Cyanoacyl (-O-CN), isocyanato (-O-N)+＝C-) Thio-isocyanoyl (-S-CN), azide (-N ═ N)+＝N-) A formate (- - (CO) - - -H), a thiocarbamate (- - (CS) - - - -H), an amino (- -NH)2),C1-C24Alkylamino radical, C5-C20Arylamino, C2-C24Alkylamides (-NH- (CO) -alkyl), C6-C20Arylamides (-NH- (CO) -aryl), imino (-CR ═ NH, where R is hydrogen, C1-C24Alkyl radical, C5-C20Aryl radical, C6-C24Alkylaryl group, C6-C24Aralkyl, etc.), alkylimino (-CR ═ N (alkyl), where R ═ hydrogen, alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (-CR ═ N (aryl), where R ═ hydrogen, alkyl, aryl, alkaryl, etc.), nitro (-NO), and the like2) Nitroso group (-NO), sulfo group (-SO)2-OH), sulfonic acid (-SO)2-O-),C1-C24Alkylsulfanyl (-S-alkyl; also known as "alkylthio"), arylsulfanyl (-S-aryl; also known as "arylthio"), C1-C24Alkylsulfinyl (- (SO) -alkyl), C5-C20Arylsulfinyl (- (SO) -aryl), C1-C24Alkylsulfonyl (-SO)2-alkyl), C5-C20Arylsulfonyl (-SO)2Aryl), sulfanilamide (-SO)2-NH2,-SO2NY2(wherein Y is independently H, aryl or alkyl), phosphono (-P (O) (OH)2) Phosphonic acid (-P (O) (O))-)2) Phosphinic acid (-P (O)) (O)-) Phosphoric acid (-PO)2) Phosphino (- -PH)2) Polyalkyl ethers, phosphoric acids, phosphoric acid esters, groups incorporating amino acids or other moieties (predicted to carry a positive or negative charge at physiological pH) and combinations thereof, and wherein R6And R7can be linked to form a cyclic or polycyclic ring wherein the ring is substituted or unsubstituted aryl, substituted or unsubstitutedHeteroaryl, substituted or unsubstituted cycloalkyl and substituted or unsubstituted heterocyclyl;
U1Is N, C-R2Or C-NR3R4Wherein R is2Selected from H, lower alkyl groups, O, (CH)2)n1OR' (where n1 is 1,2 OR 3), CF3,CH2-CH2X,O-CH2-CH2X,CH2-CH2-CH2X,O-CH2-CH2X, (wherein X ═ H, F, Cl, Br or I), CN, (C ═ O) -R ', (C ═ O) N (R')2O (CO) R ', COOR ' (wherein R ' is H or a lower alkyl group), and wherein R1And R2Can be linked to form a cyclic or polycyclic ring, wherein R3And R4are identical or different and are each selected from the group consisting of H, lower alkyl radicals, O, (CH)2)n1OR' (where n1 is 1,2 OR 3), CF3,CH2-CH2X,CH2-CH2-CH2X, (wherein X ═ H, F, Cl, Br or I), CN, (C ═ O) -R ', (C ═ O) N (R')2COOR '(wherein R' is H or a lower alkyl group), and R3Or R4Can be default;
Z1Is O, S, CRaRbOr NRaWherein R isaAnd RbIndependently is H or C1-8An alkyl group which is linear, branched or cyclic, and which is unsubstituted or substituted.
17. The method of any one of claims 1 to 13, wherein the 15-PGDH inhibitor has the following formula (V):
Wherein n is 0-2;
X6Independently is N or CRc；
R1,R6,R7and RcIndependently selected from hydrogen, substituted or unsubstituted C1-C24Alkyl radical, C2-C24Alkenyl radical, C2-C24alkynyl, C3-C20Aryl, heteroaryl, heterocycloalkenyl containing 5 to 6 ring atoms (wherein 1 to 3 ring atoms are independently selected from N, NH, N (C)1-C6Alkyl radical, NC (O) (C)1-C6Alkyl), O and S), C6-C24Alkylaryl group, C6-C24Aralkyl, halogen, -Si (C)1-C3Alkyl radical)3Hydroxy, sulfhydryl, C1-C24Alkoxy radical, C2-C24Alkenyloxy radical, C2-C24Alkynyloxy, C5-C20Aryloxy, acyl (including C)2-C24Alkylcarbonyl (- -CO-alkyl) and C6-C20Arylcarbonyl (-CO-aryl)), acyloxy (-O-acyl), C2-C24Alkoxycarbonyl (- (CO) -O-alkyl), C6-C20Aryloxycarbonyl (- (CO) -O-aryl), C2-C24Alkyl carbonic acids (-O- (CO) -O-alkyl), C6-C20Aryl carbonic acid (-O- (CO) -O-aryl), carboxyl (-COOH), carboxylic acid (-COO)-) Carbamoyl (- (CO) -NH)2),C1-C24Alkyl-carbamoyl (- (CO) -NH (C)1-C24Alkyl)), arylcarbamoyl (- (CO) -NH-aryl), thiocarbamoyl (- (CS) -NH2) Ureido (-NH- (CO) -NH)2) Cyano (-CN), isocyano (-N)+C-) Cyanoacyl (-O-CN), isocyanato (-O-N)+＝C-) Thio-isocyanoyl (-S-CN), azide (-N ═ N)+＝N-) A formate (- - (CO) - - -H), a thiocarbamate (- - (CS) - - - -H), an amino (- -NH)2),C1-C24Alkylamino radical, C5-C20Arylamino, C2-C24Alkylamides (-NH- (CO) -alkyl), C6-C20Arylamides (-NH- (CO) -aryl), imino (-CR ═ NH, where R is hydrogen, C1-C24alkyl radical, C5-C20Aryl radical, C6-C24alkylaryl group, C6-C24Aralkyl, etc.), alkylimino (-CR ═ N (alkyl), where R ═ hydrogen, alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (-CR ═ N (aryl), where R ═ hydrogen, alkyl, aryl, alkaryl, etc.), nitro (-NO), and the like2) Nitroso (-NO), sulfoRadical (-SO)2-OH), sulfonic acid (-SO)2-O-),C1-C24Alkylsulfanyl (-S-alkyl; also known as "alkylthio"), arylsulfanyl (-S-aryl; also known as "arylthio"), C1-C24Alkylsulfinyl (- (SO) -alkyl), C5-C20Arylsulfinyl (- (SO) -aryl), C1-C24Alkylsulfonyl (-SO)2-alkyl), C5-C20Arylsulfonyl (-SO)2Aryl), sulfanilamide (-SO)2-NH2,-SO2NY2(wherein Y is independently H, aryl or alkyl), phosphono (-P (O) (OH)2) Phosphonic acid (-P (O) (O))-)2) Phosphinic acid (-P (O)) (O)-) Phosphoric acid (-PO)2) Phosphino (- -PH)2) Polyalkyl ethers, phosphoric acids, phosphoric acid esters, groups incorporating amino acids or other moieties (predicted to carry a positive or negative charge at physiological pH) and combinations thereof, and wherein R6And R7Can be linked to form a ring or a polycyclic ring, wherein the ring is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclyl;
U1Is N, C-R2Or C-NR3R4Wherein R is2Selected from H, lower alkyl groups, O, (CH)2)n1OR' (where n1 is 1,2 OR 3), CF3,CH2-CH2X,O-CH2-CH2X,CH2-CH2-CH2X,O-CH2-CH2X, (wherein X ═ H, F, Cl, Br or I), CN, (C ═ O) -R ', (C ═ O) N (R')2O (CO) R ', COOR ' (wherein R ' is H or a lower alkyl group), and wherein R1And R2Can be linked to form a cyclic or polycyclic ring, wherein R3And R4Are identical or different and are each selected from the group consisting of H, lower alkyl radicals, O, (CH)2)n1OR' (where n1 is 1,2 OR 3), CF3,CH2-CH2X,CH2-CH2-CH2X, (wherein X ═ H, F, Cl, Br or I), CN, (C ═ O) -R ', (C ═ O) N (R')2COOR '(wherein R' is H or a lower alkyl group), and R3Or R4Can be default.
18. The method of any one of claims 1 to 13, wherein the 15-PGDH inhibitor has the following formula (VI):
Wherein n is 0-2;
X6Is N or CRc；
R1Selected from branched or linear alkyl radicals, including- (CH)2)n1CH3(n1＝0-7),Wherein n is20-6 and X is any one of: CF (compact flash)yHz(y+z＝3),CClyHz(y+z＝3),OH,OAc,OMe,R71,OR72,CN,N(R73)2,(n30-5, m-1-5), and(n4＝0-5)；
R5Selected from H, Cl, F, NH2And N (R)76)2；
R6And R7Can each independently be one of:
R8,R9,R10,R11,R12,R13,R14,R15,R16,R17,R18,R19,R20,R21,R22,R23,R24,R25,R26,R27,R28,R29,R30,R31,R32,R33,R34,R35,R36,R37,R38,R39,R40,R41,R42,R43,R44,R45,R46,R47,R48,R49,R50,R51,R52,R53,R54,R55,R56,R57,R58,R59,R60,R61,R62,R63,R64,R65,R66,R67,R68,R69,R70,R71,R72,R73,R74,R76And RcAre all the same or different and are independently selected from hydrogen, substituted or unsubstituted C1-C24Alkyl radical, C2-C24Alkenyl radical, C2-C24Alkynyl, C3-C20Aryl, heterocycloalkenyl containing 5 to 6 ring atoms (wherein 1 to 3 ring atoms are independently selected from N, NH, N (C)1-C6Alkyl radical, NC (O) (C)1-C6Alkyl), O and S), heteroaryl or heterocyclyl containing 5 to 14 ring atoms (wherein 1 to 6 ring atoms are independently selected from N, NH, N (C)1-C3Alkyl), O and S), C6-C24Alkylaryl group, C6-C24Aralkyl, halogen, silyl, hydroxy, sulfhydryl, C1-C24Alkoxy radical, C2-C24Alkenyloxy radical, C2-C24Alkynyloxy, C5-C20Aryloxy, acyl (including C)2-C24Alkylcarbonyl (- -CO-alkyl) and C6-C20Arylcarbonyl (-CO-aryl)), acyloxy (-O-acyl), C2-C24alkoxycarbonyl (- (CO) -O-alkyl), C6-C20Aryloxycarbonyl (- (CO) -O-aryl), C2-C24Alkyl carbonic acids (-O- (CO) -O-alkyl), C6-C20Aryl carbonic acid (-O- (CO) -O-aryl), carboxyl (-COOH), carboxylic acid (-COO)-) Carbamoyl (- - (CO) - - -NH)2),C1-C24Alkyl-carbamoyl (- (CO) -NH (C)1-C24Alkyl)), arylcarbamoyl (- (CO) -NH-aryl), thiocarbamoyl (- (CS) -NH2) Ureido (-NH- (CO) -NH)2) Cyano (-CN), isocyano (-N)+C-) Cyanoacyl (-O-CN), isocyanato (-O-N)+＝C-) Thio-isocyanoyl (-S-CN), azide (-N ═ N)+＝N-) A formate (- - (CO) - - -H), a thiocarbamate (- - (CS) - - - -H), an amino (- -NH)2),C1-C24Alkylamino radical, C5-C20Arylamino, C2-C24Alkylamides (-NH- (CO) -alkyl), C6-C20Arylamides (-NH- (CO) -aryl), sulfonamides (-SO)2N(R)2Wherein R is independently H, alkyl, aryl or heteroaryl), imino (-CR ═ NH wherein R is hydrogen, C1-C24Alkyl radical, C5-C20Aryl radical, C6-C24Alkylaryl group, C6-C24Aralkyl, etc.), alkylimino (-CR ═ N (alkyl), where R ═ hydrogen, alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (-CR ═ N (aryl), where R ═ hydrogen, alkyl, aryl, alkaryl, etc.), nitro (-NO), and the like2) Nitroso group (-NO), sulfo group (-SO)2-OH), sulfonic acid (-SO)2-O-),C1-C24Alkylsulfanyl (-S-alkyl; also known as "alkylthio"), arylsulfanyl (-S-aryl; also known as "arylthio"), C1-C24Alkylsulfinyl (- (SO) -alkyl), C5-C20Arylsulfinyl (- (SO) -aryl), C1-C24Alkylsulfonyl (-SO)2-alkyl), C5-C20Arylsulfonyl (-SO)2Aryl), sulfanilamide (-SO)2-NH2,-SO2NY2(wherein Y is independently H, aryl or alkyl), phosphono (-P (O) (OH)2) Phosphonic acid (-P (O) (O))-)2) Phosphinic acid (-P (O)) (O)-) Phosphoric acid (-PO)2) Phosphino (- -PH)2) Poly alkyl ether (- [ (CH)2)nO]m) Phosphoric acid, phosphoric ester [ -OP (O) (OR)2Wherein R is H, methyl or other alkyl]Introduction of amino acids or other moieties (expected to carry a positive charge at physiological pH orNegative charge), and combinations thereof.
19. The method of any one of claims 1 to 13, wherein the 15-PGDH inhibitor has the formula:
20. The method of any one of claims 1 to 19, wherein the 15-PGDH inhibitor i) stimulates a Vaco503 reporter cell line expressing a 15-PGDH luciferase fusion construct to luciferase output levels in excess of 70 (using the following scale: a value of 100 indicates that the output of the reporter cell line doubled from baseline); ii) at a concentration of 2.5 μ M, the V9M reporter cell line expressing the 15-PGDH luciferase fusion construct was stimulated to achieve luciferase output levels above 75; iii) at a concentration of 7.5. mu.M, the LS174T reporter cell line expressing the 15-PGDH luciferase fusion construct was stimulated to achieve luciferase output levels in excess of 70; iv) at a concentration of 7.5 μ M, the negative control V9M cell line expressing the TK-renilla luciferase reporter was not activated to a level exceeding 20; and v) in IC50Below 1 μ M, the enzyme activity of the recombinant 15-PGDH protein was inhibited.
21. The method of any one of claims 1 to 19, wherein the 15-PGDH inhibitor i) stimulates a Vaco503 reporter cell line expressing a 15-PGDH luciferase fusion construct to increase luciferase output at a concentration of 2.5 μ Μ; ii) stimulating the V9M reporter cell line expressing the 15-PGDH luciferase fusion construct to increase luciferase output at a concentration of 2.5 μ Μ; iii) stimulating the LS174T reporter cell line expressing the 15-PGDH luciferase fusion construct to increase luciferase output at a concentration of 7.5. mu.M; iv) at 7.5 μ M concentration, the negative control V9M cell line expressing the TK-renilla luciferase reporter was not activated to luciferase levels above background by more than 20%; and v) in IC50Below 1 μ M, inhibitionEnzymatic activity of recombinant 15-PGDH protein.
22. The method of any one of claims 1 to 19, wherein the 15-PGDH inhibitor is IC at a recombinant 15-PGDH concentration from about 5nM to about 10nM50Less than 1uM, or preferably IC50Less than 250nM, or more preferably IC50Less than 50nM, or more preferably IC50Less than 10nM, or more preferably IC50The enzyme activity of recombinant 15-PGDH was inhibited below 5 nM.
Background
Prostaglandins have multiple physiological functions in the central nervous system through their specific G protein-coupled receptors. The major prostaglandin, prostaglandin E2 (PGE)2) Capable of activating receptor types EP1,2,3 and 4. Activation of the EP2 and EP4 receptors can modulate adenylate cyclase, and the production of 3, 5' -cyclic adenosine monophosphate (cAMP), while activation of the EP1 and EP3 receptors can modulate Ca2+And (4) signal transmission. The EP1 and EP2 receptors are expressed in cultured neurons and microglia, as well as in neurons of the cerebral cortex, striatum and hippocampus. In addition, PGE2Activation of the EP2 receptor is involved in long-term synaptic plasticity and cognitive function, since EP2-/-Mice show impaired hippocampal synaptogenesis (Chemtob et al, Semin Perinato.1994 Feb; 18(1): 23-9; Yang et al, J neurohem.2009 Jan; 108 (1)):295-304). After activation, different PGEs2The receptor can contribute to or protect against N-methyl-D-aspartic acid (NMDA) neurotoxicity and ischemic attacks. For example, in a mouse model of ischemic brain, pretreatment with an EP2 receptor-selective agonist can significantly reduce neurological deficits and abrogate EP2 receptor-exacerbated ischemic brain injury (Ahmad et al, Exp TranslStroke Med.2010 Jul 8; 2(1): 12). Activation of the EP2 receptor by butaprost protects neurons in vitro from amyloid beta-peptide neurotoxicity (Echeverria et al, Eur J Neurosci.2005 Nov; 22(9): 2199-.
Multiple studies have shown PGE2The mechanism for providing neuroprotection is via the EP2 or EP4 receptors, since both increase cAMP and subsequently enhance the Protein Kinase A (PKA) -dependent pathway (Echeverria et al Eur JNeurosci.2005 Nov; 22(9): 2199-. Administration of PGE2Therapeutic use against the EP2 receptor has not been shown, since PGE2The half-life after intravenous injection is less than 1min and about 30 seconds in the circulatory system (Fitzpatrick et al, Prostagladins.1980 Jun; 19(6): 917-31; Kimball et al, Prostagladins.1980 Sep; 20(3): 559-69).
Summary of The Invention
Embodiments described herein relate generally to compositions and methods for promoting neuronal production or survival in the brain of a mammal, and for treating diseases, disorders and/or conditions of the nervous system. As described in the examples below, it was found that compounds that inhibit, decrease and/or antagonize short-chain dehydrogenase activity (e.g., 15-PGDH inhibitors) can be used to increase PGE2 levels in the mammalian nervous system (e.g., brain). PGE2 elevates cyclic AMP by binding to EP2 and EP4 receptors that are highly expressed in the cerebral cortex, hippocampus and striatum. Stimulation of these receptors with PGE2 by administering a compound that inhibits, reduces and/or antagonizes 15-PGDH activity (e.g., a 15-PGDH inhibitor as described herein) can promote neuroprotection in a subject from axonal degeneration, neuronal cell death and/or glial cell injury following injury; enhance neural signaling underlying learning and memory; stimulating neuronal regeneration after injury; and/or treating a disease, disorder and/or condition of the nervous system.
In some embodiments, the disease, disorder and/or condition of the nervous system that can be treated with a 15-PGDH inhibitor can include at least one of a neurological disorder, a neuropsychiatric disorder, a neurological injury, a neurotoxic disorder, neuropathic pain, or a neurodegenerative disorder.
For example, the neurological disorder can include at least one of trauma or toxic injury to peripheral or cranial nerves, spinal cord or brain, such as traumatic brain injury, stroke, cerebral aneurysm, and spinal cord injury. The neurological disorder can also include at least one of alzheimer's disease, dementia associated with alzheimer's disease, parkinson's disease, diffuse lewy body disease, senile dementia, huntington's disease, Gilles deIa Tourette's syndrome, multiple sclerosis, lateral sclerosis, hereditary motor and sensory neuropathy, diabetic neuropathy, progressive supranuclear palsy, epilepsy or Jakob-creutzfeldt disease.
In some embodiments, the nerve damage can be caused by or associated with at least one of epilepsy, cerebrovascular disorders, autoimmune disorders, sleep disorders, autonomic disorders, bladder disorders, abnormal metabolic states, muscular system disorders, infectious and parasitic diseases, neoplasms, endocrine disorders, nutritional and metabolic disorders, immune disorders, blood and hematopoietic organ disorders, mental disorders, nervous system disorders, sensory organ disorders, circulatory system disorders, respiratory system disorders, digestive system disorders, genitourinary system disorders, skin and subcutaneous tissue disorders, musculoskeletal system and connective tissue disorders, congenital disorders, or conditions originating in perinatal origin.
In certain embodiments, the 15-PGDH inhibitor can be administered to a subject or to neurons of the subject, thereby promoting the survival, growth, development and/or function of the neurons, particularly Central Nervous System (CNS), brain and hippocampal neurons. In certain embodiments, the 15-PGDH inhibitors can be used to stimulate hippocampal neurogenesis and thus in the treatment of neuropsychiatric and neurodegenerative diseases, including (but not limited to) schizophrenia, major depression, bipolar disorder, normal aging, epilepsy, traumatic brain injury, post-traumatic mental disorder, parkinson's disease, alzheimer's disease, down syndrome, spinocerebellar ataxia, lateral sclerosis, huntington's disease, stroke, radiotherapy, chronic stress, and abuse of neuroactive drugs, such as alcohol, opiates, methamphetamine, phencyclidine and ***e.
In some embodiments, the 15-PGDH inhibitor can be administered to a subject in an amount effective to increase prostaglandin levels in the nervous system (e.g., brain). The 15-PGDH inhibitors can include compounds having the formula (I):
Wherein n is 0-2;
Y1,Y2And R1Are identical or different and are each selected from hydrogen, substituted or unsubstituted C1-C24Alkyl radical, C2-C24Alkenyl radical, C2-C24Alkynyl, C3-C20Aryl, heteroaryl, heterocycloalkenyl containing 5 to 6 ring atoms (wherein 1 to 3 ring atoms are independently selected from N, NH, N (C)1-C6Alkyl radical, NC (O) (C)1-C6Alkyl), O and S), C6-C24Alkylaryl group, C6-C24Aralkyl, halogen, -Si (C)1-C3Alkyl radical)3Hydroxy, sulfhydryl, C1-C24Alkoxy radical, C2-C24Alkenyloxy radical, C2-C24Alkynyloxy, C5-C20Aryloxy, acyl (including C)2-C24Alkylcarbonyl (- -CO-alkyl) and C6-C20Arylcarbonyl (-CO-aryl)), acyloxy (-O-acyl), C2-C24Alkoxycarbonyl (- (CO) -O-alkyl), C6-C20Aryloxycarbonyl (- (CO) -O-aryl), C2-C24Alkyl carbonic acids (-O- (CO) -O-alkyl), C6-C20Aryl carbonic acid (-O- (CO) -O-aryl), carboxyl (-COOH), carboxylic acid (-COO)-) Carbamoyl (- (CO) -NH)2),C1-C24Alkyl-carbamoyl (- (CO) -NH (C)1-C24Alkyl)), arylcarbamoyl (- (CO) -NH-aryl), thiocarbamoyl (- (CS) -NH2) Ureido (-NH- (CO) -NH)2) Cyano (-CN), isocyano (-N)+C-) Cyanoacyl (-O-CN), isocyanato (-O-N)+＝C-) Thio-isocyanoyl (-S-CN), azide (-N ═ N)+＝N-) A formate (- - (CO) - - -H), a thiocarbamate (- - (CS) - - - -H), an amino (- -NH)2),C1-C24Alkylamino radical, C5-C20Arylamino, C2-C24Alkylamides (-NH- (CO) -alkyl), C6-C20Arylamides (-NH- (CO) -aryl), imino (-CR ═ NH, where R is hydrogen, C1-C24Alkyl radical, C5-C20Aryl radical, C6-C24Alkylaryl group, C6-C24Aralkyl, etc.), alkylimino (-CR ═ N (alkyl), where R ═ hydrogen, alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (-CR ═ N (aryl), where R ═ hydrogen, alkyl, aryl, alkaryl, etc.), nitro (-NO), and the like2) Nitroso group (-NO), sulfo group (-SO)2-OH), sulfonic acid (-SO)2-O-),C1-C24alkylsulfanyl (-S-alkyl; also known as "alkylthio"), arylsulfanyl (-S-aryl; also known as "arylthio"), C1-C24alkylsulfinyl (- (SO) -alkyl), C5-C20Arylsulfinyl (- (SO) -aryl), C1-C24Alkylsulfonyl (-SO)2-alkyl), C5-C20Arylsulfonyl (-SO)2Aryl), sulfanilamide (-SO)2-NH2,-SO2NY2(wherein Y is independently H, aryl or alkyl), phosphono (-P (O) (OH)2) Phosphonic acid (-P (O) (O))-)2) Phosphinic acid (-P (O)) (O)-) Phosphoric acid (-PO)2) Phosphino (- -PH)2) Polyalkyl ethers, phosphoric acids, phosphoric acid esters, groups incorporating amino acids or other moieties (predicted to carry a positive or negative charge at physiological pH) and combinations thereof, and wherein Y1And Y2Can be linked to form a ring or a polycyclic ring, wherein the ring is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclyl;
U1Is N, C-R2Or C-NR3R4Wherein R is2Selected from H, lower alkyl groups, O, (CH)2)n1OR' (where n1 is 1,2 OR 3), CF3,CH2-CH2X,O-CH2-CH2X,CH2-CH2-CH2X,O-CH2-CH2X, (wherein X ═ H, F, Cl, Br or I), CN, (C ═ O) -R ', (C ═ O) N (R')2O (CO) R ', COOR ' (wherein R ' is H or a lower alkyl group), and wherein R1And R2Can be linked to form a cyclic or polycyclic ring, wherein R3And R4Are identical or different and are each selected from the group consisting of H, lower alkyl radicals, O, (CH)2)n1OR' (where n1 is 1,2 OR 3), CF3,CH2-CH2X,CH2-CH2-CH2X, (wherein X ═ H, F, Cl, Br or I), CN, (C ═ O) -R ', (C ═ O) N (R')2COOR '(wherein R' is H or a lower alkyl group), and R3Or R4Can be default;
X1And X2Independently is N or C, and wherein when X is1And/or X2When is N, Y1And/or Y2Are respectively default;
Z1Is O, S, CRaRbOr NRaWherein R isaAnd RbIndependently is H or C1-8An alkyl group which is linear, branched or cyclic, and which is unsubstituted or substituted.
In other embodiments, the 15-PGDH inhibitor can include a compound having the following formula (V):
Wherein n is 0-2;
X6Independently is N or CRc；
R1,R6,R7And RcAre each independently selected from hydrogen, substituted or unsubstituted C1-C24Alkyl radical, C2-C24Alkenyl radical, C2-C24Alkynyl, C3-C20Aryl, heteroaryl, heterocycloalkenyl containing 5 to 6 ring atoms (wherein 1 to 3 ring atoms are independently selected from N, NH, N (C)1-C6Alkyl radical, NC (O) (C)1-C6Alkyl), O and S), C6-C24Alkylaryl group, C6-C24Aralkyl, halogen, -Si (C)1-C3Alkyl radical)3Hydroxy, sulfhydryl, C1-C24Alkoxy radical, C2-C24Alkenyloxy radical, C2-C24Alkynyloxy, C5-C20Aryloxy, acyl (including C)2-C24Alkylcarbonyl (- -CO-alkyl) and C6-C20Arylcarbonyl (-CO-aryl)), acyloxy (-O-acyl), C2-C24Alkoxycarbonyl (- (CO) -O-alkyl), C6-C20Aryloxycarbonyl (- (CO) -O-aryl), C2-C24Alkyl carbonic acids (-O- (CO) -O-alkyl), C6-C20Aryl carbonic acid (-O- (CO) -O-aryl), carboxyl (-COOH), carboxylic acid (-COO)-) Carbamoyl (- (CO) -NH)2),C1-C24Alkyl-carbamoyl (- (CO) -NH (C)1-C24Alkyl)), arylcarbamoyl (- (CO) -NH-aryl), thiocarbamoyl (- (CS) -NH2) Ureido (-NH- (CO) -NH)2) Cyano (-CN), isocyano (-N)+C-) Cyanoacyl (-O-CN), isocyanato (-O-N)+＝C-) Thio-isocyanoyl (-S-CN), azide (-N ═ N)+＝N-) A formate (- - (CO) - - -H), a thiocarbamate (- - (CS) - - - -H), an amino (- -NH)2),C1-C24Alkylamino radical, C5-C20arylamino, C2-C24Alkylamides (-NH- (CO) -alkyl), C6-C20Arylamides (-NH- (CO) -aryl), imino (-CR ═ NH, where R is hydrogen, C1-C24Alkyl radical, C5-C20Aryl radical, C6-C24Alkylaryl group, C6-C24Aralkyl, etc.), alkylimino (-CR ═ N (alkyl), where R ═ hydrogen, alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (-CR ═ N (aryl), where R ═ hydrogen, alkyl, aryl, alkaryl, etc.), nitroRadical (-NO)2) Nitroso group (-NO), sulfo group (-SO)2-OH), sulfonic acid (-SO)2-O-),C1-C24Alkylsulfanyl (-S-alkyl; also known as "alkylthio"), arylsulfanyl (-S-aryl; also known as "arylthio"), C1-C24Alkylsulfinyl (- (SO) -alkyl), C5-C20Arylsulfinyl (- (SO) -aryl), C1-C24Alkylsulfonyl (-SO)2-alkyl), C5-C20Arylsulfonyl (-SO)2Aryl), sulfanilamide (-SO)2-NH2,-SO2NY2(wherein Y is independently H, aryl or alkyl), phosphono (-P (O) (OH)2) Phosphonic acid (-P (O) (O))-)2) Phosphinic acid (-P (O)) (O)-) Phosphoric acid (-PO)2) Phosphino (- -PH)2) Polyalkyl ethers, phosphoric acids, phosphoric acid esters, groups incorporating amino acids or other moieties (predicted to carry a positive or negative charge at physiological pH) and combinations thereof, and wherein R6And R7Can be linked to form a ring or a polycyclic ring, wherein the ring is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclyl;
U1Is N, C-R2Or C-NR3R4Wherein R is2Selected from H, lower alkyl groups, O, (CH)2)n1OR' (where n1 is 1,2 OR 3), CF3,CH2-CH2X,O-CH2-CH2X,CH2-CH2-CH2X,O-CH2-CH2X, (wherein X ═ H, F, Cl, Br or I), CN, (C ═ O) -R ', (C ═ O) N (R')2o (CO) R ', COOR ' (wherein R ' is H or a lower alkyl group), and wherein R1And R2Can be linked to form a cyclic or polycyclic ring, wherein R3And R4Are identical or different and are each selected from the group consisting of H, lower alkyl radicals, O, (CH)2)n1OR' (where n1 is 1,2 OR 3), CF3,CH2-CH2X,CH2-CH2-CH2X, (wherein X ═ H, F, Cl, Br or I), CN, (C ═ O) -R ', (C ═ O) N (R')2COOR '(wherein R' is H or lower alkyl)Group) and R3Or R4Can be default.
In some embodiments, R1Selected from branched or linear alkyl radicals, including- (CH)2)n1CH3(n1＝0-7),Wherein n is20-6 and X is any one of: CF (compact flash)yHz(y+z＝3),CClyHz(y+z＝3),OH,OAc,OMe,R71,OR72,CN,N(R73)2,(n30-5, m-1-5), and(n4＝0-5)。
In other embodiments, R6And R7Each can independently be one of the following and pharmaceutically acceptable salts thereof:
R8,R9,R10,R11,R12,R13,R14,R15,R16,R17,R18,R19,R20,R21,R22,R23,R24,R25,R26,R27,R28,R29,R30,R31,R32,R33,R34,R35,R36,R37,R38,R39,R40,R41,R42,R43,R44,R45,R46,R47,R48,R49,R50,R51,R52,R53,R54,R55,R56,R57,R58,R59,R60,R61,R62,R63,R64,R65,R66,R67,R68,R69,R70,R71,R72,R73And R74Are all the same or different and are independently selected from hydrogen, substituted or unsubstituted C1-C24Alkyl radical, C2-C24Alkenyl radical, C2-C24Alkynyl, C3-C20Aryl, heterocycloalkenyl containing 5 to 6 ring atoms (wherein 1 to 3 ring atoms are independently selected from N, NH, N (C)1-C6Alkyl radical, NC (O) (C)1-C6Alkyl), O and S), heteroaryl or heterocyclyl containing 5 to 14 ring atoms (wherein 1 to 6 ring atoms are independently selected from N, NH, N (C)1-C3Alkyl), O and S), C6-C24Alkylaryl group, C6-C24Aralkyl, halogen, silyl, hydroxy, sulfhydryl, C1-C24Alkoxy radical, C2-C24Alkenyloxy radical, C2-C24Alkynyloxy, C5-C20Aryloxy, acyl (including C)2-C24Alkylcarbonyl (- -CO-alkyl) and C6-C20Arylcarbonyl (-CO-aryl)), acyloxy (-O-acyl), C2-C24Alkoxycarbonyl (- (CO) -O-alkyl), C6-C20Aryloxycarbonyl (- (CO) -O-aryl), C2-C24Alkyl carbonic acids (-O- (CO) -O-alkyl), C6-C20Aryl carbonic acid (-O- (CO) -O-aryl), carboxyl (-COOH), carboxylic acid (-COO)-) Carbamoyl (- - (CO) - - -NH)2),C1-C24Alkyl-carbamoyl (- (CO) -NH (C)1-C24Alkyl)), arylcarbamoyl (- (CO) -NH-aryl), thiocarbamoyl (- (CS) -NH2) Ureido (-NH- (CO) -NH)2) Cyano (-CN), isocyano (-N)+C-) Cyanoacyl (-O-CN), isocyanato (-O-N)+＝C-) Thio-isocyanoyl (-S-CN), azide (-N ═ N)+＝N-) A formate (- - (CO) - - -H), a thiocarbamate (- - (CS) - - - -H), an amino (- -NH)2),C1-C24Alkylamino radical, C5-C20Arylamino, C2-C24Alkylamide (-NH-) - (H-) - (CO) -alkyl), C6-C20Arylamides (-NH- (CO) -aryl), sulfonamides (-SO)2N(R)2Wherein R is independently H, alkyl, aryl or heteroaryl), imino (-CR ═ NH wherein R is hydrogen, C1-C24Alkyl radical, C5-C20Aryl radical, C6-C24Alkylaryl group, C6-C24Aralkyl, etc.), alkylimino (-CR ═ N (alkyl), where R ═ hydrogen, alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (-CR ═ N (aryl), where R ═ hydrogen, alkyl, aryl, alkaryl, etc.), nitro (-NO), and the like2) Nitroso group (-NO), sulfo group (-SO)2-OH), sulfonic acid (-SO)2-O-),C1-C24Alkylsulfanyl (-S-alkyl; also known as "alkylthio"), arylsulfanyl (-S-aryl; also known as "arylthio"), C1-C24Alkylsulfinyl (- (SO) -alkyl), C5-C20Arylsulfinyl (- (SO) -aryl), C1-C24Alkylsulfonyl (-SO)2-alkyl), C5-C20Arylsulfonyl (-SO)2aryl), sulfanilamide (-SO)2-NH2,-SO2NY2(wherein Y is independently H, aryl or alkyl), phosphono (-P (O) (OH)2) Phosphonic acid (-P (O) (O))-)2) Phosphinic acid (-P (O)) (O)-) Phosphoric acid (-PO)2) Phosphino (- -PH)2) Poly alkyl ether (- [ (CH)2)nO]m) Phosphoric acid, phosphoric ester [ -OP (O) (OR)2Wherein R is H, methyl or other alkyl]Groups incorporating amino acids or other moieties (expected to carry a positive or negative charge at physiological pH) and combinations thereof.
In some embodiments, the 15-PGDH inhibitor is capable of IC at a recombinant 15-PGDH concentration of about 5nM to about 10nM50Less than 1 μ M, or preferably IC50Less than 250nM, or more preferably IC50Less than 50nM, or more preferably in IC50Less than 10nM, or more preferably IC50The enzyme activity of recombinant 15-PGDH was inhibited below 5 nM.
Brief Description of Drawings
Figure 1 is a graph showing the pharmacokinetics of the 15-PGDH inhibitor (+) SW033291 when administered by intraperitoneal injection at 10mg/kg to female CD-1 mice, followed by measurement (in mg/ml in plasma, or mg/gm wet tissue weight in brain).
Fig. 2 is a schematic and graph showing the concentration of prostaglandin E2(PGE2) in 3 regions of the brain, averaged from samples of 3 mice 3 hours after intraperitoneal injection using Vehicle (VE) or (+) SW033291(2.5 mg/kg).
Fig. 3(a-B) is a graph and chart showing the effect of administering (+) SW033291 on mouse performance during learning and memory following traumatic brain injury.
FIG. 4 is a graph showing the detection of 15-PGDH mRNA expression in neurons of hippocampus of mice.
FIG. 5(A-B) is a graph showing the pharmacokinetics of the 15-PGDH inhibitor (+) SW0209415 when administered by intraperitoneal injection at 2.5 and 25mg/kg to female C57BL/7 mice, followed by measurement (in mg/ml in plasma, or mg/gm wet tissue weight in brain).
FIG. 6(A-C) is a graph showing 15-PGDH activity in cortex (A), cerebellum (B) and pons and medulla oblongata (C) of mouse brain following IP injection of 15-PGDH inhibitor (+) SW033291(2.5 mpk).
Fig. 7 is a graph showing PGE2 levels in rat cortex after IP injection of (+) SW033291(2.5,5.0 and 10.0 mg/kg).
Fig. 8(a-B) is a Western blot and a graph showing 15-PGDH levels in brain tissue of subjects with alzheimer's disease, relative to age-matched control subjects without alzheimer's disease.
Detailed Description
For convenience, certain terms used in the specification, examples, and appended claims are collected here. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.
The articles "a" and "an" as used herein refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. For example, "an element" refers to one element or more than one element.
The terms verbalization, "including," participle "including," verbalization "having" and "participle" having "are used in an inclusive, open sense to mean that other elements can be included. The terms "for example," "such as," as used herein, are non-limiting and are for illustrative purposes only. "including" and "including but not limited to" are used interchangeably.
The term "or" as used herein should be understood to mean "and/or" unless the content clearly dictates otherwise.
As used herein, the term "about" or "approximately" refers to a quantitative, level, value, quantity, frequency, percentage, dimension, size, amount, weight, or length that varies by up to 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% relative to a reference quantitative, level, value, amount, frequency, percentage, dimension, size, amount, weight, or length. In one embodiment, the term "about" or "approximately" refers to a range of ± 15%, ± 10%, ± 9%, ± 8%, ± 7%, ± 6%, ± 5%, ± 4%, ± 3%, ± 2% or ± 1% with respect to a reference quantity, level, value, frequency, percentage, dimension, amount, weight or length.
It should be noted that the structures of some of the compounds of the present application include asymmetric (chiral) carbon or sulfur atoms. Thus, it is to be understood that isomers formed by such asymmetry are included within the scope of the present invention unless otherwise indicated. Such isomers are obtained in substantially pure form by conventional separation techniques and by stereochemically controlled synthesis. The compounds of the present application can exist in stereoisomeric forms and can therefore be produced as single stereoisomers or as mixtures.
The term "isomerism" refers to compounds having the same molecular formula but differing in the nature or order of bonding of their atoms or in the arrangement of their atoms in space. Isomers in which their atoms are arranged differently in space are referred to as "stereoisomers". Stereoisomers that are not mirror images of each other are referred to as "diastereomers", and stereoisomers that are non-overlapping mirror images are referred to as "enantiomers", or generally optical isomers. Carbons bonded to four different substituents are referred to as "chiral centers", while sulfur bonded to three or four different substituents (e.g., sulfoxide or sulfinimide) are also referred to as "chiral centers".
The term "chiral isomer" refers to a compound having at least one chiral center. It has two enantiomeric forms of opposite chirality and can exist as a single enantiomer or as a mixture of enantiomers. Mixtures of single enantiomeric forms containing equal amounts of opposite chirality are referred to as "racemic mixtures". Compounds with more than one chiral center have 2n-1 enantiomeric pairs, where n is the number of chiral centers. Compounds having more than one chiral center can exist as a single diastereomer or as a mixture of diastereomers, referred to as "mixtures of diastereomers". When a chiral center is present, a stereoisomer can be characterized by the absolute configuration (R or S) of that chiral center. Alternatively, when one or more chiral centers are present, a stereoisomer can be characterized as (+) or (-). Absolute configuration refers to the spatial arrangement of substituents attached to a chiral center. Substituents attached to a chiral center under consideration are rated according to Sequence Rule of Cahn, Ingold and Prelog (Cahn et al, Angew. chem. Inter. Edit.1966,5,385; errata 511; Cahn et al, Angew. chem.1966,78,413; Cahn and Ingold, J chem. Soc.1951(London), 612; Cahn et al, Experientia 1956,12, 81; Cahn, J.chem. Educ.1964,41,116).
The term "disorder" refers to any disorder, disease, or condition that would benefit from an agent that promotes neuroprotection, enhances neuronal signaling, and/or stimulates neuronal regeneration after injury.
The term "geometric isomers" refers to diastereomers whose presence is attributable to hindered rotation about a double bond. These constructs are distinguished by the prefixes cis and trans, or Z and E, of their names, which indicate that the groups are located on the same side or on the opposite side of the double bond in the molecule according to the Cahn-Ingold-Prelog rule. In addition, the structures and other compounds discussed herein include all their trans isomers.
The term "trans isomer" is a type of stereoisomer in which the atoms of the two isomers are arranged differently in space. The presence of the trans isomer is due to restricted rotation caused by the hindrance of rotation of the bulky group around the central bond. Such trans isomers generally exist as mixtures, however, recent advances in chromatographic techniques have resulted in the ability to selectively separate mixtures of two trans isomers.
The terms "crystalline polymorph," "polymorph," or "crystal form" refer to a crystal structure in which a compound (or a salt or solvate thereof) is capable of crystallizing in different crystal packing arrangements, all of which have the same elemental composition. Different implementations typically have different X-ray diffraction patterns, infrared spectra, melting points, density hardness, crystal form, optical and electrical properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors can cause one form to predominate. Crystalline polymorphic forms of a compound can be prepared by crystallization under different conditions.
the term "derivative" refers to compounds having a common core structure and substituted with different groups, as described herein.
The term "bioisostere" refers to a compound resulting from the exchange of an atom or group of atoms by another broadly similar atom or group of atoms. The goal of bioisosteric replacement is to create new compounds with similar biological properties as the parent compound. Bioisosteric substitutions can be physicochemical-based or topological-based. Examples of carboxylic acid bioisosteres include acylsulfonimides, tetrazoles, sulfonic acids, and phosphonic acids. See, for example, Patani and LaVoie, chem.Rev.96,3147-3176 (1996).
The phrases "parenteral administration" and "administered parenterally" are art-recognized terms and include administration other than enteral and topical administration, such as injection, and include, but are not limited to, intravenous, intramuscular, intrapleural, intravascular, intrapericardial, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, and intratrastemal injection and infusion.
The term "treating" is art-recognized and includes inhibiting a disease, disorder or condition in a subject, e.g., arresting its progression; and alleviating the disease, disorder, or condition, e.g., causing regression of the disease, disorder, and/or condition. Treating a disease or condition includes ameliorating at least one symptom of the particular disease or condition, even if the underlying pathophysiology is unaffected.
The term "preventing" is art-recognized and includes stopping the occurrence of a disease, disorder, or condition in a subject, for which the occurrence is predictable, but has not yet been diagnosed as having. Preventing a condition associated with a disease includes ceasing the occurrence of the condition after the disease is diagnosed, but before the condition is diagnosed.
the term "pharmaceutical composition" refers to a formulation comprising a disclosed compound in a form suitable for administration to a subject. In a preferred embodiment, the pharmaceutical composition is in bulk or unit dosage form. The unit dosage form is in any of a variety of forms including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler, or a vial. The amount of active ingredient (e.g., a formulation of the disclosed compound or salt thereof) quantified in a unit dose of the composition is an effective amount and will vary depending on the particular treatment involved. It will be appreciated by those skilled in the art that, in general, the dosage will have to be routinely varied depending on the age and condition of the patient. The dosage can also depend on the route of administration. A variety of routes are contemplated including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, intranasal, inhalation, and the like. Dosage forms for topical or transdermal administration of the compounds of the present invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, nebulized compounds, and inhalants. In a preferred embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
The term "flash dose" refers to a formulation of a compound in a fast-dispersing dosage form.
The term "immediate release" is defined as the release of the compound from the dosage form within a relatively short period of time, typically up to about 60 minutes. The term "controlled release" is defined to include delayed release, delayed release and pulsed release. The term "pulsed release" is defined as the release of a drug product from a dosage form array. The term "sustained release" or "extended release" is defined as the continuous release of a compound from a dosage form over an extended period of time.
The phrase "pharmaceutically acceptable" is art-recognized. In certain embodiments, the term includes compositions, polymers, and other materials and/or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable risk-benefit ratio.
The phrase "pharmaceutically acceptable carrier" is art-recognized and includes, for example, pharmaceutically acceptable materials, compositions, or vehicles (e.g., liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials) associated with carrying or transporting any subject composition from one organ or portion of a body to another organ or portion of a body. Various carriers must be "acceptable" in the sense of being compatible with the other components of the subject composition and not injurious to the patient. In certain embodiments, the pharmaceutically acceptable carrier is pyrogen-free. Some examples of materials that can be used as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered gum tragacanth; (5) malt; (6) gelling; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) ethylene glycols, such as propylene glycol; (11) polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) no heat source water; (17) isotonic saline; (18) ringer's solution; (19) ethanol; (20) phosphoric acid buffer solution; and (21) other non-toxic compatible substances that would be useful in pharmaceutical formulations.
The compounds of the present application are capable of further salt formation. All of these forms are also contemplated within the scope of the present invention.
"pharmaceutically acceptable salts" of a compound refer to salts that are pharmaceutically acceptable and have the desired pharmaceutical activity of the parent compound. For example, the salts can be acid addition salts. One embodiment of an acid addition salt is the hydrochloride salt. Pharmaceutically acceptable salts can be synthesized from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two, generally, a non-aqueous medium (e.g., ether, ethyl acetate, ethanol, isopropanol, or acetonitrile) is preferred. A list of salts is found in Remington's Pharmaceutical Sciences,18th ed. (Mack Publishing Company, 1990).
The compounds of the present invention can also be prepared as esters, e.g., pharmaceutically acceptable esters. For example, a carboxylic acid functional group in a compound can be converted to its corresponding ester, such as a methyl, ethyl, or other ester. In addition, the alcohol groups in the compounds can be converted to their corresponding esters, such as acetates, propionates, or other esters.
the compounds of the present invention can also be prepared as prodrugs, e.g., pharmaceutically acceptable prodrugs. The terms "pro-drug" and "prodrug" are used interchangeably herein and refer to any compound that releases the active parent drug in vivo. Since prodrugs are known to enhance various desirable qualities of drugs (e.g., solubility, bioavailability, manufacturability, etc.), the compounds can be delivered in prodrug form. Thus, the compounds described herein are intended to encompass prodrugs of the compounds claimed herein, methods of delivering the prodrugs, and compositions comprising the prodrugs. "prodrug" is intended to include any covalently bonded carriers that release the active parent drug in vivo when such prodrug is administered to a subject. Prodrugs are prepared by modifying functional groups present in a compound in the following manner: the modifying group is cleaved from the parent compound either in routine manipulation or in vivo. Prodrugs include compounds wherein a hydroxy, amino, sulfhydryl, carboxy or carbonyl group is bonded to any group that is cleavable in vivo to form a free hydroxy, free amino, free sulfhydryl, free carboxy or free carbonyl group, respectively. Prodrugs can also include precursors (leads) of the compounds of the invention that undergo a chemical transformation by metabolic processes and then become active or more active pharmaceutical agents or active compounds of the invention.
Examples of prodrugs include, but are not limited to, esters (e.g., acetate, dialkylaminoacetate, formate, phosphate, sulfate, and benzoate derivatives) and carbamates (e.g., N-dimethylaminocarbonyl), ester groups (e.g., ethyl ester, morpholinoethanol ester) of carboxyl functional groups, N-acyl derivatives (e.g., N-acetyl) of amino functional groups (e.g., N-acetyl) N-Mannich bases, Schiff bases, and enaminones, oximes, acetals, ketals and enol esters of ketone and aldehyde functional groups in compounds, and the like, and sulfides which are oxidized to form sulfoxides or sulfones.
The term "protecting group" refers to a class of atoms that when attached to a reactive group in a molecule masks, reduces, or organizes its reactivity. Examples of Protective Groups can be found in Green and Wuts, Protective Groups in organic Chemistry, (Wiley,2.sup. nd ed.1991); harrison and Harrison et al, Compendium of Synthetic Organic Methods, Vols.1-8(John Wiley and Sons,1971-rded.2003).
The term "amino protecting group" is intended to mean a functional group that converts an amino, amide, or other nitrogen-containing moiety into a different chemical group that is substantially inert to the particular chemical reaction conditions. The amino protecting group is preferably easily and selectively removed in good yield without affecting the other functional groups of the molecule. Examples of amino protecting groups include, but are not limited to, formyl, acetyl, benzyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, t-butoxycarbonyl (Boc), p-methoxybenzyl, methoxymethyl, tosyl, trifluoroacetyl, Trimethylsilyl (TMS), fluorenyl-methoxycarbonyl, 2-trimethylsilyl-ethoxycarbonyl, 1-methyl-1- (4-diphenyl) ethoxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl (CBZ), 2-trimethylsilyl-ethanesulfonyl (SES), trityl and substituted trityl groups, 9-Fluorenylmethoxycarbonyl (FMOC), nitro-veratryloxycarbonyl (NVOC), and the like. Those skilled in the art will be able to identify suitable amino protecting groups.
Representative hydroxy protecting groups include those in which the hydroxy group is acylated or alkylated, such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers and allyl ethers.
In addition, salts of the compounds of the present invention can exist in hydrogenated or non-hydrogenated (anhydrous) form, or as solvates with other solvent molecules. Non-limiting examples of hydrates include the monohydrate, dihydrate, and the like. Non-limiting examples of solvates include ethanol solvates, acetone solvates, and the like.
The term "solvate" refers to a solvent addition form comprising a stoichiometric or non-stoichiometric amount of solvent. Some compounds have a tendency to trap a fixed molar proportion of solvent molecules in the crystalline solid state, thereby forming solvates. If the solvent is water, the solvate formed is a hydrate, and when the solvate is an alcohol, the solvate formed is an alcoholate. Hydrates are formed by the binding of one or more water molecules to a substance in which the water retains its H2Molecular state of O, such binding being capable ofOne or more hydrates are formed.
The compounds, salts and prodrugs described herein can exist in a variety of tautomeric forms, including enol and imine forms, ketone and enamine forms, and geometric isomers and mixtures thereof. Tautomers exist in solution as mixtures of tautomeric sets. In solid form, usually one tautomer predominates. Even if one tautomer can be described, the present application includes all tautomers of the compounds of the present invention. A tautomer is one of two or more structural isomers that exists in equilibrium and is readily converted from one isomeric form to another. This reaction results in the formal migration of hydrogen atoms with the transformation of adjacent conjugated double bonds. In solutions where tautomerism is possible, the chemical equilibrium of the tautomer is reached. The exact ratio of tautomers depends on a variety of factors including temperature, solvent and pH. The concept of tautomers that can be interconverted by tautomerism is referred to as tautomerism.
Of the various types of tautomerism that can occur, two types are commonly observed. In the tautomerism of keto-enols, both electron and hydrogen atoms are transferred.
Tautomerism can be catalyzed by: alkali: 1. deprotonation; 2. formation of off-threshold anions (e.g., enolates); 3. protonation at different anion positions; acid: 1. protonation; 2. formation of off-threshold cations; 3. deprotonation at different positions adjacent to the cation.
The term "analog" refers to a chemical compound that is structurally similar to another substance, but differs slightly in composition (e.g., one atom is replaced by an atom of a different element, or a particular functional group is present, or one functional group is replaced by another functional group). Thus, an analog is a compound that is similar or equivalent in function and appearance, but that differs from a reference compound in structure or origin.
A "patient," "subject," or "host" treated by a subject method can refer to a human or non-human animal, e.g., a mammal, fish, bird, reptile, or amphibian. Thus, the subject of the presently disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig, or rodent. The term does not denote a particular age or gender. Thus, both adult and newborn subjects, as well as fetuses (male or female) are intended to be encompassed. In one aspect, the subject is a mammal. A patient refers to a subject suffering from a disease or disorder.
The terms "prophylactic" or "therapeutic" treatment are art-recognized and include the administration of one or more of the subject compositions to a host. If administered prior to clinical manifestation of the undesired condition (e.g., disease or other undesired state of the host animal), the treatment is prophylactic, i.e., it protects the host against developing the undesired condition, whereas if administered after manifestation of the undesired condition, the treatment is therapeutic (i.e., it is intended to diminish, ameliorate or stabilize the existing undesired condition or side effects thereof).
The terms "therapeutic agent", "drug", "medicament" and "biologically active substance" are art-recognized and include molecules and other agents of biologically, physiologically or pharmacologically active substances that act locally or systemically in a patient or subject to be treated for a disease or condition. The term includes, but is not limited to, pharmaceutically acceptable salts and prodrugs. Such agents can be acidic, basic or salt; they can be neutral molecules, polar molecules or molecular complexes capable of forming hydrogen bonds; they can be prodrugs in the form of ethers, esters, amides, etc., which are biologically active when administered to a patient or subject.
The phrase "therapeutically effective amount" or "pharmaceutically effective amount" is a term recognized in the art. In certain embodiments, the term refers to an amount of a therapeutic agent that produces some desired effect at a reasonable risk-benefit ratio applicable to any medical treatment. In certain embodiments, the term refers to an amount necessary or sufficient to eliminate, reduce, or maintain the goal of a particular treatment regimen. The effective amount can vary depending on the following factors: the disease or condition to be treated, the particular targeting construct administered, the size of the subject, or the severity of the disease or condition. Any person of ordinary skill in the art can empirically determine an effective amount of a particular compound without undue experimentation. In certain embodiments, a therapeutically effective amount of a therapeutic agent for in vivo use may depend on a variety of factors, including: the rate of release of the agent from the polymer matrix, which depends in part on the chemical and physical characteristics of the polymer; the nature of the reagent; the mode and method of administration; and any other material incorporated into the polymer matrix in addition to the agent.
The term "ED 50" is art recognized. In certain embodiments, ED50 refers to the dose of a drug product that produces 50% of the maximal response or effect, alternatively, the dose that produces a predetermined response in 50% of the test subjects or preparations. The term "LD 50" is art recognized. In certain embodiments, LD50 refers to the dose of a drug that is lethal to 50% of the test subjects. The term "therapeutic index" is a art-recognized term that refers to the therapeutic index of a pharmaceutical product, and is defined as LD50/ED 50.
The term "IC50"or" semi-inhibitory concentration "is intended to mean the concentration of a substance (e.g., a compound or drug) required to inhibit a biological process or portion of a process by 50%, including proteins, subunits, organelles, nucleoproteins, and the like.
For any chemical compound, this application is intended to include all isotopes of atoms formed in the compounds of the invention. Isotopes include those atoms having the same atomic number, but different mass numbers. By way of general example, but not limitation, isotopes of hydrogen include deuterium and tritium, while isotopes of carbon include C-13 and C-14.
When the bond to the substituent shows a cross-over with the bond connecting two atoms on the ring, then the substituent is capable of bonding to any atom on the ring. When a substituent is listed without an atom through which the substituent is bonded to the remainder of the compound of a given formula, then the substituent can be bonded through any atom in the substituent. Combinations of substituents and/or variants are possible, provided that such combinations result in stable compounds.
When an atom or chemical moiety is followed by a subscript number range (e.g. C)1-6) It is intended to cover each and every number within the range, as well as all intermediate ranges. E.g. "C1-6Alkyl "is intended to include alkyl groups having 1,2,3,4,5,6, 1-5, 1-4, 1-3, 1-2, 2-6, 2-5, 2-4, 2-3, 3-6, 3-5, 3-4, 4-6, 4-5, and 5-6 carbons.
The term "alkyl" is intended to include branched (e.g., isopropyl, t-butyl, isobutyl), straight-chain (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl), and cycloalkyl (alicyclic) groups (e.g., cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups. Such aliphatic hydrocarbon groups have the specified number of carbon atoms. E.g. C1-6Alkyl is intended to include C1,C2,C3,C4,C5And C6An alkyl group. As used herein, "lower alkyl" refers to an alkyl group having 1 to 6 carbon atoms in the backbone of the carbon chain. "alkyl" further includes alkyl groups in which an oxygen, nitrogen, sulfur, or phosphorus atom replaces one or more of the hydrocarbon backbone carbon atoms. In certain embodiments, a linear or branched alkyl group has 6 or fewer carbon atoms in its backbone (e.g., a linear chain has C)1-C6The branch chain has C3-C6) For example 4 or less. Similarly, certain cycloalkyl groups have 3 to 8 carbon atoms in their ring structure, e.g., 5 or 6 carbons in the ring structure.
The term "substituted alkyl" refers to an alkyl moiety wherein a substituent replaces a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylic acid, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphoric acid, phosphonic acid, phosphinic acid, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylic acid, sulfuric acid, alkylsulfinyl, sulfonic acid, sulfonamide, sulfonamido, nitro, trifluoromethyl, cyano, azide, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Cycloalkyl groups can be further substituted, for example, with substituents described above. An "alkylaryl" or "arylalkyl" moiety is an alkyl group substituted with an aryl group, such as phenylmethyl (benzyl). The terms "alkyl" and "lower" alkyl, if not otherwise stated, include linear, branched, cyclic, unsubstituted, substituted and/or heteroatom-containing alkyl or lower alkyl, respectively.
The term "alkenyl" refers to a linear, branched, or cyclic hydrocarbyl group of 2 to about 24 carbon atoms containing at least one double bond, such as ethenyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, octenyl, decenyl, tetradecenyl, octadecenyl, hexadecenyl, tetradecanoyl, cyclopentenyl, cyclohexenyl, cyclooctenyl, and the like. Typically, although again not necessarily, an alkenyl group can contain 2 to about 18 carbon atoms, more particularly 2 to 12 carbon atoms. The term "lower alkenyl" refers to an alkenyl group of 2 to 6 carbon atoms, and the specific term "cycloalkenyl" refers to a cyclic alkenyl group, preferably having 5 to 8 carbon atoms. The term "substituted alkenyl" refers to alkenyl substituted with one or more substituent groups, and the terms "heteroatom-containing alkenyl" and "heteroalkenyl" refer to alkenyl or heterocycloalkenyl (e.g., heterocyclohexenyl) in which at least one carbon atom is replaced with a heteroatom. The terms "alkenyl" and "lower alkenyl", if not otherwise stated, include linear, branched cyclic, unsubstituted, substituted and/or heteroatom-containing alkenyl and lower alkenyl, respectively.
The term "alkynyl" refers to a linear or branched hydrocarbyl group of 2 to 24 carbon atoms containing at least one triple bond, such as ethynyl, n-propynyl, and the like. Typically, although again not necessarily, alkynyl groups can contain 2 to about 18 carbon atoms, and more particularly can contain 2 to 12 carbon atoms. The term "lower alkynyl" refers to alkynyl groups of 2 to 6 carbon atoms. The term "substituted alkynyl" refers to alkynyl groups substituted with one or more substituent groups, and the terms "heteroatom-containing alkynyl" and "heteroalkynyl" refer to alkynyl groups in which at least one carbon atom is replaced with a heteroatom. The terms "alkynyl" and "lower alkynyl" include linear, branched, unsubstituted, substituted and/or heteroatom-containing alkynyl and lower alkynyl groups, respectively, if not otherwise specified.
The terms "alkyl", "alkenyl" and "alkynyl" are meant to include them as part of a diradical, i.e., having two points of attachment. A non-limiting example of such an alkyl moiety as a diradical is- -CH2CH2- -, i.e. C covalently bonded to the remainder of the molecule through each terminal carbon atom2An alkyl group.
The term "alkoxy" refers to an alkyl group bonded through a single terminal ether linkage; in other words, an "alkoxy" group can be represented as — O-alkyl, wherein alkyl is as defined above. "lower alkoxy" group refers to an alkoxy group containing 1 to 6 carbon atoms and includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy and the like. In the present invention, it is identified as "C1-C6Preferred substituents for alkoxy "or" lower alkoxy "contain 1 to 3 carbon atoms, and it is particularly preferred that such substituents contain 1 or 2 carbon atoms (i.e., methoxy and ethoxy).
The term "aryl" refers to an aromatic substituent comprising a single aromatic ring or multiple aromatic rings that are fused together either by direct or indirect linkage (such that the different aromatic rings are bonded to a common group, such as a methylene or ethylene moiety). The aryl group can contain 5 to 20 carbon atoms, and it is particularly preferred that the aryl group can contain 5 to 14 carbon atoms. Examples of aryl groups include benzene, phenyl, pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like. Furthermore, the term "aryl" includes polycyclic aryl groups, such as tricyclic, bicyclic, e.g. naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzimidazole, benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline, naphthyridine, indole, benzofuran, purine, benzofuran, azapurine or indolizine. These aryl groups having heteroatoms in the ring structure can also be referred to as "aryl heterocycles," heteroaryls, "or" aromatic heterocycles. The aromatic ring can be substituted at one or more ring positions with such substituents as described above, for example, halogen, hydroxy, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylic acid, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphoric acid, phosphonic acid, phosphinic acid, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylic acid, sulfuric acid, alkylsulfinyl, sulfonic acid, sulfonamide, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl or an aromatic or heteroaromatic moiety. The aryl group can also be fused or bridged with an alicyclic or heterocyclic ring, which is not aromatic, thereby forming a polycyclic ring system (e.g., tetralin, methylenedioxyphenyl). The term "aryl", if not otherwise stated, includes unsubstituted, substituted and/or heteroatom-containing aromatic substituents.
The term "alkaryl" refers to an aryl group having an alkyl substituent, while the term "aralkyl" refers to an alkyl group having an aryl substituent, wherein "aryl" and "alkyl" are as defined above. Exemplary aralkyl groups contain 6 to 24 carbon atoms, with aralkyl groups containing 6 to 16 carbon atoms being particularly preferred. Examples of aralkyl groups include, but are not limited to, benzyl, 2-phenyl-ethyl, 3-phenyl-propyl, 4-phenyl-butyl, 5-phenyl-pentyl, 4-phenylcyclohexyl, 4-benzylcyclohexyl, 4-phenylcyclohexylmethyl, 4-benzylcyclohexylmethyl, and the like. Alkylaryl groups include, for example, p-methylphenyl, 2, 4-dimethylphenyl, p-cyclohexylphenyl, 2, 7-dimethylnaphthyl, 7-cyclooctylphenyl, 3-ethyl-cyclopenta-1, 4-diene, and the like.
the term "heterocyclyl" or "heterocyclic group" includes closed ring structures, such as 3-to 10-, or 4-to 7-membered rings, which include one or more heteroatoms. "heteroatom" includes atoms of any element in addition to carbon or hydrogen. Examples of heteroatoms include nitrogen, oxygen, sulfur, and phosphorus.
Heterocyclyl groups can be saturated or unsaturated and include pyrrolidine, oxolane, tetrahydrothiophene, piperidine, piperazine, morpholine, lactones, lactams, such as azetidinones and pyrrolidones, sultams and sultones. Heterocyclic groups such as pyrrole and furan can have aromatic character. They include fused ring structures such as quinoline and isoquinoline. Other examples of heterocyclic groups include pyridine and purine. The heterocyclic ring can be substituted at one or more positions with substituents described above, such as halogen, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylic acid, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxy l, phosphoric acid, phosphonic acid, phosphinic acid, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylic acid, sulfuric acid, sulfonic acid, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azide, heterocyclyl or an aromatic or heteroaromatic moiety. The heterocyclic group can also be substituted at one or more positions by, for example, lower alkyl, lower alkenyl, lower alkoxy, lower alkylthio, lower alkylamino, lower alkylcarboxyl, nitro, hydroxy, - -CF3or-CN, etc.
The term "halo" or "halogen" refers to fluoro, chloro, bromo, and iodo. "counter ion" is used to denote small negatively charged species such as fluoride, chloride, bromide, iodide, hydroxide, acetic acid, and sulfuric acid. The term sulfoxide refers to sulfur attached to 2 different carbon atoms and 1 oxygen, and S — O bonds can be represented by letters with a double bond (S ═ O), an uncharged single bond (S-O), and a charged single bond [ S (+) -O (-) ].
The term "substituted" in "substituted alkyl", "substituted aryl", and the like, as referred to in some instances in the above definitions, means that at least one hydrogen atom bonded to a carbon (or other) element is replaced with one or more non-hydrogen substituents in the alkyl, aryl, or other moiety. Examples of such substituents include, but are not limited to, functional groups such as halogen, hydroxy, silyl, sulfhydryl, C1-C24Alkoxy radical, C2-C24Alkenyloxy radical, C2-C24Alkynyloxy, C5-C20aryloxy, acyl (including C)2-C24Alkylcarbonyl (-CO-alkyl) and C6-C20Arylcarbonyl (-CO-aryl)), acyloxy (-O-acyl), C2-C24Alkoxycarbonyl (- (CO) -O-alkyl), C6-C20Aryloxycarbonyl (- (CO) -O-aryl), C2-C24Alkyl carbonic acids (-O- (CO) -O-alkyl), C6-C20Aryl carbonic acid (-O- (CO) -O-aryl), carboxyl (-COOH), carboxylic acid (-COO-), carbamoyl (- (CO) -NH2) Is one- (C)1-C24Alkyl) -substituted carbamoyl (- (CO) -NH (C)1-C24Alkyl)), di- (C)1-C4Alkyl) -substituted carbamoyl (- - (CO) - - -N (C)1-C24Alkyl radical)2) Mono-substituted arylcarbamoyl (- (CO) -NH-aryl), thiocarbamoyl (- (CS) -NH2) Ureido (-NH- (CO) -NH)2) Cyano (-CN), isocyano (-N)+C-) Cyanoyl (- -O- -CN), isocyanato (- -ON)+C-) Thio-isocyanoyl (-S-CN), azide (-N ═ N)+＝N-) Formate (- - (CO) - - -H), thiocarbamate (- - (CS) - -H), amino (- -NH)2) Mono-and di- (C)1-C24Alkyl) -substituted amino, mono-and di- (C)5-C20Aryl) -substituted amino, C2-C24Alkylamides (-NH- (CO) -alkyl), C6-C20Arylamides (-NH- (CO) -aryl), imino (-CR ═ NH, where R ═ hydrogen, C1-C24alkyl radical, C5-C20Aryl radical, C6-C24Alkylaryl group, C6-C24Aralkyl, etc.), alkylimino (- -CR ═ N (alkyl), whichWhere R ═ hydrogen, alkyl, aryl, alkaryl, etc.), arylimino (-CR ═ N (aryl), where R ═ hydrogen, alkyl, aryl, alkaryl, etc.), nitro (-NO), and the like2) Nitroso group (-NO), sulfo group (-SO)2-OH), sulfonic acid (-SO)2-O-),C1-C24Alkylsulfanyl (-S-alkyl; also known as "alkylthio"), arylsulfanyl (-S-aryl; also known as "arylthio"), C1-C24Alkylsulfinyl (- - (SO) -alkyl), C5-C20Arylsulfinyl (- (SO) -aryl), C1-C24Alkylsulfonyl (-SO)2-alkyl), C5-C20Arylsulfonyl (-SO)2Aryl), phosphono (-P (O) (OH)2) Phosphonic acid (-P (O) (O))-)2) Phosphinic acid (-P (O)) (O)-) Phosphoric acid (-PO)2) And phosphino (-PH)2) (ii) a And a hydrocarbyl moiety C1-C24Alkyl radical, C2-C24Alkenyl radical, C2-C24Alkynyl, C5-C20Aryl radical, C6-C24Alkylaryl and C6-C24An aralkyl group.
Furthermore, if a particular group is allowed, the functional group can be further substituted with one or more other functional groups or one or more hydrocarbyl moieties, such as those listed in detail above. Similarly, the hydrocarbyl moieties mentioned above can be further substituted with one or more functional groups or other hydrocarbyl moieties, such as those specifically enumerated.
When the term "substituted" precedes a group of groups that can be substituted, it is meant that the term applies to each member of the group. For example, the phrase "substituted alkyl, alkenyl, and aryl" is interpreted as "substituted alkyl, substituted alkenyl, and substituted aryl". Similarly, when the term "heteroatom-containing" appears before a group of groups capable of containing heteroatoms, it is intended that the term applies to each member of the group. For example, the phrase "heteroatom-containing alkyl, alkenyl, and aryl" is interpreted to mean "heteroatom-containing alkyl, substituted alkenyl, and substituted aryl".
"optional" or "optionally" means that the subsequently described environment can or cannot occur, and thus the description includes instances where the described environment occurs and instances where it does not. For example, the phrase "optionally substituted" means that a non-hydrogen substituent can be present or absent on a given atom, and thus the description includes structures in which a non-hydrogen substituent is present and structures in which a non-hydrogen substituent is absent.
The terms "stable compound" and "stable structure" refer to the following compounds: it is sufficient to survive strongly in the separation procedure and, if appropriate, in the purification procedure and to form an effective therapeutic agent.
The term "free compound" is used herein to describe a compound in an unbound state.
Throughout the specification, where a composition is described as having, containing or comprising specific ingredients, it is contemplated that the composition also consists essentially of or consists of the recited ingredients. Similarly, where a method or process is described as having, including, or comprising particular process steps, the process also consists essentially of, or consists of, the recited process steps. Further, it should be understood that the order of steps or order for performing certain actions is immaterial so long as the compositions and methods described herein remain operable. Further, two or more steps or actions can be performed concurrently.
The term "small molecule" is a term recognized in the art. In certain embodiments, the term refers to molecules having a molecular weight of less than about 2000amu, less than about 1000amu, and even less than about 500 amu.
All percentages and ratios used herein are by weight unless otherwise specified.
The term "gene expression" or "protein expression" includes any information relating to the amount of gene transcript or protein present in a sample, as well as information relating to the rate at which the gene or protein is produced, accumulated, or degraded (e.g., data for reporter genes, data obtained from nuclear runaway assays, pulse-chase data, etc.). Certain kinds of data can be considered to be related to the expression of genes and proteins. For example, the level of protein in a cell reflects the level of protein as well as the level of transcription, and this data is intended to be included in the phrase "gene or protein expression information". Such information can be given in terms of the amount of each cell, relative to the amount of a control gene or protein, a unitless measure, etc.; the term "information" is not limited to any particular means of presentation and refers to any presentation that provides related information. The term "expression level" refers to the amount of quantification reflected or derived from gene or protein expression data, regardless of whether the data relates to accumulation of gene transcripts, protein accumulation, or the rate of protein synthesis, etc.
The terms "healthy" and "normal" are used interchangeably herein and refer to a subject or a particular cell or tissue that is deficient in (at least reaching the detection limit) a disease condition.
The term "nucleic acid" refers to a polynucleotide, such as deoxyribonucleic acid (DNA), and, where appropriate, ribonucleic acid (RNA). The term should also be understood to include analogs of RNA or DNA made from nucleotide analogs, as well as single-stranded (e.g., sense or antisense) and double-stranded polynucleotides (as applicable to the embodiments). In some embodiments, "nucleic acid" refers to a consensus nucleic acid. Some classifications of identical nucleic acid compounds include antisense nucleic acids, RNAi constructs, and catalytic nucleic acid constructs. Such classification of nucleic acids is well known in the art.
Embodiments described herein relate generally to compositions and methods for promoting neuronal production or survival in the nervous system (e.g., brain) of a mammal, and for treating diseases, disorders, and/or conditions of the nervous system. As described in the examples below, it was found that compounds that inhibit, decrease and/or antagonize short chain dehydrogenase activity (e.g., 15-PGDH inhibitors) can be used to increase PGE2 levels in the mammalian nervous system (e.g., brain). PGE2 elevates cyclic AMP by binding to EP2 and EP4 receptors that are highly expressed in the cerebral cortex, hippocampus and striatum. Stimulation of these receptors with PEG2 by administering a compound that inhibits, reduces, and/or antagonizes 15-PGDH activity (e.g., a 15-PGDH inhibitor as described herein) can promote neuroprotection from the subject against axonal degeneration, neuronal cell death, and/or glial cell injury following injury; enhance neural signaling underlying learning and memory; stimulating neuronal regeneration after injury; and/or treating a disease, disorder and/or condition of the nervous system.
In some embodiments, the diseases, disorders, and/or conditions of the nervous system that can be treated with a 15-PGDH inhibitor can include at least one of a neurological disorder, a neuropsychiatric disorder, a neurological injury, a neurotoxic disorder, neuropathic pain, and a neurodegenerative disorder.
In some embodiments, the 15-PGDH inhibitors described herein can be used in a method of treating (e.g., controlling, reducing, ameliorating, alleviating, or slowing the progression of) or a method of inhibiting (e.g., delaying the onset of or reducing the risk of developing) one or more diseases, disorders, or conditions that are caused by or associated with insufficient (e.g., abnormal) neurogenesis or unwanted neuronal cell death in a subject in need thereof. The method comprises administering to a subject an effective amount of a 15-PGDH inhibitor according to the invention (and/or any one of the compounds of the other general formula according to the invention) or a salt (e.g. a pharmaceutically acceptable salt) of a compound according to any definition in the invention. The one or more diseases, disorders or conditions can include neuropathy, neurotrauma and neurodegenerative diseases.
In some embodiments, one or more diseases, disorders or conditions can be caused by or associated with insufficient neurogenesis (e.g., abnormal hippocampal neurogenesis), which is thought to occur in neuropsychiatric diseases, or abnormal neuronal cell death, which is thought to occur in neurodegenerative diseases. Examples of one or more diseases, disorders or conditions include, but are not limited to, schizophrenia, major depression, bipolar disorder, normal aging, epilepsy, traumatic brain injury, post-traumatic psychotic disorder, Parkinson's disease, Alzheimer's disease, Down's syndrome, spinocerebellar ataxia, lateral sclerosis, Huntington's disease, stroke, radiation therapy, chronic stress and abuse of neuroactive drugs, such as alcohol, opiates, methamphetamine, phencyclidine and ***e.
In some embodiments, the subject can be a subject in need thereof (e.g., defined as a subject in need of such treatment), e.g., a subject having or at risk of having one or more diseases or conditions described herein. Identifying a subject in need of such treatment can be at the discretion of the subject or a health care professional, and can be subjective (e.g., opinion) or objective (e.g., measurable by testing or diagnostic methods). In some embodiments, the subject can be a mammal. In certain embodiments, the subject can be a human.
In other embodiments, the 15-PGDH inhibitor can be used to treat diseases, disorders, or conditions associated with the nervous system, including the central, somatic, autonomic, sympathetic, and parasympathetic components of the nervous system, the neurosensory tissue within the eye, ear, nose, mouth, and other organs, and the glial tissue associated with neuronal cells and structures. Such neurological disorders can result from damage to neurons (e.g., mechanical damage or damage due to toxic compounds), abnormal growth or development of neurons, or misregulation of neuronal activity (e.g., modulation as follows).
Neurological disorders can adversely affect nervous system functions, such as sensory function (the ability to sense changes in the body and external environment of the muscle); integrated functions (ability to account for changes); and motor function (by initiating the ability of the behavior to respond to the instructions, such as muscle contraction or glandular secretion).
Examples of neurological disorders that can be treated by administering a 15-PGDH inhibitor to a subject in need thereof include traumatic or toxic injury to peripheral or cerebral nerves, the spinal cord or the brain, such as traumatic brain injury, stroke, cerebral aneurysm and spinal cord injury. Other neurological disorders that can be treated by administering a 15-PGDH inhibitor to a subject in need thereof include cognitive disorders and neurodegenerative diseases, such as alzheimer's disease, alzheimer's disease-associated dementia (e.g., Pick's disease), parkinson's disease and other diffuse lewy body diseases, senile dementia, huntington's disease, Gilles de Ia Tourette's syndrome, multiple sclerosis, lateral sclerosis, hereditary motor and sensory neuropathy (Charcot-Marie-Tooth disease), diabetic neuropathy, progressive supranuclear palsy, epilepsy, and Jakob-creutzfeldt disease. Autonomic dysfunction includes hypertension and sleep disorders.
Neuropsychiatric disorders, such as depression, schizophrenia, schizoaffective disorder, Korsakoff psychosis, mania, anxiety disorder, phobic disorder, learning or memory disorders (such as amnesia and age-related memory loss), attention deficit disorder, mood disorder, major depressive disorder, mania, obsessive compulsive disorder, psychoactive substance use disorder, anxiety, fear, panic disorder, bipolar disorder, psychogenic pain syndrome and eating disorder can also be treated using the 15-PGDH inhibitors described herein.
Other examples of neurological disorders that can be treated by administering a 15-PGDH inhibitor to a subject in need thereof include damage to the nervous system due to infectious diseases (e.g., meningitis, hyperpyrexia of various etiologies, HIV, syphilis or post-polio syndrome) and damage to the nervous system due to electrical current (including contact with electrical current or lightning and complications resulting from electrical tic psychotherapy). Other neurological disorders can be associated with ophthalmic conditions, including retinal and optic nerve damage, glaucoma and age-related macular degeneration.
In the developing central nervous system, the developing brain becomes a target for neurotoxicity through various stages OF pregnancy as well as during infancy and infancy, and the 15-PGDH inhibitors OF the invention can be used for the prevention or treatment OF neurological deficits in the uterine embryo or fetus, in preterm infants, or in children in need OF such treatment, including, for example, those listed in HARRISON 'S PRINCIPLES OF INTERNAL MEDICINE (Braunwald et al, McGraw-Hill,2001) and in AMERICAN PSYCHIATRIC ASSOCIATION' S DIAGNOSTIC AND STATISTICAL MANUAL OFMINAL DISORDERS DSM-IV (American Psychiatric Press, 2000).
the 15-PGDH inhibitors described herein can also be used in methods of treating medical conditions associated with nerve damage. Medical conditions associated with nerve damage can refer to any movement disorder, epilepsy, cerebrovascular disease, autoimmune disease, sleep disorder, autonomic dysfunction, bladder disease, abnormal metabolic state, muscular system disorder, infectious and parasitic diseases, neoplasms, endocrine diseases, nutritional and metabolic diseases, immune diseases, blood and hematopoietic organ diseases, mental disorders, nervous system diseases, sensory organ diseases, circulatory system diseases, respiratory system diseases, digestive system diseases, genitourinary system diseases, skin and subcutaneous tissue diseases, musculoskeletal system and connective tissue diseases, congenital abnormalities, certain conditions of perinatal origin, as well as symptoms, signs and undefined conditions.
Treatable cerebrovascular disease can result from a variety of conditions including, but not limited to, aneurysm, stroke, arrhythmia, myocardial infarction, ischemia reperfusion injury, and cerebral hemorrhage.
Treatable autoimmune diseases include, but are not limited to, multiple sclerosis.
Sleep disorders that can be treated by 15-PGDH inhibitors can be caused by a variety of conditions, including but not limited to sleep apnea and parasomnia.
Autonomic dysfunction treatable by a 15-PGDH inhibitor can result from a variety of conditions, including, but not limited to, gastrointestinal disorders, including, but not limited to, gastrointestinal motility disorders, nausea, vomiting, diarrhea, chronic hiccup, gastroesophageal reflux disease, hypersecretion of gastric acid, autonomic insufficiency; excessive epiphoras and rhinorrhea; and cardiovascular disorders including, but not limited to, cardiac dysrythmias, cardiac arrhythmias, hypertension, and carotid sinus disease.
Bladder diseases that can be treated by 15-PGDH inhibitors can result from a variety of conditions, including but not limited to spinal cord injury and bladder spasms or relaxations.
the abnormal metabolic state that can be treated by the 15-PGDH inhibitor can result from a variety of conditions, including but not limited to hyperthyroidism or hypothyroidism.
Disorders of the muscular system that can be treated by a 15-PGDH inhibitor can include, but are not limited to, muscular dystrophy and upper airway and facial spasms.
The 15-PGDH inhibitors can also be used to treat neuropathic pain caused by a variety of conditions, including, but not limited to, migraine headaches including migraine headaches of premonitory, migraine without aura, menstrual migraine, migraine variants, atypical migraine, migraine complexity, hemiplegic migraine, transition migraine and chronic daily migraine, paroxysmal tension headache, chronic tension headache, pain-medication rebound headache, paroxysmal cluster headache, chronic cluster headache, cluster headache variants, chronic paroxysmal hemicrania pain, continuous hemicrania pain, post-traumatic headache, post-traumatic cervical pain, post-herpetic neuralgia (associated with head and face), spinal fracture pain secondary to osteoporosis, spondyloarthritis pain, headache associated with cerebrovascular disease and stroke, headache caused by vascular disease, reflex sympathetic dystrophy, Neck pain (which can be due to a variety of causes including, but not limited to, muscular, discogenic or degenerative, including arthritic, posture-related or metastatic), tongue pain, carotid pain, annular cartilage pain, dizziness due to middle ear injury, stomach pain, sciatica, maxillary neuralgia, laryngalgia, cervical myalgia, trigeminal neuralgia (also commonly referred to as cramps), post-lumbar puncture headache, headache with cerebrospinal fluid depression, temporomandibular joint disorder, atypical facial pain, ciliary neuralgia, parasympathetic neuralgia (also commonly referred to as Raeder syndrome); lithologic neuralgia, Eagle syndrome, idiopathic intracranial hypertension, orofacial pain, myofascial pain syndrome (associated with the head, neck, and shoulders), chronic migraine neuralgia, cervicogenic headache, parapsorial trigeminal paralysis, SPG neuralgia (also commonly referred to as lower-half headache, lower-half facial neuralgia syndrome, Sluder neuralgia, and Sluder syndrome), carotid pain, winged-canal neuralgia, causalgia, and/or combinations thereof.
As used herein, the term "headache" can refer to migraine, tension headache, cluster headache, trigeminal neuralgia, secondary headache, tension headache, chronic and digestive headache, drug abuse/rebound headache, chronic paroxysmal migraine, continuous hemicrania pain, post-traumatic headache, post-herpetic headache, vascular headache, reflex sympathetic dystrophy-associated headache, crvicalgia headaches, caroodynia headaches, sciatica headache, trigeminal headache, occipital headache, maxillary headache, daily headache, accessory trigeminal headache, lithologic headache, Sluder headache, winged vessel headache, cerebrospinal fluid low pressure headache, TMJ headache, causalgia headache, myofascial headache, all primary headaches (e.g., primary stabbing headache, primary coughing headaches, primary headache associated with sexual activity, primary headache, sleeping and new daily persistent headache)' a pre-tension headache, cluster headache, chronic and a chronic headache, All trigeminal autonomic headaches (e.g. paroxysmal cranial pain, SUNCT, all possible TAC and SUNA), chronic daily headaches, occipital neuralgia, atypical facial pain, neuropathic trigeminal neuralgia and mixed headaches.
In other embodiments, the 15-PGDH inhibitor can be used to promote survival, plasticity, and/or growth of neural stem cells or progenitor cells. The 15-PGDH inhibitor is capable of being administered to stem or progenitor cells in vitro, ex vivo or in vivo. When the stem or progenitor cells are administered in vitro or ex vivo, the stem or progenitor cells can then be transplanted into a subject for therapeutic use.
For example, in the case of neural stem/progenitor cells, the method of transplanting the neural stem/progenitor cell(s) into the desired area (which is typically used in the regenerative medicine field) can be used in combination with 15-PGDH inhibitors administered to the cell or area. More specifically, for example, a method of transplanting neural stem cell/progenitor cell(s) to a region of interest by the following procedure can be exemplified: suspending neural stem/progenitor cells in phosphate buffered saline with a 15-PGDH inhibitor; and adding/injecting the resulting cell suspension to said area.
In other embodiments, the 15-PGDH inhibitors described herein can be used in nerve grafts. The graft can include any tissue intended for implantation into a human or animal. Various types of grafts are contemplated as being within the scope of the subject invention, such as autografts, allografts, xenografts, and xenografts. The size (e.g., length and diameter) of the graft is not important. For example, the nerve graft can be about 1 cm to about 10 cm in length, or more than about 10 cm in length. The diameter of the nerve graft can be matched to the diameter of any damaged nerve or portion of a nerve, as desired. The nerve graft can be structurally an intact nerve segment, bridging a gap along the length of the recipient nerve, or replacing a distal, i.e., end-to-end, graft. Alternatively, the nerve graft can be a partial nerve segment, or eccentrically shaped (i.e., a nerve flap), and is intended to reconstruct a torn nerve that has some structural disruption but maintains its physical continuity.
When 15-PGDH inhibitors are used in nerve grafts, the entire graft can be treated. The 15-PGDH inhibitor can be used for the whole nerve graft. The entire treatment can be applied to a live (fresh) or previously frozen nerve graft. The 15-PGDH inhibitor can also be used in nerve grafts before, during or after implantation. The 15-PGDH inhibitor can be used on any part of the graft, for example one or more ends linked to the remnants of the damaged nerve. If the 15-PGDH inhibitor is to be used in an injured nerve, the 15-PGDH inhibitor can be used in any area of the injured nerve that will promote repair of the injured nerve, such as at or adjacent to the site of injury.
The 15-PGDH inhibitor can be placed in culture medium for application to the nerve graft. The culture medium can be, for example, undefined medium, defined medium or defined medium supplemented with serum. Embodiments described herein also include a storage solution for storing a nerve graft prior to implantation. The storage solution comprises a culture medium and at least one 15-PGDH inhibitor. The storage solution can also include other bioactive agents, such as growth factors as described below.
In some embodiments, a 15-PGDH inhibitor for use in treating a disease, disorder or condition of the nervous system can be identified using a variety of assays in which a putative inhibitor compound is administered to cells expressing 15-PGDH and then a functional effect on 15-GPDH activity is determined. The degree of effect was examined by comparing samples or tests containing 15-PGDH (treated with a potential inhibitor) with control samples without inhibitor. Control samples (not treated with the modulator) were assigned a relative 15-PGDH activity value of 100%. Inhibition of 15-PGDH was achieved when the 15-PGDH activity value was approximately 80% (optionally 50%, 25%, 10%, 5% or 1%) relative to the control.
The agent tested as an inhibitor of 15-PGDH can be any small chemical molecule or compound. Typically, the test compound is a small chemical molecule, a natural product, or a peptide. The test is designed to screen large chemical libraries by automatically performing the test steps and providing compounds from any convenient source to the test (which is typically a repeated run, e.g., a microtiter format on a microtiter plate in a machine test).
In some embodiments, the 15-PGDH inhibitor can include a compound having the following formula (I):
Wherein n is 0-2;
Y1,Y2And R1Are identical or different and are each selected from hydrogen, substituted or unsubstituted C1-C24Alkyl radical, C2-C24Alkenyl radical, C2-C24Alkynyl, C3-C20Aryl, heteroaryl, heterocycloalkenyl containing 5 to 6 ring atoms (wherein 1 to 3 ring atoms are independently selected from N, NH, N (C)1-C6Alkyl radical, NC (O) (C)1-C6Alkyl), O and S), C6-C24Alkylaryl group, C6-C24Aralkyl, halogen, -Si (C)1-C3Alkyl radical)3Hydroxy, sulfhydryl, C1-C24Alkoxy radical, C2-C24Alkenyloxy radical, C2-C24Alkynyloxy, C5-C20Aryloxy, acyl (including C)2-C24Alkylcarbonyl (- -CO-alkyl) and C6-C20Arylcarbonyl (-CO-aryl)), acyloxy (-O-acyl), C2-C24Alkoxycarbonyl (- (CO) -O-alkyl), C6-C20aryloxycarbonyl (- (CO) -O-aryl), C2-C24Alkyl carbonic acids (-O- (CO) -O-alkyl), C6-C20aryl carbonic acid (-O- (CO) -O-aryl), carboxyl (-COOH), carboxylic acid (-COO)-) Carbamoyl (- (CO) -NH)2),C1-C24Alkyl-carbamoyl (- (CO) -NH (C)1-C24Alkyl)), arylcarbamoyl (- (CO) -NH-aryl), thiocarbamoyl (- (CS) -NH2) Ureido (-NH- (CO) -NH)2) Cyano (-CN), isocyano (-N)+C-) Cyanoacyl (-O-CN), isocyanato (-O-N)+＝C-) Thio-isocyanoyl (-S-CN), azide (-N ═ N)+＝N-) A formate (- - (CO) - - -H), a thiocarbamate (- - (CS) - - - -H), an amino (- -NH)2),C1-C24Alkylamino radical, C5-C20Arylamino, C2-C24Alkylamides (-NH- (CO) -alkyl), C6-C20Arylamides (-NH- (CO) -aryl), imino (-CR ═ NH, where R is hydrogen, C1-C24Alkyl radical, C5-C20Aryl radical, C6-C24Alkylaryl group, C6-C24Aralkyl, etc.), alkylimino (-CR ═ N (alkyl), where R ═ hydrogen, alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (-CR ═ N (aryl), where R ═ hydrogen, alkyl, aryl, alkaryl, etc.), nitro (-NO), and the like2) Nitroso group (-NO), sulfo group (-SO)2-OH), sulfonic acid (-SO)2-O-),C1-C24Alkylsulfanyl (-S-alkyl; also known as "alkylthio"), arylsulfanyl (-S-aryl; also known as "arylthio"), C1-C24Alkylsulfinyl (- (SO) -alkyl), C5-C20Arylsulfinyl (- (SO) -aryl), C1-C24Alkylsulfonyl (-SO)2-alkyl), C5-C20Arylsulfonyl (-SO)2Aryl), sulfanilamide (-SO)2-NH2,-SO2NY2(wherein Y is independentlyIs H, aryl or alkyl), phosphono (-P (O) (OH)2) Phosphonic acid (-P (O) (O))-)2) Phosphinic acid (-P (O)) (O)-) Phosphoric acid (-PO)2) Phosphino (- -PH)2) Polyalkyl ethers, phosphoric acids, phosphoric acid esters, groups incorporating amino acids or other moieties (predicted to carry a positive or negative charge at physiological pH) and combinations thereof, and wherein Y1And Y2Can be linked to form a ring or a polycyclic ring, wherein the ring is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclyl;
U1Is N, C-R2Or C-NR3R4Wherein R is2Selected from H, lower alkyl groups, O, (CH)2)n1OR' (where n1 is 1,2 OR 3), CF3,CH2-CH2X,O-CH2-CH2X,CH2-CH2-CH2X,O-CH2-CH2X, (wherein X ═ H, F, Cl, Br or I), CN, (C ═ O) -R ', (C ═ O) N (R')2O (CO) R ', COOR ' (wherein R ' is H or a lower alkyl group), and wherein R1And R2Can be linked to form a cyclic or polycyclic ring, wherein R3And R4Are identical or different and are each selected from the group consisting of H, lower alkyl radicals, O, (CH)2)n1OR' (where n1 is 1,2 OR 3), CF3,CH2-CH2X,CH2-CH2-CH2X, (wherein X ═ H, F, Cl, Br or I), CN, (C ═ O) -R ', (C ═ O) N (R')2COOR '(wherein R' is H or a lower alkyl group), and R3Or R4Can be default;
X1And X2Independently is N or C, and wherein when X is1And/or X2When is N, Y1And/or Y2Are respectively default;
Z1Is O, S, CRaRbOr NRaWherein R isaAnd RbIndependently is H or C1-8An alkyl group which is linear, branched or cyclic, and which is unsubstituted or substituted.
examples of 15-PGDH inhibitors having formula (I) include the following compounds and pharmaceutically acceptable salts thereof:
in other embodiments, the 15-PGDH inhibitor can include a compound having the following formula (II):
Wherein n is 0-2;
X4,X5,X6And X7Independently is N or CRc；
R1,R6,R7And RcIndependently selected from hydrogen, substituted or unsubstituted C1-C24Alkyl radical, C2-C24Alkenyl radical, C2-C24Alkynyl, C3-C20Aryl, heteroaryl, heterocycloalkenyl containing 5 to 6 ring atoms (wherein 1 to 3 ring atoms are independently selected from N, NH, N (C)1-C6Alkyl radical, NC (O) (C)1-C6Alkyl), O and S), C6-C24Alkylaryl group, C6-C24Aralkyl, halogen, -Si (C)1-C3Alkyl radical)3Hydroxy, sulfhydryl, C1-C24Alkoxy radical, C2-C24Alkenyloxy radical, C2-C24Alkynyloxy, C5-C20Aryloxy, acyl (including C)2-C24Alkylcarbonyl (- -CO-alkyl) and C6-C20Arylcarbonyl (-CO-aryl)), acyloxy (-O-acyl), C2-C24Alkoxycarbonyl (- (CO) -O-alkyl), C6-C20Aryloxycarbonyl (- (CO) -O-aryl), C2-C24Alkyl carbonic acids (-O- (CO) -O-alkyl), C6-C20Aryl carbonic acid (-O- (CO) -O-aryl), carboxyl (-COOH), carboxylic acid (-COO)-) Carbamoyl (- (CO) -NH)2),C1-C24Alkyl-carbamoyl (- (CO) -NH (C)1-C24Alkyl)), arylcarbamoyl (- (CO) -NH-aryl), thiocarbamoyl (- (CS) -NH2) Ureido (-NH- (CO) -NH)2) Cyano (-CN), isocyano (-N)+C-) Cyanoacyl (-O-CN), isocyanato (-O-N)+＝C-) Thio-isocyanoyl (-S-CN), azide (-N ═ N)+＝N-) A formate (- - (CO) - - -H), a thiocarbamate (- - (CS) - - - -H), an amino (- -NH)2),C1-C24Alkylamino radical, C5-C20Arylamino, C2-C24Alkylamides (-NH- (CO) -alkyl), C6-C20Arylamides (-NH- (CO) -aryl), imino (-CR ═ NH, where R is hydrogen, C1-C24Alkyl radical, C5-C20Aryl radical, C6-C24Alkylaryl group, C6-C24Aralkyl, etc.), alkylimino (-CR ═ N (alkyl), where R ═ hydrogen, alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (-CR ═ N (aryl), where R ═ hydrogen, alkyl, aryl, alkaryl, etc.), nitro (-NO), and the like2) Nitroso group (-NO), sulfo group (-SO)2-OH), sulfonic acid (-SO)2-O-),C1-C24Alkylsulfanyl (-S-alkyl; also known as "alkylthio"), arylsulfanyl (-S-aryl; also known as "arylthio"), C1-C24Alkylsulfinyl (- (SO) -alkyl), C5-C20Arylsulfinyl (- (SO) -aryl), C1-C24Alkylsulfonyl (-SO)2-alkyl), C5-C20Arylsulfonyl (-SO)2Aryl), sulfanilamide (-SO)2-NH2,-SO2NY2(wherein Y is independently H, aryl or alkyl), phosphono (-P (O) (OH)2) Phosphonic acid (-P (O) (O))-)2) Phosphinic acid (-P (O)) (O)-) Phosphoric acid (-PO)2) Phosphino (- -PH)2) Polyalkyl ethers, phosphoric acids, phosphoric acid esters, groups incorporating amino acids or other moieties (predicted to carry a positive or negative charge at physiological pH) and combinations thereof, and wherein R6And R7Can be linked to form a ring or a polycyclic ring, wherein the ring is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclyl;
U1Is N, C-R2Or C-NR3R4Wherein R is2Selected from H, lower alkyl groups, O, (CH)2)n1OR' (where n1 is 1,2 OR 3), CF3,CH2-CH2X,O-CH2-CH2X,CH2-CH2-CH2X,O-CH2-CH2X, (wherein X ═ H, F, Cl, Br or I), CN, (C ═ O) -R ', (C ═ O) N (R')2O (CO) R ', COOR ' (wherein R ' is H or a lower alkyl group), and wherein R1And R2Can be linked to form a cyclic or polycyclic ring, wherein R3And R4Are identical or different and are each selected from the group consisting of H, lower alkyl radicals, O, (CH)2)n1OR' (where n1 is 1,2 OR 3), CF3,CH2-CH2X,CH2-CH2-CH2X, (wherein X ═ H, F, Cl, Br or I), CN, (C ═ O) -R ', (C ═ O) N (R')2COOR '(wherein R' is H or a lower alkyl group), and R3Or R4Can be default;
X1And X2Independently is N or C, and wherein when X is1And/or X2When is N, Y1And/or Y2Are respectively default;
Z1Is O, S, CRaRbOr NRaWherein R isaAnd RbIndependently is H or C1-8An alkyl group which is linear, branched or cyclic, and which is unsubstituted or substituted.
Examples of 15-PGDH inhibitors having formula (II) include the following compounds and pharmaceutically acceptable salts thereof:
In other embodiments, the 15-PGDH inhibitor can include a compound having the following formula (III) or (IV):
Wherein n is 0-2;
X6Independently is N or CRc；
R1,R6,R7And RcIndependently selected from hydrogen, substituted or unsubstituted C1-C24Alkyl radical, C2-C24Alkenyl radical, C2-C24Alkynyl, C3-C20Aryl, heteroaryl, heterocycloalkenyl containing 5 to 6 ring atoms (wherein 1 to 3 ring atoms are independently selected from N, NH, N (C)1-C6Alkyl radical, NC (O) (C)1-C6Alkyl), O and S), C6-C24Alkylaryl group, C6-C24Aralkyl, halogen, -Si (C)1-C3Alkyl radical)3hydroxy, sulfhydryl, C1-C24Alkoxy radical, C2-C24Alkenyloxy radical, C2-C24Alkynyloxy, C5-C20Aryloxy, acyl (including C)2-C24Alkylcarbonyl (- -CO-alkyl) and C6-C20Arylcarbonyl (-CO-aryl)), acyloxy (-O-acyl), C2-C24Alkoxycarbonyl (- (CO) -O-alkyl), C6-C20aryloxycarbonyl (- (CO) -O-aryl), C2-C24Alkyl carbonic acids (-O- (CO) -O-alkyl), C6-C20Aryl carbonic acid (-O- (CO) -O-aryl), carboxyl (-COOH), carboxylic acid (-COO)-) Carbamoyl (- (CO) -NH)2),C1-C24Alkyl-carbamoyl (- (CO) -NH (C)1-C24Alkyl)), arylcarbamoyl (- (CO) -NH-aryl), thiocarbamoyl (- (CS) -NH2) Ureido (-NH- (CO) -NH)2) Cyano (-CN), isocyano (-N)+C-) Cyanoacyl (-O-CN), isocyanato (-O-N)+＝C-) Thio-isocyanoyl (-S-CN), azide (-N ═ N)+＝N-) A formate (- - (CO) - - -H), a thiocarbamate (- - (CS) - - - -H), an amino (- -NH)2),C1-C24Alkylamino radical, C5-C20Arylamino, C2-C24Alkylamides (-NH- (CO) -alkyl), C6-C20Arylamides (-NH- (CO) -aryl), imino (-CR ═ NH, where R is hydrogen, C1-C24Alkyl radical, C5-C20Aryl radical, C6-C24Alkylaryl group, C6-C24Aralkyl, etc.), alkylimino (-CR ═ N (alkyl), where R ═ hydrogen, alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (-CR ═ N (aryl), where R ═ hydrogen, alkyl, aryl, alkaryl, etc.), nitro (-NO), and the like2) Nitroso group (-NO), sulfo group (-SO)2-OH), sulfonic acid (-SO)2-O-),C1-C24Alkylsulfanyl (-S-alkyl; also known as "alkylthio"), arylsulfanyl (-S-aryl; also known as "arylthio"), C1-C24Alkylsulfinyl (- (SO) -alkyl), C5-C20Arylsulfinyl (- (SO) -aryl), C1-C24Alkylsulfonyl (-SO)2-alkyl), C5-C20Arylsulfonyl (-SO)2Aryl), sulfanilamide (-SO)2-NH2,-SO2NY2(wherein Y is independently H, aryl or alkyl), phosphono (-P (O) (OH)2) Phosphonic acid (-P (O) (O))-)2) Phosphinic acid (-P (O)) (O)-) Phosphoric acid (-PO)2) Phosphino (- -PH)2) Polyalkyl ethers, phosphoric acids, phosphoric acid esters, groups incorporating amino acids or other moieties (predicted to carry a positive or negative charge at physiological pH) and combinations thereof, and wherein R6And R7Can be linked to form a ring or a polycyclic ring, wherein the ring is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclyl;
U1Is N, C-R2Or C-NR3R4Wherein R is2Selected from H, lower alkyl groups, O, (CH)2)n1OR' (where n1 is 1,2 OR 3), CF3,CH2-CH2X,O-CH2-CH2X,CH2-CH2-CH2X,O-CH2-CH2X, (wherein X ═ H, F, Cl, Br or I), CN, (C ═ O) -R ', (C ═ O) N (R')2o (CO) R ', COOR ' (wherein R ' is H or a lower alkyl group), and wherein R1And R2Can be linked to form a cyclic or polycyclic ring, wherein R3And R4Are the sameOr are different and are each selected from H, lower alkyl groups, O, (CH)2)n1OR' (where n1 is 1,2 OR 3), CF3,CH2-CH2X,CH2-CH2-CH2X, (wherein X ═ H, F, Cl, Br or I), CN, (C ═ O) -R ', (C ═ O) N (R')2COOR '(wherein R' is H or a lower alkyl group), and R3Or R4Can be default;
Z1Is O, S, CRaRbOr NRaWherein R isaAnd RbIndependently is H or C1-8An alkyl group which is linear, branched or cyclic, and which is unsubstituted or substituted.
in some embodiments, R1Selected from branched or linear alkyl radicals, including- (CH)2)n1CH3(n1＝0-7),Wherein n is20-6 and X is any one of: CF (compact flash)yHz(y+z＝3),CClyHz(y+z＝3),OH,OAc,OMe,R71,OR72,CN,N(R73)2,(n30-5, m-1-5), and(n4＝0-5)。
In other embodiments, R6And R7Each can independently be one of the following and pharmaceutically acceptable salts thereof:
R8,R9,R10,R11,R12,R13,R14,R15,R16,R17,R18,R19,R20,R21,R22,R23,R24,R25,R26,R27,R28,R29,R30,R31,R32,R33,R34,R35,R36,R37,R38,R39,R40,R41,R42,R43,R44,R45,R46,R47,R48,R49,R50,R51,R52,R53,R54,R55,R56,R57,R58,R59,R60,R61,R62,R63,R64,R65,R66,R67,R68,R69,R70,R71,R72,R73And R74Are all the same or different and are independently selected from hydrogen, substituted or unsubstituted C1-C24Alkyl radical, C2-C24Alkenyl radical, C2-C24Alkynyl, C3-C20Aryl, heterocycloalkenyl containing 5 to 6 ring atoms (wherein 1 to 3 ring atoms are independently selected from N, NH, N (C)1-C6Alkyl radical, NC (O) (C)1-C6Alkyl), O and S), heteroaryl or heterocyclyl containing 5 to 14 ring atoms (wherein 1 to 6 ring atoms are independently selected from N, NH, N (C)1-C3Alkyl), O and S), C6-C24Alkylaryl group, C6-C24Aralkyl, halogen, silyl, hydroxy, sulfhydryl, C1-C24Alkoxy radical, C2-C24Alkenyloxy radical, C2-C24Alkynyloxy, C5-C20Aryloxy, acyl (including C)2-C24Alkylcarbonyl (- -CO-alkyl) and C6-C20Arylcarbonyl (-CO-aryl)), acyloxy (-O-acyl), C2-C24Alkoxycarbonyl (- (CO) -O-alkyl), C6-C20Aryloxycarbonyl (- (CO) -O-aryl), C2-C24Alkyl carbonAcids (-O- (CO) -O-alkyl), C6-C20Aryl carbonic acid (-O- (CO) -O-aryl), carboxyl (-COOH), carboxylic acid (-COO)-) Carbamoyl (- - (CO) - - -NH)2),C1-C24Alkyl-carbamoyl (- (CO) -NH (C)1-C24Alkyl)), arylcarbamoyl (- (CO) -NH-aryl), thiocarbamoyl (- (CS) -NH2) Ureido (-NH- (CO) -NH)2) Cyano (-CN), isocyano (-N)+C-) Cyanoacyl (-O-CN), isocyanato (-O-N)+＝C-) Thio-isocyanoyl (-S-CN), azide (-N ═ N)+＝N-) A formate (- - (CO) - - -H), a thiocarbamate (- - (CS) - - - -H), an amino (- -NH)2),C1-C24Alkylamino radical, C5-C20Arylamino, C2-C24Alkylamides (-NH- (CO) -alkyl), C6-C20Arylamides (-NH- (CO) -aryl), sulfonamides (-SO)2N(R)2Wherein R is independently H, alkyl, aryl or heteroaryl), imino (-CR ═ NH wherein R is hydrogen, C1-C24Alkyl radical, C5-C20Aryl radical, C6-C24Alkylaryl group, C6-C24Aralkyl, etc.), alkylimino (-CR ═ N (alkyl), where R ═ hydrogen, alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (-CR ═ N (aryl), where R ═ hydrogen, alkyl, aryl, alkaryl, etc.), nitro (-NO), and the like2) Nitroso group (-NO), sulfo group (-SO)2-OH), sulfonic acid (-SO)2-O-),C1-C24Alkylsulfanyl (-S-alkyl; also known as "alkylthio"), arylsulfanyl (-S-aryl; also known as "arylthio"), C1-C24Alkylsulfinyl (- (SO) -alkyl), C5-C20Arylsulfinyl (- (SO) -aryl), C1-C24Alkylsulfonyl (-SO)2-alkyl), C5-C20Arylsulfonyl (-SO)2Aryl), sulfanilamide (-SO)2-NH2,-SO2NY2(wherein Y is independently H, aryl or alkyl), phosphono (-P (O) (OH)2) Phosphonic acid (-P (O) (O))-)2) Phosphinic acid (-P (O)) (O)-) Phosphoric acid (-PO)2) Phosphino (- -PH)2) Poly alkyl ether (- [ (CH)2)nO]m) Phosphoric acid, phosphoric ester [ -OP (O) (OR)2Wherein R is H, methyl or other alkyl]groups incorporating amino acids or other moieties (expected to carry a positive or negative charge at physiological pH) and combinations thereof.
in other embodiments, R6And R7Groups capable of being independently improved in water solubility, e.g. phosphate (-OPO)3H2) With phosphoric acid esters (-OPO)3H2) A linked phenyl ring, a phenyl ring substituted with one or more methoxyethoxy groups, morpholine, aryl or heteroaryl substituted with said groups.
Examples of 15-PGDH inhibitors having formula (III) or (IV) include the following compounds and pharmaceutically acceptable salts thereof:
In other embodiments, the 15-PGDH inhibitor can include a compound having the following formula (V):
Wherein n is 0-2;
X6Independently is N or CRc；
R1,R6,R7And RcIndependently selected from hydrogen, substituted or unsubstituted C1-C24Alkyl radical, C2-C24Alkenyl radical, C2-C24Alkynyl, C3-C20Aryl, heteroaryl, heterocycloalkenyl containing 5 to 6 ring atoms (wherein 1 to 3 ring atoms are independently selected from N, NH, N (C)1-C6Alkyl radical, NC (O) (C)1-C6Alkyl), O and S), C6-C24Alkylaryl group, C6-C24Aralkyl, halogen, -Si (C)1-C3Alkyl radical)3Hydroxy, sulfhydryl, C1-C24Alkoxy radical, C2-C24Alkenyloxy radical, C2-C24Alkynyloxy, C5-C20Aryloxy, acyl (including C)2-C24Alkylcarbonyl (- -CO-alkyl) and C6-C20Arylcarbonyl (-CO-aryl)), acyloxy (-O-acyl), C2-C24Alkoxycarbonyl (- (CO) -O-alkyl), C6-C20Aryloxycarbonyl (- (CO) -O-aryl), C2-C24Alkyl carbonic acids (-O- (CO) -O-alkyl), C6-C20Aryl carbonic acid (-O- (CO) -O-aryl), carboxyl (-COOH), carboxylic acid (-COO)-) Carbamoyl (- (CO) -NH)2),C1-C24Alkyl-carbamoyl (- (CO) -NH (C)1-C24Alkyl)), arylcarbamoyl (- (CO) -NH-aryl), thiocarbamoyl (- (CS) -NH2) Ureido (-NH- (CO) -NH)2) Cyano (-CN), isocyano (-N)+C-) Cyanoacyl (-O-CN), isocyanato (-O-N)+＝C-) Thio-isocyanoyl (-S-CN), azide (-N ═ N)+＝N-) A formate (- - (CO) - - -H), a thiocarbamate (- - (CS) - - - -H), an amino (- -NH)2),C1-C24Alkylamino radical, C5-C20Arylamino, C2-C24Alkylamides (-NH- (CO) -alkyl), C6-C20arylamides (-NH- (CO) -aryl), imino (-CR ═ NH, where R is hydrogen, C1-C24Alkyl radical, C5-C20Aryl radical, C6-C24Alkylaryl group, C6-C24Aralkyl, etc.), alkylimino (-CR ═ N (alkyl), where R ═ hydrogen, alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (-CR ═ N (aryl), where R ═ hydrogen, alkyl, aryl, alkaryl, etc.), nitro (-NO), and the like2) Nitroso group (-NO), sulfo group (-SO)2-OH), sulfonic acid (-SO)2-O-),C1-C24alkylsulfanyl (-S-alkyl; also known as "alkylthio"), arylsulfanyl (-S-aryl; also known as "arylthio"),C1-C24Alkylsulfinyl (- (SO) -alkyl), C5-C20Arylsulfinyl (- (SO) -aryl), C1-C24Alkylsulfonyl (-SO)2-alkyl), C5-C20Arylsulfonyl (-SO)2Aryl), sulfanilamide (-SO)2-NH2,-SO2NY2(wherein Y is independently H, aryl or alkyl), phosphono (-P (O) (OH)2) Phosphonic acid (-P (O) (O))-)2) Phosphinic acid (-P (O)) (O)-) Phosphoric acid (-PO)2) Phosphino (- -PH)2) Polyalkyl ethers, phosphoric acids, phosphoric acid esters, groups incorporating amino acids or other moieties (predicted to carry a positive or negative charge at physiological pH) and combinations thereof, and wherein R6And R7Can be linked to form a ring or a polycyclic ring, wherein the ring is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclyl;
U1Is N, C-R2Or C-NR3R4Wherein R is2Selected from H, lower alkyl groups, O, (CH)2)n1OR' (where n1 is 1,2 OR 3), CF3,CH2-CH2X,O-CH2-CH2X,CH2-CH2-CH2X,O-CH2-CH2X, (wherein X ═ H, F, Cl, Br or I), CN, (C ═ O) -R ', (C ═ O) N (R')2O (CO) R ', COOR ' (wherein R ' is H or a lower alkyl group), and wherein R1And R2Can be linked to form a cyclic or polycyclic ring, wherein R3And R4Are identical or different and are each selected from the group consisting of H, lower alkyl radicals, O, (CH)2)n1OR' (where n1 is 1,2 OR 3), CF3,CH2-CH2X,CH2-CH2-CH2X, (wherein X ═ H, F, Cl, Br or I), CN, (C ═ O) -R ', (C ═ O) N (R')2COOR '(wherein R' is H or a lower alkyl group), and R3Or R4Can be default.
In some embodiments, R1Selected from branched or linear alkyl radicals, including- (CH)2)n1CH3(n1＝0-7),Wherein n is20-6 and X is any one of: CF (compact flash)yHz(y+z＝3),CClyHz(y+z＝3),OH,OAc,OMe,R71,OR72,CN,N(R73)2,(n30-5, m-1-5), and(n4＝0-5)。
In other embodiments, R6And R7Each can independently be one of the following and pharmaceutically acceptable salts thereof:
R8,R9,R10,R11,R12,R13,R14,R15,R16,R17,R18,R19,R20,R21,R22,R23,R24,R25,R26,R27,R28,R29,R30,R3,,R32,R33,R34,R35,R36,R37,R38,R39,R40,R41,R42,R43,R44,R45,R46,R47,R48,R49,R50,R51,R52,R53,R54,R55,R56,R57,R58,R59,R60,R61,R62,R63,R64,R65,R66,R67,R68,R69,R70,R71,R72,R73And R74Are all the same or different and are independently selected from hydrogen, substituted or unsubstituted C1-C24Alkyl radical, C2-C24Alkenyl radical, C2-C24Alkynyl, C3-C20Aryl, heterocycloalkenyl containing 5 to 6 ring atoms (wherein 1 to 3 ring atoms are independently selected from N, NH, N (C)1-C6Alkyl radical, NC (O) (C)1-C6Alkyl), O and S), heteroaryl or heterocyclyl containing 5 to 14 ring atoms (wherein 1 to 6 ring atoms are independently selected from N, NH, N (C)1-C3Alkyl), O and S), C6-C24Alkylaryl group, C6-C24Aralkyl, halogen, silyl, hydroxy, sulfhydryl, C1-C24Alkoxy radical, C2-C24Alkenyloxy radical, C2-C24Alkynyloxy, C5-C20Aryloxy, acyl (including C)2-C24Alkylcarbonyl (- -CO-alkyl) and C6-C20arylcarbonyl (-CO-aryl)), acyloxy (-O-acyl), C2-C24Alkoxycarbonyl (- (CO) -O-alkyl), C6-C20Aryloxycarbonyl (- (CO) -O-aryl), C2-C24Alkyl carbonic acids (-O- (CO) -O-alkyl), C6-C20Aryl carbonic acid (-O- (CO) -O-aryl), carboxyl (-COOH), carboxylic acid (-COO)-) Carbamoyl (- - (CO) - - -NH)2),C1-C24Alkyl-carbamoyl (- (CO) -NH (C)1-C24Alkyl)), arylcarbamoyl (- (CO) -NH-aryl), thiocarbamoyl (- (CS) -NH2) Ureido (-NH- (CO) -NH)2) Cyano (-CN), isocyano (-N)+C-) Cyanoacyl (-O-CN), isocyanato (-O-N)+＝C-) Thio-isocyanoyl (-S-CN), azide (-N ═ N)+＝N-) A formate (- - (CO) - - -H), a thiocarbamate (- - (CS) - - - -H), an amino (- -NH)2),C1-C24Alkylamino radical, C5-C20Arylamino, C2-C24Alkylamides (-NH- (CO) -alkyl), C6-C20Arylamides (-NH- (CO) -aryl), sulfonamides (-SO)2N(R)2Wherein R is independently H, alkyl, aryl or heteroaryl), imino (-CR ═ NH wherein R is hydrogen, C1-C24Alkyl radical, C5-C20Aryl radical, C6-C24Alkylaryl group, C6-C24Aralkyl, etc.), alkylimino (-CR ═ N (alkyl), where R ═ hydrogen, alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (-CR ═ N (aryl), where R ═ hydrogen, alkyl, aryl, alkaryl, etc.), nitro (-NO), and the like2) Nitroso group (-NO), sulfo group (-SO)2-OH), sulfonic acid (-SO)2-O-),C1-C24Alkylsulfanyl (-S-alkyl; also known as "alkylthio"), arylsulfanyl (-S-aryl; also known as "arylthio"), C1-C24Alkylsulfinyl (- (SO) -alkyl), C5-C20Arylsulfinyl (- (SO) -aryl), C1-C24Alkylsulfonyl (-SO)2-alkyl), C5-C20Arylsulfonyl (-SO)2Aryl), sulfanilamide (-SO)2-NH2,-SO2NY2(wherein Y is independently H, aryl or alkyl), phosphono (-P (O) (OH)2) Phosphonic acid (-P (O) (O))-)2) Phosphinic acid (-P (O)) (O)-) Phosphoric acid (-PO)2) Phosphino (- -PH)2) Poly alkyl ether (- [ (CH)2)nO]m) Phosphoric acid, phosphoric ester [ -OP (O) (OR)2Wherein R is H, methyl or other alkyl]Groups incorporating amino acids or other moieties (expected to carry a positive or negative charge at physiological pH) and combinations thereof.
In other embodiments, R6And R7Groups capable of being independently improved in water solubility, e.g. phosphate (-OPO)3H2) With phosphoric acid esters (-OPO)3H2) A linked phenyl ring, a phenyl ring substituted with one or more methoxyethoxy groups, morpholine, aryl or heteroaryl substituted with said groups.
In other embodiments, the 15-PGDH inhibitor can include a compound having the following formula (VI):
Wherein n is 0-2;
X6Is N or CRc；
R1Selected from branched or linear alkyl radicals, including- (CH)2)n1CH3(n1＝0-7),Wherein n is20-6 and X is any one of: CF (compact flash)yHz(y+z＝3),CClyHz(y+z＝3),OH,OAc,OMe,R71,OR72,CN,N(R73)2,(n30-5, m-1-5), and(n4＝0-5)；
R5Selected from H, Cl, F, NH2And N (R)76)2；
R6And R7Can each independently be one of:
R8,R9,R10,R11,R12,R13,R14,R15,R16,R17,R18,R19,R20,R21,R22,R23,R24,R25,R26,R27,R28,R29,R30,R31,R32,R33,R34,R35,R36,R37,R38,R39,R40,R41,R42,R43,R44,R45,R46,R47,R48,R49,R50,R51,R52,R53,R54,R55,R56,R57,R58,R59,R60,R61,R62,R63,R64,R65,R66,R67,R68,R69,R70,R71,R72,R73,R74,R76And RcAre all the same or different and are independently selected from hydrogen, substituted or unsubstituted C1-C24Alkyl radical, C2-C24Alkenyl radical, C2-C24Alkynyl, C3-C20Aryl, heterocycloalkenyl containing 5 to 6 ring atoms (wherein 1 to 3 ring atoms are independently selected from N, NH, N (C)1-C6Alkyl radical, NC (O) (C)1-C6Alkyl), O and S), heteroaryl or heterocyclyl containing 5 to 14 ring atoms (wherein 1 to 6 ring atoms are independently selected from N, NH, N (C)1-C3Alkyl), O and S), C6-C24Alkylaryl group, C6-C24Aralkyl, halogen, silyl, hydroxy, sulfhydryl, C1-C24Alkoxy radical, C2-C24alkenyloxy radical, C2-C24Alkynyloxy, C5-C20Aryloxy, acyl (including C)2-C24Alkylcarbonyl (- -CO-alkyl) and C6-C20Arylcarbonyl (-CO-aryl)), acyloxy (-O-acyl), C2-C24Alkoxycarbonyl (- (CO) -O-alkyl), C6-C20Aryloxycarbonyl (- (CO) -O-aryl), C2-C24Alkyl carbonic acids (-O- (CO) -O-alkyl), C6-C20Aryl carbonic acid (-O- (CO) -O-aryl), carboxyl (-COOH), carboxylic acid (-COO)-) Carbamoyl (- - (CO) - - -NH)2),C1-C24alkyl-carbamoyl (- (CO) -NH (C)1-C24Alkyl)), arylcarbamoyl (- (CO) -NH-aryl), thiocarbamoyl (- (CS) -NH2) Ureido (-NH- (CO) -NH)2) Cyano (-CN), isocyano (-N)+C-) Cyanoacyl (-O-CN), isocyanato (-O-N)+＝C-) Thio-isocyanoyl (-S-CN), azide (-N ═ N)+＝N-) A formate (- - (CO) - - -H), a thiocarbamate (- - (CS) - - - -H), an amino (- -NH)2),C1-C24Alkylamino radical, C5-C20arylamino, C2-C24Alkylamides (-NH- (CO) -alkyl), C6-C20Arylamides (-NH- (CO) -aryl), sulfonamides (-SO)2N(R)2Wherein R is independently H, alkyl, aryl or heteroaryl), imino (-CR ═ NH wherein R is hydrogen, C1-C24alkyl radical, C5-C20aryl radical, C6-C24Alkylaryl group, C6-C24Aralkyl, etc.), alkylimino (-CR ═ N (alkyl), where R ═ hydrogen, alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (-CR ═ N (aryl), where R ═ hydrogen, alkyl, aryl, alkaryl, etc.), nitro (-NO), and the like2) Nitroso group (-NO), sulfo group (-SO)2-OH), sulfonic acid (-SO)2-O-),C1-C24Alkylsulfanyl (-S-alkyl; also known as "alkylthio"), arylsulfanyl (-S-aryl; also known as "arylthio"), C1-C24Alkylsulfinyl (- (SO) -alkyl), C5-C20Arylsulfinyl (- (SO) -aryl), C1-C24Alkylsulfonyl (-SO)2-alkyl), C5-C20Arylsulfonyl (-SO)2aryl), sulfanilamide (-SO)2-NH2,-SO2NY2(wherein Y is independently H, aryl or alkyl), phosphono (-P (O) (OH)2) Phosphonic acid (-P (O) (O))-)2) Phosphinic acid (-P (O)) (O)-) Phosphoric acid (-PO)2) Phosphino (- -PH)2) Poly alkyl ether (- [ (CH)2)nO]m) Phosphoric acid, phosphoric ester [ -OP (O) (OR)2Wherein R is H, methyl or other alkyl]Groups incorporating amino acids or other moieties (expected to carry a positive or negative charge at physiological pH) and combinations thereof.
In other embodiments, the 15-PGDH inhibitor can include a compound having the following formula (VII):
Wherein n is 0-2;
X6is N or CRc；
R1selected from branched or linear alkyl radicals, including- (CH)2)n1CH3(n1＝0-7),Wherein n is20-6 and X is any one of: CF (compact flash)yHz(y+z＝3),CClyHz(y+z＝3),OH,OAc,OMe,R71,OR72,CN,N(R73)2,(n30-5, m-1-5), and(n4＝0-5)；
R5Selected from H, Cl, F, NH2And N (R)76)2；
R7Can each independently be one of:
R8,R9,R10,R11,R12,R13,R14,R15,R16,R17,R18,R19,R20,R21,R22,R23,R24,R25,R26,R27,R28,R29,R30,R31,R32,R33,R34,R35,R36,R37,R38,R39,R40,R41,R42,R43,R44,R45,R46,R47,R48,R49,R50,R51,R52,R53,R54,R55,R56,R57,R58,R59,R60,R61,R62,R63,R64,R65,R66,R67,R68,R69,R70,R71,R72,R73,R74,R76And RcAre all the same or different and are independently selected from hydrogen, substituted or unsubstituted C1-C24Alkyl radical, C2-C24Alkenyl radical, C2-C24Alkynyl, C3-C20Aryl, heterocycloalkenyl containing 5 to 6 ring atoms (wherein 1 to 3 ring atoms are independently selected from N, NH, N (C)1-C6Alkyl radical, NC (O) (C)1-C6Alkyl), O and S), heteroaryl or heterocyclyl containing 5 to 14 ring atoms (wherein 1 to 6 ring atoms are independently selected from N, NH, N (C)1-C3Alkyl), O and S), C6-C24Alkylaryl group, C6-C24Aralkyl, halogen, silyl, hydroxy, sulfhydryl, C1-C24Alkoxy radical, C2-C24Alkenyloxy radical, C2-C24Alkynyloxy, C5-C20Aryloxy, acyl (including C)2-C24Alkylcarbonyl (- -CO-alkyl) and C6-C20Arylcarbonyl (-CO-aryl)), acyloxy (-O-acyl), C2-C24Alkoxycarbonyl (- (CO) -O-alkyl), C6-C20Aryloxycarbonyl (- (CO) -O-aryl), C2-C24Alkyl carbonic acids (-O- (CO) -O-alkyl), C6-C20Aryl carbonic acid (-O- (CO) -O-aryl), carboxyl (-COOH), carboxylic acid (-COO)-) Carbamoyl (- - (CO) - - -NH)2),C1-C24Alkyl-carbamoyl (- (CO) -NH (C)1-C24Alkyl)), arylcarbamoyl (- (CO) -NH-aryl), thiocarbamoyl (- (CS) -NH2) Ureido (-NH- (CO) -NH)2) Cyano (-CN), isocyano (-N)+C-) Cyanoacyl (-O-CN), isocyanato (-O-N)+＝C-) Thio-isocyanoyl (-S-CN), azide (-N ═ N)+＝N-) A formate (- - (CO) - - -H), a thiocarbamate (- - (CS) - - - -H), an amino (- -NH)2),C1-C24Alkylamino radical, C5-C20Arylamino, C2-C24Alkylamides (-NH- (CO) -alkyl), C6-C20Arylamides (-NH- (CO) -aryl), sulfonamides (-SO)2N(R)2Wherein R is independently H, alkyl, aryl or heteroaryl), imino (-CR ═ NH wherein R is hydrogen, C1-C24Alkyl radical, C5-C20Aryl radical, C6-C24Alkylaryl group, C6-C24Aralkyl, etc.), alkylimino (-CR ═ N (alkyl), where R ═ hydrogen, alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (-CR ═ N (aryl), where R ═ hydrogen, alkyl, aryl, alkaryl, etc.), nitro (-NO), and the like2) Nitroso group (-NO), sulfo group (-SO)2-OH), sulfonic acid (-SO)2-O-),C1-C24Alkylsulfanyl (-S-alkyl; also known as "alkylthio"), arylsulfanyl (-S-aryl; also known as "arylthio"), C1-C24Alkylsulfinyl (- (SO) -alkyl), C5-C20Arylsulfinyl (- (SO) -aryl), C1-C24Alkylsulfonyl (-SO)2-alkyl), C5-C20Arylsulfonyl (-SO)2Aryl), sulfanilamide (-SO)2-NH2,-SO2NY2(wherein Y is independently H, aryl or alkyl), phosphono (-P (O) (OH)2) Phosphonic acid (-P (O) (O))-)2) Phosphinic acid (-P (O)) (O)-) Phosphoric acid (-PO)2) Phosphino (- -PH)2) Poly alkyl ether (- [ (CH)2)nO]m) Phosphoric acid, phosphoric ester [ -OP (O) (OR)2Wherein R is H, methyl or other alkyl]Groups incorporating amino acids or other moieties (expected to carry a positive or negative charge at physiological pH) and combinations thereof.
Examples of compounds having formula (V), (VI) or (VII) are selected from the following and pharmaceutically acceptable salts thereof:
In certain embodiments, a 15-PGDH inhibitor having the formula (I), (II), (IV), (V), (VI) and (VII) can be selected, which can be ia) at 2.5 μ M concentrationAt this point, the Vaco503 reporter cell line expressing the 15-PGDH luciferase fusion construct was stimulated to achieve luciferase output levels in excess of 70 (using the following scale: a value of 100 indicates that the output of the reporter cell line doubled over baseline); iia) stimulated the V9M reporter cell line expressing the 15-PGDH luciferase fusion construct to luciferase output levels above 75 at a concentration of 2.5 μ M; iiia) stimulated the LS174T reporter cell line expressing the 15-PGDH luciferase fusion construct to luciferase output levels in excess of 70 at a concentration of 7.5 μ M; iva) did not activate the TK-renilla luciferase reporter expressing negative control V9M cell line to a level of more than 20 at a concentration of 7.5 μ M; and va) in IC50Below 1 μ M, the enzyme activity of the recombinant 15-PGDH protein was inhibited.
In other embodiments, the 15-PGDH inhibitor is capable of ib) stimulating a Vaco503 reporter cell line expressing the 15-PGDH luciferase fusion construct to increase luciferase output at a concentration of 2.5 μ M; iib) stimulated the V9M reporter cell line expressing the 15-PGDH luciferase fusion construct to increase luciferase output at a concentration of 2.5 μ M; iiib) at a concentration of 7.5 μ M, the LS174T reporter cell line expressing the 15-PGDH luciferase fusion construct was stimulated to increase luciferase output; ivb) at a concentration of 7.5 μ M, a negative control V9M cell line expressing the TK-renilla luciferase reporter was not activated to luciferase levels above 20% above background; and vb) in IC50Below 1 μ M, the enzyme activity of the recombinant 15-PGDH protein was inhibited.
In other embodiments, the 15-PGDH inhibitor is capable of IC at recombinant 15-GPDH concentrations of about 5nM to about 10nM50Less than 1 μ M, or preferably IC50Less than 250nM, or more preferably IC50Less than 50nM, or more preferably IC50Less than 10nM, or more preferably IC50The enzyme activity of recombinant 15-PGDH was inhibited below 5 nM.
In other embodiments, the 15-PGDH inhibitor is capable of increasing the cellular level of PGE-2 following stimulation of A459 cells with a suitable agent (e.g., IL1- β).
In some embodiments, the 15-PGDH inhibitor can include a compound having the following formula (VIII):
Wherein n is 0-2;
R1,R6And R7Are identical or different and are each selected from hydrogen, substituted or unsubstituted C1-C24Alkyl radical, C2-C24Alkenyl radical, C2-C24Alkynyl, C3-C20Aryl, heterocycloalkenyl containing 5 to 6 ring atoms (wherein 1 to 3 ring atoms are independently selected from N, NH, N (C)1-C6Alkyl radical, NC (O) (C)1-C6Alkyl), O and S), heteroaryl or heterocyclyl containing 5 to 14 ring atoms (wherein 1 to 6 ring atoms are independently selected from N, NH, N (C)1-C3Alkyl), O and S), C6-C24Alkylaryl group, C6-C24Aralkyl, halogen, silyl, hydroxy, sulfhydryl, C1-C24alkoxy radical, C2-C24Alkenyloxy radical, C2-C24Alkynyloxy, C5-C20Aryloxy, acyl (including C)2-C24Alkylcarbonyl (- -CO-alkyl) and C6-C20Arylcarbonyl (-CO-aryl)), acyloxy (-O-acyl), C2-C24Alkoxycarbonyl (- (CO) -O-alkyl), C6-C20Aryloxycarbonyl (- (CO) -O-aryl), C2-C24Alkyl carbonic acids (-O- (CO) -O-alkyl), C6-C20Aryl carbonic acid (-O- (CO) -O-aryl), carboxyl (-COOH), carboxylic acid (-COO)-) Carbamoyl (- - (CO) - - -NH)2),C1-C24Alkyl-carbamoyl (- (CO) -NH (C)1-C24Alkyl)), arylcarbamoyl (- (CO) -NH-aryl), thiocarbamoyl (- (CS) -NH2) Ureido (-NH- (CO) -NH)2) Cyano (-CN), isocyano (-N)+C-) Cyanoacyl (-O-CN), isocyanato (-O-N)+＝C-) Thio-isocyanoyl (-S-CN), azide (-N ═ N)+＝N-) A formate (- - (CO) - - -H), a thiocarbamate (- - (CS) - - - -H), an amino (- -NH)2),C1-C24Alkylamino radical, C5-C20Arylamino, C2-C24Alkylamides (-NH- (CO) -alkyl), C6-C20Arylamides (-NH- (CO) -aryl), sulfonamides (-SO)2N(R)2Wherein R is independently H, alkyl, aryl or heteroaryl), imino (-CR ═ NH wherein R is hydrogen, C1-C24Alkyl radical, C5-C20Aryl radical, C6-C24Alkylaryl group, C6-C24Aralkyl, etc.), alkylimino (-CR ═ N (alkyl), where R ═ hydrogen, alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (-CR ═ N (aryl), where R ═ hydrogen, alkyl, aryl, alkaryl, etc.), nitro (-NO), and the like2) Nitroso group (-NO), sulfo group (-SO)2-OH), sulfonic acid (-SO)2-O-),C1-C24Alkylsulfanyl (-S-alkyl; also known as "alkylthio"), arylsulfanyl (-S-aryl; also known as "arylthio"), C1-C24Alkylsulfinyl (- (SO) -alkyl), C5-C20Arylsulfinyl (- (SO) -aryl), C1-C24Alkylsulfonyl (-SO)2-alkyl), C5-C20Arylsulfonyl (-SO)2Aryl), sulfanilamide (-SO)2-NH2,-SO2NY2(wherein Y is independently H, aryl or alkyl), phosphono (-P (O) (OH)2) Phosphonic acid (-P (O) (O))-)2) Phosphinic acid (-P (O)) (O)-) Phosphoric acid (-PO)2) Phosphino (- -PH)2) Poly alkyl ether (- [ (CH)2)nO]m) Phosphoric acid, phosphoric ester [ -OP (O) (OR)2Wherein R is H, methyl or other alkyl]groups incorporating amino acids or other moieties (expected to carry a positive or negative charge at physiological pH), and wherein R6And R7Can be linked to form a ring or a polycyclic ring, wherein the ring is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclyl.
The 15-PGDH inhibitor having formula (VIII) can be synthesized as follows:
Any reaction solvent can be used in the above production process as long as it does not participate in the reaction. For example, the reaction solvent includes ethers such as diethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as dichloromethane and chloroform; amines such as pyridine, piperidine and triethylamine; alkyl ketones such as acetone, methyl ethyl ketone and methyl isobutyl; alcohols such as methanol, ethanol and propanol; aprotic polar solvents such as N, N-dimethylformamide, N-dimethylacetamide, acetonitrile, dimethyl sulfoxide and hexamethylphosphoric triamide. Among the non-reactive organic solvents commonly used in organic synthesis, the preferred solvents are those that dissolve: the water formed in the reaction can be removed via a Dean-Stark trap. Examples of such solvents include, but are not limited to, benzene, toluene, xylene, and the like. The reaction product thus obtained can be isolated and purified by condensation, extraction and the like, and if necessary, the isolation and purification is usually carried out in an organic synthesis field by silica gel column chromatography. The individual enantiomers of PGDH inhibitors having formula III can be prepared by preparative HPLC using a chromatography column comprising a chiral stationary phase.
furthermore, embodiments of such uses include any modifications of the methods of preparation of 15-PGDH described above. In this connection, any intermediate product resulting from any step of the preparation process can be used as starting material in other steps. The starting material can be formed in situ under certain reaction conditions. The reagents can be used in the form of their salts or optical isomers.
Depending on the nature of the substituents used in the preparation of the 15-PGDH inhibitors, the intermediates and the chosen preparation method, the novel 15-PGDH inhibitors can be in any feasible isomeric form, e.g. substantially pure geometric (cis or trans) isomers, optical isomers (enantiomers) and racemates.
In some embodiments, the 15-PGDH inhibitor having formula (VIII) can include compounds having the following formula (IX):
Advantageously, it was found that 15-PGDH inhibitors having formula (IX) are capable of: i) inhibiting recombinant 15-PGDH at a concentration of 1 nM; ii) inhibits 15-PGDH in the cell line at a concentration of 100 nM; iii) increasing PGE of cell lines2Generation of (1); iv) is chemically stable in aqueous solution over a wide range of pH; v) is chemically stable when incubated with hepatocyte extracts; vi) is chemically stable when incubated with a liver cell line; vii) when IP injected into mice, shows a plasma half-life of 253 minutes; and viii) showed no immediate toxicity within 24 hours when injected into mice at 0.6 μmole per mouse and 1.2 μmole per mouse IP, and also showed no toxicity when injected into mice at 0.3 μmole per mouse IP twice daily over 21 days.
In other embodiments, the 15-PGDH inhibitor having formula (IX) can include compounds having the following formula (Ixa) and pharmaceutically acceptable salts thereof:
In other embodiments, the 15-PGDH inhibitor having formula (IX) can include compounds having the following formula (Ixb):
In other embodiments, the 15-PDHG inhibitor can comprise a (+) or (-) optical isomer of a 15-PGDH inhibitor having formula (IX). In other embodiments, the 15-PDHG inhibitor can comprise a mixture of at least one of the (+) or (-) optical isomers of the 15-PGDH inhibitor having formula (IX). For example, the 15-PGDH inhibitor can comprise a mixture of: less than about 50% by weight of the (-) optical isomer of the 15-PGDH inhibitor having the formula (IX) and greater than about 50% by weight of the (+) optical isomer of the 15-PGDH inhibitor having the formula (IX), less than about 25% by weight of the (-) optical isomer of the 15-PGDH inhibitor having the formula (IX) and greater than about 75% by weight of the (+) optical isomer of the 15-PGDH inhibitor having the formula (IX), less than about 10% by weight of the (-) optical isomer of the 15-PGDH inhibitor having the formula (IX) and greater than about 95% by weight of the (+) optical isomer of the 15-PGDH inhibitor having the formula (IX), less than about 1% by weight of the (-) optical isomer of the 15-PGDH inhibitor having the formula (IX) and greater than about 99% by weight of the (+) optical isomer of the 15-PGDH inhibitor having the formula (IX), greater than about 50% by weight of the (-) optical isomer of the 15-PGDH inhibitor having the formula (IX) and less than about 50% by weight of the (+) optical isomer of the 15-PGDH inhibitor having the formula (IX), greater than about 75% by weight of the (-) optical isomer of the 15-PGDH inhibitor having the formula (IX) and less than about 25% by weight of the (+) optical isomer of the 15-PGDH inhibitor having the formula (IX), greater than about 90% by weight of the (-) optical isomer of the 15-PGDH inhibitor having the formula (IX) and less than about 10% by weight of the (+) optical isomer of the 15-PGDH inhibitor having the formula (IX), or greater than about 99% by weight of the (-) optical isomer of the 15-PGDH inhibitor having the formula (IX) and less than about 1% by weight of the (+) optical isomer of the 15-PGDH inhibitor having the formula (IX).
In another embodiment, the 15-PDGH inhibitor can consist essentially of, or consist of, the (+) optical isomer of a 15-PGDH inhibitor having formula (IX). In another embodiment, the PDGH inhibitor can consist essentially of or consist of the (-) optical isomer of the 15-PGDH inhibitor having formula (IX).
In other embodiments, the 15-PGDH inhibitor having formula (VIII) can include compounds having the following formula (X):
advantageously, it was found that 15-PDGH inhibitors having formula (X) are capable of: i) inhibiting recombinant 15-PGDH at a concentration of 3 nM; ii) increase PGE in cell lines at 20nM2Generation of (1); iii) is chemically stable in aqueous solution over a wide pH range; iv) when in contact with a mouse,Rat and human liver extracts are chemically stable when incubated; v) when IP injected into mice, shows a plasma half-life of 33 minutes; and viii) showed no immediate toxicity within 24 hours when IP injected into mice at 50mg/kg body weight, and ix) dissolved in water at 1mg/mL (pH 3).
In other embodiments, the 15-PGDH inhibitor having formula (X) can include compounds having the following formula (Xa):
In other embodiments, the 15-PGDH inhibitor having formula (X) can include compounds having the following formula (Xb):
In other embodiments, the 15-PDHG inhibitor can comprise a (+) or (-) optical isomer of a 15-PGDH inhibitor having formula (X). In other embodiments, the 15-PDHG inhibitor can comprise a mixture of at least one of the (+) or (-) optical isomers of the 15-PGDH inhibitor having formula (X). For example, the 15-PGDH inhibitor can comprise a mixture of: less than about 50% by weight of the (-) optical isomer of the 15-PGDH inhibitor having formula (X) and greater than about 50% by weight of the (+) optical isomer of the 15-PGDH inhibitor having formula (X), less than about 25% by weight of the (-) optical isomer of the 15-PGDH inhibitor having formula (X) and greater than about 75% by weight of the (+) optical isomer of the 15-PGDH inhibitor having formula (X), less than about 10% by weight of the (-) optical isomer of the 15-PGDH inhibitor having formula (X) and greater than about 90% by weight of the (+) optical isomer of the 15-PGDH inhibitor having formula (X), less than about 1% by weight of the (-) optical isomer of the 15-PGDH inhibitor having formula (X) and greater than about 99% by weight of the (+) optical isomer of the 15-PGDH inhibitor having formula (X), greater than about 50% by weight of the (-) optical isomer of the 15-PGDH inhibitor having formula (X) and less than about 50% by weight of the (+) optical isomer of the 15-PGDH inhibitor having formula (X), greater than about 75% by weight of the (-) optical isomer of the 15-PGDH inhibitor having formula (X) and less than about 25% by weight of the (+) optical isomer of the 15-PGDH inhibitor having formula (X), greater than about 90% by weight of the (-) optical isomer of the 15-PGDH inhibitor having formula (X) and less than about 10% by weight of the (+) optical isomer of the 15-PGDH inhibitor having formula (X), or greater than about 99% by weight of the (-) optical isomer of the 15-PGDH inhibitor having formula (X) and less than about 1% by weight of the (+) optical isomer of the 15-PGDH inhibitor having formula (X).
In another embodiment, the 15-PDGH inhibitor can consist essentially of, or consist of, the (+) optical isomer of a 15-PGDH inhibitor having formula (X). In another embodiment, the PDGH inhibitor can consist essentially of or consist of the (-) optical isomer of the 15-PGDH inhibitor of formula (X).
It is understood that other 15-PGDH inhibitors can be used in the methods of the invention. These other 15-PGDH inhibitors can include known 15-PGDH inhibitors, including, for example, tetrazole compounds of formula (I) and (II), 2-alkyleneaminooxyacetamide compounds of formula (I), heterocyclic compounds of formula (VI) and (VII), pyrazole compounds of formula (III) described in U.S. patent application publication No.2006/0034786 and U.S. patent No.7,705,041, benzylidene-1, 3-thiazolidine compounds of formula (I) described in U.S. patent application publication No.2007/0071699, phenylfurylmethyl thiazolidine-2, 4-dione and phenylthienylmethyl thiazolidine-2, 4-dione compounds described in U.S. patent application publication No.2007/0078175, thiazolidinedione derivatives described in U.S. patent application publication No.2011/0269954, phenylfuran described in U.S. patent No.7,294,641, phenylthiophene and phenylpyrazole compounds, 5- (3, 5-substituted phenylazo) -2-hydroxyphenyl-acetic acid, salts and lactones as described in U.S. Pat. No.4,725,676.
The 15-PGDH inhibitors according to the invention can be provided in pharmaceutical or cosmetic compositions, depending on the pathological or cosmetic condition or disorder to be treated. A pharmaceutical composition comprising the 15-PGDH inhibitor of the present invention as an active ingredient can be manufactured by diluting the derivative with a pharmaceutically acceptable carrier(s) or excipient(s) or using a diluent to dilute the 15-PGDH inhibitor according to a conventional method. The pharmaceutical composition can further comprise fillers, anti-adherents, emollients, wetting agents, flavoring agents, emulsifiers, preservatives and the like. The pharmaceutical composition can be formulated into a suitable formulation according to methods known to those skilled in the art such that it provides immediate, controlled or sustained release of the 15-PGDH inhibitor after administration to a mammal.
In some embodiments, the pharmaceutical composition can be formulated as a parenteral or oral dosage form. If desired, solid dosage forms for oral administration can be manufactured by adding excipients, as well as binders, disintegrants, lubricants, colorants and/or flavoring agents, together with the 15-PGDH inhibitor, and molding the resulting mixture into tablets, sugar-coated pills, granules, powders, or capsules. Additives that can be added to the composition can be those common in the art. Examples of excipients include, for example, lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, silicates, and the like. Exemplary binders include water, ethanol, propanol, sweet syrup, sucrose solution, starch solution, gelatin solution, carboxymethyl cellulose, hydroxypropyl starch, methyl cellulose, ethyl cellulose, shellac, calcium phosphonate and pyrrolidone. Examples of the disintegrating agent include dry starch, sodium alginate, agar powder, sodium bicarbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, and lactose. In addition, purified talc, stearate, sodium borate and polyethylene glycol can be used as a lubricant; and sucrose, bitter orange peel, citric acid, tartaric acid can be used as flavoring agent. In some embodiments, the pharmaceutical compositions can be prepared as aerosol formulations that are administered by inhalation (e.g., they can be nebulized).
The 15-PGDH inhibitors of the present invention can be combined with flavoring agents, buffers, stabilizers, etc., and incorporated into oral liquid dosage forms, such as solutions, syrups or elixirs, according to conventional methods. An example of a buffer can be sodium citrate. Examples of stabilizers include tragacanth, acacia and gelatin.
In some embodiments, the 15-PGDH inhibitors according to the invention can be introduced into injectable dosage forms, for example for subcutaneous, intramuscular or intravenous routes by adding them to pH-adjusting agents, buffers, stabilizers, retarders, local anesthetics. Examples of pH adjusters and buffers include sodium citrate, sodium acetate, and sodium phosphate. Examples of stabilizers include sodium metabisulfite, EDTA, thioglycolic acid and thiolactic acid. The local anesthetic can be procaine HCl, lidocaine HCl, or the like. The retarder can be sodium chloride, glucose, etc.
In other embodiments, the 15-PGDH inhibitors described herein can be incorporated into suppositories (e.g., polyethylene glycol, lanolin, cocoa butter or fatty acid triglycerides) by introducing them into pharmaceutically acceptable carriers known in the art (along with surfactants such as Tween, if desired) according to conventional methods.
The pharmaceutical compositions can be formulated in a variety of dosage forms as discussed above and then administered by a variety of routes including oral, adsorptive, transdermal, subcutaneous, intravenous, intramuscular routes. The dosage can be a pharmaceutically or therapeutically effective amount.
In various embodiments, a therapeutically effective amount of a 15-PGDH inhibitor can be present in varying amounts. For example, in some embodiments, the therapeutically effective amount of the 15-PGDH inhibitor can be about 10-1000mg (e.g., about 20mg-1,000mg,30mg-1,000mg,40mg-1,000mg,50mg-1,000mg,60mg-1,000mg,70mg-1,000mg,80mg-1,000mg,90mg-1,000mg, about 10-900mg,10-800mg,10-700mg,10-600mg,10-500mg,100-1000mg,100-900mg,100-800mg,100-700mg,100-600mg,100-500mg, 200-1000mg,200-900mg,200-800mg,200-700mg,200-600mg,200-500mg,200-400mg,300-1000mg, 300-800mg,300-700mg,300-600mg,300-500mg, 400-1,000 mg, 500-1,000 mg,100-900mg, 200-800mg, 300-700mg, 400-700 mg and 500-600 mg). In some embodiments, the 15-PGDH inhibitor is present in an amount equal to or greater than about 10mg,50mg,100mg,150mg,200mg,250mg,300mg,350mg,400mg,450mg,500mg,550mg,600mg,650mg,700mg,750mg,800 mg. In some embodiments, the 15-PGDH inhibitor is present in an amount equal to or less than about 1000mg,950mg,900mg,850mg,800mg,750mg,700mg,650mg,600mg,550mg,500mg,450mg,400mg,350mg,300mg,250mg,200mg,150mg, or 100 mg.
In other embodiments, a therapeutically effective dose can be, for example, about 0.001mg/kg to 500mg/kg weight, e.g., about 0.001mg/kg to 400mg/kg weight, about 0.001mg/kg to 300mg/kg weight, about 0.001mg/kg to 200mg/kg weight, about 0.001mg/kg to 100mg/kg weight, about 0.001mg/kg to 90mg/kg weight, about 0.001mg/kg to 80mg/kg weight, about 0.001mg/kg to 70mg/kg weight, about 0.001mg/kg to 60mg/kg weight, about 0.001mg/kg to 50mg/kg weight, about 0.001mg/kg to 40mg/kg weight, about 0.001mg/kg to 30mg/kg weight, about 0.001mg/kg to 25mg/kg weight, about 0.001mg/kg to 20mg/kg weight, about 0.001mg/kg to 15mg/kg weight, about 0.001mg/kg to 10mg/kg weight.
In other embodiments, a therapeutically effective dose can be, for example, about 0.0001mg/kg to 0.1mg/kg weight, e.g., about 0.0001mg/kg to 0.09mg/kg weight, about 0.0001mg/kg to 0.08mg/kg weight, about 0.0001mg/kg to 0.07mg/kg weight, about 0.0001mg/kg to 0.06mg/kg weight, about 0.0001mg/kg to 0.05mg/kg weight, about 0.0001mg/kg to about 0.04mg/kg weight, about 0.0001mg/kg to 0.03mg/kg weight, about 0.0001mg/kg to 0.02mg/kg weight, about 0.0001mg/kg to 0.019mg/kg weight, about 0.0001mg/kg to 0.018mg/kg weight, about 0.017mg/kg to 0.017mg/kg weight, about 0.0001mg/kg to 0.016mg/kg weight, about 0.0001mg/kg to 0.015mg/kg weight, about 0.0001mg/kg to 0.014mg/kg weight, about 0.0001mg/kg to 0.013mg/kg weight, about 0.0001mg/kg to 0.012mg/kg weight, about 0.0001mg/kg to 0.011mg/kg weight, about 0.0001mg/kg to 0.01mg/kg weight, about 0.0001mg/kg to 0.009mg/kg weight, about 0.0001mg/kg to 0.008mg/kg weight, about 0.0001mg/kg to 0.007mg/kg weight, about 0.0001mg/kg to 0.006mg/kg weight, about 0.0001mg/kg to 0.005mg/kg weight, about 0.0001mg/kg to 0.004mg/kg weight, about 0.0001mg/kg to 0.003mg/kg weight, about 0.0001mg/kg to 0.002mg/kg weight. In some embodiments, a therapeutically effective dose can be 0.0001mg/kg weight, 0.0002mg/kg weight, 0.0003mg/kg weight, 0.0004mg/kg weight, 0.0005mg/kg weight, 0.0006mg/kg weight, 0.0007mg/kg weight, 0.0008mg/kg weight, 0.0009mg/kg weight, 0.001mg/kg weight, 0.002mg/kg weight, 0.003mg/kg weight, 0.004mg/kg weight, 0.005mg/kg weight, 0.006mg/kg weight, 0.007mg/kg weight, 0.008mg/kg weight, 0.009mg/kg weight, 0.01mg/kg weight, 0.02mg/kg weight, 0.03mg/kg weight, 0.04mg/kg weight, 0.05mg/kg weight, 0.06mg/kg weight, 0.07mg/kg weight, 0.08mg/kg weight, 0.09mg/kg weight, or 1.09 mg/kg weight. The effective dose for a particular individual can vary (e.g., increase or decrease) over a period of time depending on the individual's needs.
In some embodiments, a therapeutically effective dose can be a dose of 10 μ g/kg/day, 50 μ g/kg/day, 100 μ g/kg/day, 250 μ g/kg/day, 500 μ g/kg/day, 1000 μ g/kg/day or higher. In various embodiments, the amount of the 15-PGDH inhibitor or the pharmaceutical salt thereof is sufficient to provide 0.01 to 10 μ g/kg to the patient; 0.1 to 5 mug/kg; 0.1 to 1000. mu.g/kg; 0.1 to 900. mu.g/kg; 0.1 to 900. mu.g/kg; 0.1 to 800. mu.g/kg; 0.1 to 700. mu.g/kg; 0.1 to 600. mu.g/kg; 0.1 to 500. mu.g/kg; or a dose of 0.1 μ g/kg to 400 μ g/kg.
The particular dose or amount administered according to the present invention can vary depending, for example, on the nature and/or extent of the desired result, the particular circumstances of the route and/or timing of administration, and/or one or more characteristics (e.g., weight, age, personal history, genetic characteristics, lifestyle parameters, severity of cardiac defect and/or risk level of cardiac defect, etc., or combinations thereof). Such dosages or amounts can be determined by those of ordinary skill. In some embodiments, the appropriate dose or amount is determined according to standard clinical techniques. For example, in some embodiments, a suitable dose or amount is a dose or amount sufficient to reduce a disease severity index score by 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,25,30,35,40,45,50,55,60,65,70,75,80,85,90,95, 100% or more. For example, in some embodiments, a suitable dose or amount is a dose or amount sufficient to reduce a disease severity index score by 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,25,30,35,40,45,50,55,60,65,70,75,80,85,90,95, 100%. Alternatively or additionally, in some embodiments, the appropriate dose or amount is determined by using one or more ex vivo or in vivo tests to help identify the ideal or optimal dosage range or amount to be administered.
Various embodiments can include different dosage regimens. In some embodiments, the 15-PGDH inhibitor can be administered by continuous infusion. In some embodiments, the continuous infusion is intravenous. In other embodiments, the continuous infusion is subcutaneous. Alternatively or additionally, in some embodiments, the 15-PGDH inhibitor is capable of being administered every two months, every month, twice a month, once every three weeks, once every two weeks, once a week, twice a week, three times a week, once a day, twice a day, or on another clinically desirable dosage schedule. The dosage regimen for an individual subject need not be at fixed intervals, but can vary over time according to the needs of the subject.
For topical application, the compositions can be administered in the form of aqueous, alcoholic, aqueous-alcoholic or oily solutions or suspensions, dispersions of lotions or serotypes, emulsions (which have a liquid or semi-liquid consistency, or are pasty, obtainable by dispersing a fatty phase in an aqueous phase (O/W), or vice versa (W/O)) or emulsions, free of or with the compacted powder to be used (as it is or will be introduced into a physiologically acceptable medium), other forms of microcapsules or microparticles, or vesicular dispersions of the ionic and/or anionic type. Thus, it is in the form of a salve, tincture, milk, cream, ointment, powder, patch, impregnated pad, solution, emulsion or vesicle dispersion, lotion, aqueous or anhydrous gel, spray, suspension, detergent, aerosol or foam. It can be anhydrous or aqueous. It can also include solid preparations of structured soap or cleansing bars.
Comprising 1 described in the present inventionThe pharmaceutical and/or cosmetic composition of the 5-PGDH inhibitor can additionally comprise, for example, a prostaglandin (in particular prostaglandin PGE)1,PGE2) At least one compound of their salts, their esters, their analogs and their derivatives, in particular those described in WO 98/33497, WO 95/11003, JP 97-100091, JP 96-134242, in particular agonists of prostaglandin receptors. It can in particular comprise at least one compound, for example prostaglandin F2Agonists of the alpha receptor (acid or precursor forms, particularly ester forms), such as latanoprost, fluprostenol, treprost, bimatoprost, unoprostone; prostaglandin E2agonists of receptors (and their precursors, especially esters, e.g. travoprost), e.g. 17-phenyl PGE2Viprostenol, butaprost, misoprostol, sulprostone, 16, 16-dimethyl PGE211-deoxy PGE11-deoxy PGE1(ii) a Agonists of the prostacyclin (IP) receptor and their precursors, in particular esters, such as cicaprost, iloprost, isocarbacyline, beraprost synthetic preparations, epostenol, treprostinil; prostaglandin D2Agonists of the receptor and their precursors, in particular esters, such as BW245C ((4S) - (3- [ (3R, S) -3-cyclohexyl-3-isopropyl)]-2, 5-dioxo) -4-imidazolidinoheptan-oic acid), BW246C ((4R) - (3- [ (3R, S) -3-cyclohexyl-3-isopropyl)]-2, 5-dioxo) -4-imidazolidine heptanic acid); agonists of the thromboxane A2(TP) receptor and their precursors, in particular esters, such as I-BOP ([1S- [1a,2a (Z),3b (1E,3S),4a]]-7- [3- [ 3-hydroxy-4- [4- (iodophenoxy) -1-butenyl radical]-7-oxabicyclo- [2.2.1]Hept-2-yl]-5-heptenoic acid).
Advantageously, said composition can comprise at least one 15-PGDH inhibitor as defined above, and at least one prostaglandin or one prostaglandin derivative, such as, for example, the prostaglandins of series 2, including in particular PGF in the form of a salt or precursor form2αand PGE2In particular in the form of esters (e.g. isopropyl esters), their derivatives, e.g. 16, 16-dimethyl PGE217-phenyl PGE2And 16, 16-dimethyl PGF2α17-phenyl PGF2α(ii) a Prostaglandins of series 1, e.g. 11-deoxyprostaglandin E11-deoxyprostaglandin E1 in salt or ester form is an analogue thereof, in particular latanoprost, travoprost, fluprostenol, unoprostone, bimatoprost, lorprostenol, veraprostol, butaprost, misoprostol, a salt thereof or an ester thereof.
The invention is further illustrated by the following examples, which are not intended to limit the scope of the claims.
Examples
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