# US 7,410,968 B2 · Capped pyrazinoylguanidine sodium channel blockers

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- Number: US 7,410,968 B2
- Document ID: US7410968B2
- Status: Granted
- Kind: B2
- Application number: 11/211,707
- Filed: 2005-08-26
- Published: 2006-09-14
- Granted: 2008-08-12
- Earliest claimed: 2003-08-18
- Assignees: Parion Sciences, Inc.
- Inventors: Michael R. Johnson; Bruce F. Molino; Jianzhong Zhang; Bruce Sargent
- Web page: https://patentgrep.com/patent/US7410968B2

## CPC

- C07D 241/26: with nitrogen atoms directly attached to ring carbon atoms
- A61K 31/4965: Non-condensed pyrazines
- A61K 31/497: containing further heterocyclic rings
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/02: Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
- A61P 1/10: Laxatives
- A61P 7/10: Antioedematous agents; Diuretics
- A61P 9/12: Antihypertensives
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/06: Antiasthmatics
- A61P 11/12: Mucolytics
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/16: Emollients or protectives, e.g. against radiation
- A61P 27/02: Ophthalmic agents
- A61P 27/16: Otologicals
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 241/32: (Amino-pyrazinoyl) guanidines
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D 473/00: Heterocyclic compounds containing purine ring systems
- C07D 473/16: two nitrogen atoms
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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 compounds represented by formula (I): where the structural variables are as defined herein. The compounds are useful for promoting hydration of mucosal surfaces.

## Claims

### Claim 1

A compound represented by formula (I):
wherein
X is hydrogen, halogen, trifluoromethyl, lower alkyl, unsubstituted or substituted phenyl, lower alkyl-thio, phenyl-lower alkyl-thio, lower alkyl-sulfonyl, or phenyl-lower alkyl-sulfonyl;
Y is hydrogen, hydroxyl, mercapto, lower alkoxy, lower alkyl-thio, halogen, lower alkyl, unsubstituted or substituted mononuclear aryl, or —N(R2)2;
R1 is hydrogen or lower alkyl;
each R2 is, independently, —R7, —(CH2)m—OR8, —(CH2)m—NR7R10, —(CH2)n(CHOR8)(CHOR8)n—CH2OR8, —(CH2CH2O)m—R8, —(CH2CH2O)m—CH2CH2NR7R10, —(CH2)n—C(═O)NR7R10, —(CH2)n-Zg-R7, —(CH2)m—NR10—CH2(CHOR8)(CHOR8)n—CH2OR8, —(CH2)n—CO2R7, or
R3 and R4 are each, independently, hydrogen, a group represented by formula (A), lower alkyl, hydroxy lower alkyl, phenyl, phenyl-lower alkyl, (halophenyl)-lower alkyl, lower-(alkylphenylalkyl), lower (alkoxyphenyl)-lower alkyl, naphthyl-lower alkyl, or pyridyl-lower alkyl, with the proviso that at least one of R3 and R4 is a group represented by formula (A):
wherein
each RL is, independently, —R7, —(CH2)n—OR8, —O—(CH2)m—OR8, —(CH2)n—NR7R10, —O— (CH2)m—NR7R10, —(CH2)n(CHOR8)(CHOR8)n—CH2OR8, —O—(CH2)m(CHOR8)(CHOR8)n—CH2OR8, —(CH2CH2O)m—R8, —O—(CH2CH2O)m—R8, —(CH2CH2O)m—CH2CH2NR7R10, —O—(CH2CH2O)m—CH2CH2NR7R10, —(CH2)n—C(═O)NR7R10, —O—(CH2)m—C(═O)NR7R10, —(CH2)n-(Z)g-R7, —O—(CH2)m-(Z)g-R7, —(CH2)n—NR10—CH2(CHOR8)(CHOR8)n—CH2OR8, —O—(CH2)m—NR10—CH2(CHOR8)(CHOR8)n—CH2OR8, —(CH2)n—CO2R7, —O—(CH2)m—CO2R7, —OSO3H, —O-glucuronide, —O-glucose,
each o is, independently, an integer from 0 to 10;
each p is an integer from 0 to 10;
with the proviso that the sum of o and p in each contiguous chain is from 1 to 10;
each x is, independently, O, NR10, C(═O), CHOH, C(═N—R10), CHNR7R10, or represents a single bond;
wherein each R5 is, independently, Link-(CH2)n-CAP, Link-(CH2)n(CHOR8)(CHOR8)n-CAP, Link-(CH2CH2O)m—CH2-CAP, Link-(CH2CH2O)m—CH2CH2-CAP, Link-(CH2)n-(Z)g-CAP, Link-(CH2)n(Z)g-(CH2)m-CAP, Link-(CH2)n—NR13—CH2(CHOR8)(CHOR8)n-CAP, Link-(CH2)n—(CHOR8)mCH2—NR13-(Z)g-CAP, Link-(CH2)nNR13—(CH2)m(CHOR8)nCH2NR13-(Z)g-CAP, Link-(CH2)m-(Z)g-(CH2)m-CAP, Link-NH—C(═O)—NH—(CH2)m-CAP, Link-CH2)m—C(═O)NR13—(CH2)m—C(═O)NR10R10, Link-(CH2)m—C(═O)NR13—(CH2)m-CAP, Link-(CH2)m—C(═O)NR11R11, Link-(CH2)m—C(═O)NR12R12, Link-(CH2)n-(Z)g-(CH2)m-(Z)g-CAP, Link-Zg-(CH2)m-Het-(CH2)m-CAP;
each Link is, independently, —O—, —(CH2)n—, —O(CH2)m—, —NR13—C(═O)—NR13, —NR13—C(═O)—(CH2)m—, —C(═O)NR13—(CH2)m, —(CH2)n-Zg-(CH2)n, —S—, —SO—, —SO2—, —SO2NR7—, —SO2NR10—, or -Het-;
each CAP is, independently, thiazolidinedione, oxazolidinedione, heteroaryl-C(═O)N R13R13, heteroaryl-W, —CN, —O—C(═S)NR13 R13, -ZgR13, —CR10(ZgR13)(ZgR13), —C(═O)OAr, —C(═O)N R13Ar, imidazoline, tetrazole, tetrazole amnide, —SO2NHR13, —SO2NH—C(R13R13)-(Z)g-R13, a cyclic sugar or oligosaccharide, a cyclic amino sugar or oligosaccharide,
each Ar is, independently, phenyl, substituted phenyl, wherein the substituents of the substituted phenyl are 1-3 substituents independently selected from the group consisting of OH, OCH3, NR13R13, Cl, F, and CH3, or heteroaryl;
each W is independently, thiazolidinedione, oxazolidinedione, heteroaryl-C(═O)N R13R13, —CN, —O—C(═S)NR13 R13, -ZgR13, —CR10(ZgR13)(ZgR13), —C(═O)OAr, —C(═O)N R13Ar, imidazoline, tetrazole, tetrazole amide, —SO2NHR13, —SO2NH—C(R13R13)-(Z)g-R13, a cyclic sugar or oligosaccharide, a cyclic amino sugar or oligosaccharide,
each R6 is, independently, —R7, —OR7, —OR11, —N(R7)2, —(CH2)mOR8, —O—(CH2)m—OR, —(CH2)n—NR7R10, —O—(CH2)m—NR7R10, —(CH2)n(CHOR8)(CHOR8)n—CH2OR8, —O—(CH2)m(CHOR8)(CHOR8)n—CH2OR8, —(CH2CH2O)m—R8, —O—(CH2CH2O)m—R8, —(CH2CH2O)m—CH2CH2NR7R10, —O—(CH2CH2O)m—CH2CH2NR7R10, —(CH2)n—C(═O)NR7R10, —O—(CH2)m—C(═O)NR7R10, —(CH2)n-(Z)g-R7, —O—(CH2)m-(Z)g-R7, —(CH2)n—NR10—CH2(CHOR8)(CHOR8)n—CH2OR8, —O—(CH2)m—NR10—CH2(CHOR8)(CHOR8)n—CH2OR8, —(CH2)n—CO2R7, —O—(CH2)m—CO2R7, —OSO3H, —O-glucuronide, —O-glucose,
wherein when two R6 are —OR11 and are located adjacent to each other on a phenyl ring, the alkyl moieties of the two R6 may be bonded together to form a methylenedioxy group;
each R7 is, independently, hydrogen lower alkyl, phenyl, or substituted phenyl;
each R8 is, independently, hydrogen, lower alkyl, —C(═O)—R11, glucuronide, 2-tetrahydropyranyl, or
each R9 is, independently, —CO2R13, —CON(R13)2, —SO2CH2R13, or —C(═O)R13;
each R10 is, independently, —H, —SO2CH3, —CO2R13, —C(═O)NR13R13, —C(═)R13, or —(CH2)m—(CHOH)n—CH2OH;
each Z is, independently, CHOH, C(═O), —(CH2)n—, CHNR13R13, C═NR13, or NR13;
each R11 is, independently, lower alkyl;
each R12 is independently, —SO2CH3, —CO2R13, —C(═O)NR13R13, —C(═O)R13, or —CH2—(CHOH)n—CH2OH;
each R13 is, independently, hydrogen, lower alkyl, phenyl, substituted phenyl, —SO2CH3, —CO2R7, —C(═O)NR7R7, —C(═O)NR7SO2CH3, —(═O)NR7—CO2R7, —C(═O)NR7—C(═O)NR7R7, —C(═O)NR7—C(═O)R7, —C(═O)NR7—(CH2)m—(CHOH)n—CH2OH, —C(═O)R7, or —(CH2)m—(CHOH)n—CH2OH;
each Het is independently, —NR13, —S—, —SO—, —SO2—, —O—,—SO2NR13—, —NHSO2—, —NR13CO—, or —CONR—;
each g is, independently, an integer from 1 to 6;
each m is, independently, an integer from 1 to 7;
each n is, independently, an integer from 0 to 7;
each Q is, independently, C—R5, C—R6, or a nitrogen atom, wherein three Q in a ring are a nitrogen atom;
each V is, independently, —(CH2)m—NR7R10, —(CH2)m—NR7R7, —(CH2)m—
+
NR11R11R11, —(CH2)n—(CHOR8)m—(CH2)mNR7R10, —(CH2)n—NR10R10,
+
—(CH2)n—(CHOR8)m—(CH2)mNR7R7, —(CH2)n—(CHOR8)m—(CH2)mNR11R11R11,
with the proviso that when V is attached directly to a nitrogen atom, then V can also be, independently, R7, R10, or (R11)2;
with the proviso that, when any two —CH2OR8 groups are located 1,2 or 1,3- with respect to each other, the R8 groups may be joined to form a cyclic mono- or di-substituted 1,3-dioxane or 1,3-dioxolane;
or a pharmaceutically acceptable salt thereof; and
inclusive of all enantiomers, diastereomers, and racemic mixtures thereof.

### Claim 2 (depends on 1)

The compound of claim 1, wherein Y is —NH2.

### Claim 3 (depends on 2)

The compound of claim 2, wherein R2 is hydrogen.

### Claim 4 (depends on 3)

The compound of claim 3, wherein Rhu 1 is hydrogen.

### Claim 5 (depends on 4)

The compound of claim 4, wherein X is chlorine.

### Claim 6 (depends on 5)

The compound of claim 5, wherein R3 is hydrogen.

### Claim 7 (depends on 6)

The compound of claim 6, wherein each RL is hydrogen.

### Claim 8 (depends on 7)

The compound of claim 7, wherein o is 4.

### Claim 9 (depends on 8)

The compound of claim 8, wherein p is 0.

### Claim 10 (depends on 9)

The compound of claim 9, wherein x represents a single bond.

### Claim 11 (depends on 10)

The compound of claim 10, wherein R5 is Link—(CH2)n—CAP.

### Claim 12 (depends on 10)

The compound of claim 10, wherein Link is —O— and CAP is thiazolidinedione.

### Claim 13 (depends on 10)

The compound of claim 10, wherein Link is —O— and CAP is tetrazole.

### Claim 14 (depends on 10)

The compound of claim 10, wherein Link is —O— and CAP is N,N-dimethyl sulfonamide.

### Claim 15 (depends on 10)

The compound of claim 10, wherein Link is —O— and CAP is sulfonamide.

### Claim 16 (depends on 10)

The compound of claim 10, wherein Link is —O— and CAP is oxazolidinedione.

### Claim 17 (depends on 10)

The compound of claim 10, wherein Link is —O— and CAP is —C(═O)N—R10Ar.

### Claim 18 (depends on 10)

The compound of claim 10, wherein Link is —O— and CAP is imidazole.

### Claim 19 (depends on 10)

The compound of claim 10, wherein Link is —O— and CAP is cyano.

### Claim 20 (depends on 10)

The compound of claim 10, wherein the CAP is SO2NH—CR7R10ZgR7.

### Claim 21 (depends on 10)

The compound of claim 10, wherein R5 is Link—(CH2)n(CHOR8)(CHOR8)n—CAP.

### Claim 22 (depends on 10)

The compound of claim 10, wherein R5 is Link—(CH2CH2O)m—CH2—CAP.

### Claim 23 (depends on 10)

The compound of claim 10, wherein R5 is Link—(CH2CH2O)m—CH2CH2—CAP.

### Claim 24 (depends on 10)

The compound of claim 10, wherein R5 is Link—(CH2)n(Z)g—CAP.

### Claim 25 (depends on 10)

The compound of claim 10, wherein R5 is Link—(CH2)m(Z)g(CH2)m—CAP.

### Claim 26 (depends on 10)

The compound of claim 10, wherein R5 is Link—(CH2)n—NR10—CH2(CHOR8)(CHOR8)n—CAP.

### Claim 27 (depends on 10)

The compound of claim 10, wherein R5 is Link—(CH2)n(CHOR8)mCH2—NR10—(Z)g—CAP.

### Claim 28 (depends on 10)

The compound of claim 10, wherein R5 is Link—(CH2)nNR10—(CH2)m(CHOR8)nCH2NR10—(Z)g—CAP.

### Claim 29 (depends on 10)

The compound of claim 10, wherein R5 is Link—(CH2)m(Z)g(CH2)m—CAP.

### Claim 30 (depends on 10)

The compound of claim 10, wherein R5 is Link—NH—C(═O)—NH—(CH2)m—CAP.

### Claim 31 (depends on 10)

The compound of claim 10, wherein R5 is Link—(CH2)m—C(═O)NR10—(CH2)m—C(═O)NR10R10.

### Claim 32 (depends on 10)

The compound of claim 10, wherein R5 is Link—(CH2)m—C(═O)NR11R11.

### Claim 33 (depends on 10)

The compound of claim 10, wherein R5 is Link—(CH2)m—C(═O)NR11R11.

### Claim 34 (depends on 10)

The compound of claim 10, wherein R5 is Link—(CH2)m—C(═O)NR12R12.

### Claim 35 (depends on 10)

The compound of claim 10, wherein R5 is Link—(CH2)n(Z)g—(CH2)m —(Z)g—CAP.

### Claim 36 (depends on 1)

The compound of claim 1, wherein R5 is Link—(CH2)n—CAP.

### Claim 37 (depends on 1)

The compound of claim 1, wherein R5 is Link—(CH2)n(CHOR8)(CHOR8)n—CAP.

### Claim 38 (depends on 1)

The compound of claim 1, wherein R5 is Link—(CH2CH2O)m—CH2—CAP.

### Claim 39 (depends on 1)

The compound of claim 1, wherein R5 is Link—(CH2CH2O)m—CH2CH2—CAP.

### Claim 40 (depends on 1)

The compound of claim 1, wherein R5 is Link—(CH2)n(Z)g—CAP.

### Claim 41 (depends on 1)

The compound of claim 1, wherein R9 is Link—(CH2)n(Z)g—(CH2)m—CAP.

### Claim 42 (depends on 1)

The compound of claim 1, wherein R5 is Link—(CH2)n—NR10—CH2(CHOR8)(CHOR8)n—CAP.

### Claim 43 (depends on 1)

The compound of claim 1, wherein R5 is Link—(CH2)n—(CHOR8)mCH2—NR10—(Z)g—CAP.

### Claim 44 (depends on 1)

The compound of claim 1, wherein R5 is Link—(CH2)nNR10—(CH2)m(CHOR8)nCH2NR10—(Z)g—CAP.

### Claim 45 (depends on 1)

The compound of claim 1, wherein R5 is Link—(CH2)m—(Z)g—(CH2)m—CAP.

### Claim 46 (depends on 1)

The compound of claim 1, wherein R5 is Link—NH—C(═O)—NH—(CH2)m—CAP.

### Claim 47 (depends on 1)

The compound of claim 1, wherein R5 is Link—(CH2)m—C(═O)NR10—(CH2)m—C(═O)NR10R10.

### Claim 48 (depends on 1)

The compound of claim 1, wherein R5 is Link—(CH2)m—C(═O)NR10—(CH2)m—CAP.

### Claim 49 (depends on 1)

The compound of claim 1, wherein R5 is Link—(CH2)m—C(═O)NR11R11.

### Claim 50 (depends on 1)

The compound of claim 1, wherein R5 is Link—(CH2)m—C(═O)NR12R12.

### Claim 51 (depends on 1)

The compound of claim 1, wherein R5 is Link—(CH2)n—(Z)g—(CH2)m—(Z)g—CAP.

### Claim 52 (depends on 1)

The compound of claim 1, wherein x is a single bond.

### Claim 53 (depends on 1)

The compound of claim 1, wherein the heteroaryl is a pyridyl, pyrazyl, tinazyl, furyl, furfuryl, thienyl, tetrazyl, thiazolidinedionyl and imidazoyl, pyrrolyl, furanyl, thiophenyl, quinolyl, indolyl, adenyl, pyrazolyl, thiazolyl, isoxazolyl, indolyl, benzimidazolyl, purinyl, quinolinyl, isoquinolinyl, pyridazyl, pyrimidyl, pyrazyl, 1,2,3-triazyl, 1,2,4-triazyl, 1,3,5-triazyl, cinnolyl, phthalazyl, quinazolyl, quinoxalyl or pterdyl.

### Claim 54 (depends on 1)

The compound of claim 1, which is in the form of a pharmaceutically acceptable salt.

### Claim 55 (depends on 1)

A composition, comprising:
the compound of claim 1; and
a P2Y2 receptor agonist.

### Claim 56 (depends on 1)

A composition, comprising:
the compound of claim 1; and
a bronchodilator.

### Claim 57 (depends on 1)

A pharmaceutical composition, comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

### Claim 58 (depends on 1)

A method of promoting hydration of mucosal surfaces, comprising:
administering an effective amount of the compound of claim 1 to a mucosal surface of a subject.

### Claim 59 (depends on 1)

A method of blocking sodium channels, comprising:
contacting sodium channels with an effective amount of the compound of claim 1.

### Claim 60 (depends on 1)

A method of treating chronic bronchitis, comprising:
administering an effective amount of the compound of claim 1 to a subject in need thereof.

### Claim 61 (depends on 1)

A method of treating cystic fibrosis, comprising:
administering an effective amount of the compound of claim 1 to a subject in need thereof.

### Claim 62 (depends on 1)

A method of treating sinusitis, comprising:
administering an effective amount of the compound of claim 1 to a subject in need thereof.

### Claim 63 (depends on 1)

A method of treating vaginal dryness, comprising:
administering an effective amount of the compound of claim 1 to the vaginal tract of a subject in need thereof.

### Claim 64 (depends on 1)

A method of treating dry eye, comprising:
administering an effective amount of the compound of claim 1 to the eye of a subject in need thereof.

### Claim 65 (depends on 1)

A method of promoting ocular hydration, comprising:
administering an effective amount of the compound of claim 1 to the eye of a subject.

### Claim 66 (depends on 1)

A method of promoting corneal hydration, comprising:
administering an effective amount of the compound of claim 1 to the eye of a subject.

### Claim 67 (depends on 1)

A method of promoting mucus clearance in mucosal surfaces, comprising:
administering an effective amount of the compound of claim 1 to a mucosal surface of a subject.

### Claim 68 (depends on 1)

A method of treating Sjogren's disease, comprising:
administering an effective amount of the compound of claim 1 to a subject in need thereof.

### Claim 69 (depends on 1)

A method of treating distal intestinal obstruction syndrome, comprising:
administering an effective amount of the compound of claim 1 to a subject in need thereof.

### Claim 70 (depends on 1)

A method of treating dry skin, comprising:
administering an effective amount of the compound of claim 1 to the skin of a subject in need thereof.

### Claim 71 (depends on 1)

A method of treating esophagitis, comprising:
administering an effective amount of the compound of claim 1 to a subject in need thereof.

### Claim 72 (depends on 1)

A method of treating dry mouth (xerostomia), comprising:
administering an effective amount of the compound of claim 1 to the mouth of a subject in need thereof.

### Claim 73 (depends on 1)

A method of treating nasal dehydration, comprising:
administering an effective amount of the compound of claim 1 to the nasal passages of a subject in need thereof.

### Claim 74 (depends on 73)

The method of claim 73, wherein the nasal dehydration is brought on by administering dry oxygen to the subject.

### Claim 75 (depends on 1)

A method of treating ventilator-induced pneumonia, comprising:
administering an effective amount of the compound of claim 1 to a subject on a ventilator.

### Claim 76 (depends on 1)

A method of treating asthma, comprising:
administering an effective amount of the compound of claim 1 to a subject in need thereof.

### Claim 77 (depends on 1)

A method of treating primary ciliary dyskinesia, comprising:
administering an effective amount of the compound of claim 1 to a subject in need thereof.

### Claim 78 (depends on 1)

A method of treating otitis media, comprising:
administering an effective amount of the compound of claim 1 to a subject in need thereof.

### Claim 79 (depends on 1)

A method of inducing sputum for diagnostic purposes, comprising:
administering an effective amount of the compound of claim 1 to a subject in need thereof.

### Claim 80 (depends on 1)

A method of treating chronic obstructive pulmonary disease, comprising:
administering an effective amount of the compound of claim 1 to a subject in need thereof.

### Claim 81 (depends on 1)

A method of treating emphysema, comprising:
administering an effective amount of the compound of claim 1 to a subject in need thereof.

### Claim 82 (depends on 1)

A method of treating pneumonia, comprising:
administering an effective amount of the compound of claim 1 to a subject in need thereof.

### Claim 83 (depends on 1)

A method of treating constipation, comprising:
administering an effective amount of the compound of claim 1 to a subject in need thereof.

### Claim 84 (depends on 83)

The method of claim 83, wherein the compound is
administered orally or via a suppository or enema.

### Claim 85 (depends on 1)

A method of treating chronic diverticulitis, comprising:
administering an effective amount of the compound of claim 1 to a subject in need thereof.

### Claim 86 (depends on 1)

A method of treating rhinosinusitis, comprising:
administering an effective amount of the compound of claim 1 to a subject in need thereof.

### Claim 87 (depends on 1)

A method of treating hypertension, comprising
administering the compound of claim 1 to a subject in need thereof.

### Claim 88 (depends on 1)

A method of reducing blood pressure, comprising administering the compound of claim 1 to a subject in need thereof.

### Claim 89 (depends on 1)

A method of treating edema, comprising administering the compound of claim 1 to a subject in need thereof.

### Claim 90 (depends on 1)

A method of promoting diuresis, comprising administering the compound of claim 1 to a subject in need thereof.

### Claim 91 (depends on 1)

A method of promoting natriuresis, comprising administering the compound of claim 1 to a subject in need thereof.

### Claim 92 (depends on 1)

A method of promoting saluresis, comprising administering the compound of claim 1 to a subject in need thereof.