# US 11,439,627 B2 · Pharmaceutical composition for the treatment of autism

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- Number: US 11,439,627 B2
- Document ID: US11439627B2
- Status: Granted
- Kind: B2
- Application number: 17/126,412
- Filed: 2020-12-18
- Published: 2021-05-20
- Granted: 2022-09-13
- Earliest claimed: 2017-11-06
- Assignees: Stalicla S.A.
- Applicants: Stalicla S.A.
- Inventors: Lynn Durham
- Web page: https://patentgrep.com/patent/US11439627B2

## CPC

- A61K 31/437: the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
- A61K 31/015: carbocyclic
- A61K 31/196: the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
- A61K 45/00: Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61P 25/00: Drugs for disorders of the nervous system
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to a pharmaceutical composition or a kit comprising, a first substance capable of raising intracellular cAMP levels, and a second substance capable of modulating intracellular calcium concentration. Likewise, the present invention relates to methods of treating patients suffering from autism spectrum disorder (ASD) phenotype 1 by administering an effective amount of a substance capable of raising intracellular cAMP levels and, optionally, an effective amount of a substance capable of modulating intracellular calcium concentration.

## Claims

### Claim 1

A method of treating a patient diagnosed with autism spectrum disorder (ASD) comprising administering to a patient in need thereof an effective amount of a first substance capable of raising intracellular cAMP levels in human neuronal cells and an effective amount of a second substance capable of modulating intracellular calcium concentration in human neuronal cells,
wherein the first substance and the second substance are distinct from each otherl and wherein
the substance capable of raising intracellular cAMP levels is a PDE4 inhibitor selected from the group consisting of ibudilast, caffeine, theobromine, theophylline, enprofylline, pentoxifylline, dyphylline, etazolate, roflumilast, crisaborole, resembrenone, drotaverin, apremila st, cilomilast, tetomilast, rolipram, (S)-rolipram, (R)-rolipram, daxalipram (R-mesopram), lirimilast, AWD-12-281, cipamfylline, oglemilast, tofimilast, CI-1044 ((R)-N-(9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]diazepino[6,7,1-hi]indol-3-yl)nicotinamide), HT-0712 ((3S,5S)-2-Piperidinone, 5-(3-(cyclopentyloxy)-4-methoxyphenyl)-3-((3-methylphenyl)methyl), MK-0873 (3-(2-{3-[3-(cyclopropylcarbamoyl)-4-oxo-1,4-dihydro-1,8-naphthyridin-1-yl]phenyl}ethynyl)pyridin-1-ium-1-olate), arofylline, CI-1018 (N-(3,4,6,7-tetrahydro-9-methyl-4-oxo-1-phenylpyrrolo(3,2,1-ik)(1,4)benzodiazepin-3-yl)-4-Pyridinecarboxamide), T-2585 (2-{4-2,3-bis(hydroxymethyl)-6,7-diethoxy-1-naphthalenyll-2-pyridinyll-4-(3-pyridinyl)-1(2H)-phthalazinone), YM-976 (4-(3-chlorophenyl)-1,7-diethyl-1 H,2 H-pyrido[2,3-d]pyrimidin-2-one), V-1l1294A (3-(3-Cyclopentyloxy-4-methoxy-benzyl)-8-isopropyl-adenine), piclamilast, atizoram, filaminast, SCH 351591 (N-(3,5-Dichloro-1-oxido-4-pyridinyl)-8-methoxy-2-(trifluoromethyl)-5-quinolinecarboxamide), IC-485, D-4418 (N-(2,5-dichloro-3-pyridinyl)-8-methoxy-5-quinolinecarboxamide), CDP-840 (4-[(2R)-2-[3-(Cyclopentyloxy)-4-methoxyphenyl]-2-phenylethyl]-pyridine hydrochloride), L-826,141 (4-(2-(3,4-bis(difluoromethoxy)phenyl)-2-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)ethyl)-3-methylpyridine 1-oxide), BPN14770 (2-(4-((2-(3-chlorophenyl)-6-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)acetamide) and TDP101, and
the substance capable of modulating intracellular calcium concentration is a NKCC1 inhibitor selected from the group consisting of fluspirilene, pimozide, gentamycin, kanamycin, clopamide, cyproheptadine, isonepecotic acids, thalidomide, torasemide, etacrynic acid, furosemide, trichlormethiazide, hydroflumethiazide, methylclothiazide, 4-substituted derivatives of sulfamoylbenzoic acid, bumetanide, AqB007, AqB011, PF-2178, BUM13, BUM5 and bumepamine.

### Claim 2 (depends on 1)

The method according to claim 1, wherein the patient exhibits characteristics consistent with being an ASD phenotype 1 patient.

### Claim 3 (depends on 1)

The method according to claim 1, wherein the PDE-4 inhibitor is ibudilast.

### Claim 4 (depends on 3)

The method according to claim 3, wherein ibudilast is administered to the patient at a daily total dosage ranging from about 1-150 mg, divided among one, two, or three doses.

### Claim 5 (depends on 3)

The method according to claim 3, wherein ibudilast is administered orally once, twice, or thrice daily to the patient in a dosage form that comprises 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 mg ibudilast or a pharmaceutically acceptable salt thereof.

### Claim 6

A method of treating a patient diagnosed with autism spectrum disorder (ASD), wherein the treatment comprises
(i) determining whether the patient suffers from ASD phenotype 1 and
(ii) administering a therapeutically effective amount of a pharmaceutical composition comprising a substance capable of raising intracellular cAMP levels in human neuronal cells and a substance capable of modulating intracellular calcium concentration in human neuronal cells to the patient that suffers from ASD phenotype 1,
wherein the substance capable of raising intracellular cAMP levels and the substance capable of modulating intracellular calcium concentration are distinct from each other,
wherein determining whether the patient suffers from ASD phenotype 1 includes at least one selected from
a) subjecting the patient to a challenge test with Nrf2-activator,
b) verifying for clinical signs of heightened expression of proliferation-associated pathways,
c) verifying for upregulation of Nrf2, or
d) verifying for low levels of protein kinase A; and
wherein it is determined that the patient suffers from ASD phenotype 1 if said patient shows at least one of the following: negative behavioral response in the challenge test with a Nrf2 inducer; clinical signs of heightened expression of proliferation-associated pathways; upregulation of Nrf2 or low blood levels of protein kinase A, and wherein
the substance capable of raising intracellular cAMP levels is a PDE4 inhibitor selected from the group consisting of ibudilast, caffeine, theobromine, theophylline, enprofylline, pentoxifylline, dyphylline, etazolate, roflumilast, crisaborole, resembrenone, drotaverin, apremilast, cilomilast, tetomilast, rolipram, (S)-rolipram, (R)-rolipram, daxalipram (R-mesopram), lirimilast, AWD-12-281, cipamfylline, oglemilast, tofimilast, CI-1044 ((R)-N-(9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]diazepino[6,7,1-hi]indol-3-yl)nicotinamide), HT-0712 ((3S,5S)-2-Piperidinone, 5-(3-(cyclopentyloxy)-4-methoxyphenyl)-3-((3-methylphenyl)methyl), MK-0873 (3-(2-{3-[3-(cyclopropylcarbamoyl)-4-oxo-1,4-dihydro-1,8-naphthyridin-1-yl]phenyl}ethynyl)pyridin-1-ium-1-olate), arofylline, C1-1018 (N-(3,4,6,7-tetrahydro-9-methyl-4-oxo-1-phenylpyrrolo(3,2,1-jk)(1,4)benzodiazepin-3-yl)-4-Pyridinecarboxamide), T-2585 (2-{4-2,3-bis(hydroxymethyl)-6,7-diethoxy-1-naphthalenyl}-2-pyridinyl]-4-(3-pyridinyl)-1(2H)-phthalazinone), YM-976 (4-(3-chlorophenyl)-1,7-diethyl-1H,2H-pyrido[2,3-d]pyrimidin-2-one), V-11294A (3-(3-Cyclopentyloxy-4-methoxy-benzyl)-8-isopropyl-adenine), piclamilast, atizoram, filaminast, SCH 351591 (N-(3,5-Dichloro-1-oxido-4-pyridinyl)-8-methoxy-2-(trifluoromethyl)-5-quinolinecarboxamide), IC-485, D-4418 (N-(2,5-dichloro-3-pyridinyl)-8-methoxy-5-quinolinecarboxamide), CDP-840 (4-[(2R)-2-[3-(Cyclopentyloxy)-4-methoxyphenyl]-2-phenylethyl]-pyridine hydrochloride), L-826,141 (4-(2-(3,4-bis(difluoromethoxy)phenyl)-2-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)ethyl)-3-methylpyridine 1-oxide), BPN14770 (2-(4-((2-(3-chlorophenyl)-6-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)acetamide) and TDP101, and
the substance capable of modulating intracellular calcium concentration is a NKCC1 inhibitor selected from the group consisting of fluspirilene, pimozide, gentamycin, kanamycin, clopamide, cyproheptadine, isonepecotic acids, thalidomide, torasemide, etacrynic acid, furosemide, trichlormethiazide, hydroflumethiazide, methylclothiazide, 4-substituted derivatives of sulfamoylbenzoic acid, bumetanide, AqB007, AqB011, PF-2178, BUM13, BUM5 and bumepamine.

### Claim 7 (depends on 1)

The method according to claim 1, wherein the administration is by a tablet or capsule suitable for oral administration to a human, which consists of said first substance and said second substance as active ingredients and one or more pharmaceutically acceptable carriers, excipients and/or diluents.

### Claim 8 (depends on 1)

The method according to claim 1, wherein the PDE-4 inhibitor is selected from the group consisting of theophylline, caffeine, theobromine, etazolate, roflumilast, crisaborole, drotaverin, ibudilast, cilomilast, rolipram, (S)-rolipram, (R)-rolipram, daxalipram (R-mesopram), lirimilast, cipamfylline, tofimilast, CI-1044, HT-0712, MK-0873, CI-1018, T-2585, V-11294A, piclamilast, atizoram, filaminast, IC-485, CDP-840, and L-826,141.

### Claim 9 (depends on 1)

The method according to claim 1, wherein the substance capable of raising intracellular cAMP levels is ibudilast and the substance capable of modulating intracellular calcium concentration is bumetanide.

### Claim 10 (depends on 1)

The method according to claim 1, wherein lithium is not administered.

### Claim 11 (depends on 1)

The method according to claim 1, wherein a substance capable of inhibiting glycogen synthetase kinase-3-beta is not administered.

### Claim 12

A method of treating a patient diagnosed with autism spectrum disorder (ASD), comprising administering to a patient in need thereof an effective amount of a first substance capable of raising intracellular c-AMP levels in human neuronal cells and an effective amount of a second substance capable of modulating intracellular calcium concentration in human neuronal cells,
wherein the first substance and the second substance are distinct from each other,
wherein the administration of the first and second substances are preceded by the administration of the first substance without the administration of the second substance resulting in a loss of efficacy of the first substance, which efficacy is restored upon administration of the second substance,
and wherein
the substance capable of raising intracellular cAMP levels is a PDE4 inhibitor selected from the group consisting of ibudilast, caffeine, theobromine, theophylline, enprofylline, pentoxifylline, dyphylline, etazolate, roflumilast, crisaborole, resembrenone, drotaverin, apremila st, cilomilast, tetomilast, rolipram, (S)-rolipram, (R)-rolipram, daxalipram (R-mesopram), lirimilast, AWD-12-281, cipamfylline, oglemilast, tofimilast, CI-1044 ((R)-N-(9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]diazepino[6,7,1-hi]indol-3-yl)nicotinamide), HT-0712 ((3S,5S)-2-Piperidinone, 5-(3-(cyclopentyloxy)-4-methoxyphenyl)-3-((3-methylphenyl)methyl), MK-0873 (3-(2-{3-[3-(cyclopropylcarbamoyl)-4-oxo-1,4-dihydro-1,8-naphthyridin-1-yl]phenyl}ethynyl)pyridin-1-ium-1-olate), arofylline, CI-1018 (N-(3,4,6,7-tetrahydro-9-methyl-4-oxo-1-phenylpyrrolo(3,2,1-jk)(1,4)benzodiazepin-3-yl)-4-Pyridinecarboxamide), T-2585 (2-{4-2,3-bis(hydroxymethyl)-6,7-diethoxy-1-naphthalenyll-2-pyridinyll-4-(3-pvridinvl)-1(2H)-phthalazinone), YM-976 (4-(3-chlorophenyl)-1,7-diethyl-1 H,2 H-pyrido[2,3-dlpvrimidin-2-one), V-1l1294A (3-(3-Cyclopentyloxy-4-methoxv-benzvl)-8-isopropyl-adenine), piclamilast, atizoram, filaminast, SCH 351591 (N-(3,5-Dichloro-1-oxido-4-pvridinvl)-8-methoxv-2-(trifluoromethyl)-5-quinolinecarboxamide), IC-485, D-4418 (N-(2,5-dichloro-3-pvridinvl)-8-methoxv-5-quinolinecarboxamide), CDP-840 (4-[(2R)-2-[3-(Cyclopentyloxy)-4-methoxyphenyl]-2-phenylethyl]-pyridine hydrochloride), L-826,141 (4-(2-(3,4-bis(difluoromethoxy)phenyl)-2-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)ethyl)-3-methylpyridine 1-oxide), BPN14770 (2-(4-((2-(3-chlorophenyl)-6-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)acetamide) and TDP101, and
the substance capable of modulating intracellular calcium concentration is a NKCC1 inhibitor selected from the group consisting of fluspirilene, pimozide, qentamycin, kanamycin, clopamide, cyproheptadine, isonepecotic acids, thalidomide, torasemide, etacrynic acid, furosemide, trichlormethiazide, hydroflumethiazide, methylclothiazide, 4-substituted derivatives of sulfamoylbenzoic acid, bumetanide, AqB007, AqB011, PF-2178, BUM13, BUM5 and bumepamine.